Azolopyrimidine for the treatment of cancer-related disorders

Abstract

Adenosine A 2A Receptor (A 2A R) or adenosine A 2B Receptor (A 2B The present invention provides a pharmaceutical composition for the treatment of a disease, disorder, or condition at least partially mediated by R). [Solution] Use a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, or solvate thereof. JPEG2026086620000481.jpg45167

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 448,608 filed on 20 January 2017 and U.S. Provisional Application No. 62 / 479,005 filed on 30 March 2017, the contents of which are incorporated herein by reference for all purposes.

[0002] Statement regarding the rights to inventions made under federally funded research and development. Not applicable

[0003] The "arrangement list," table, or computer registered on the compact disc Refer to the program list appendix. Not applicable [Background technology]

[0004] Background of the Invention Adenosine is a purine nucleoside compound containing a complex of adenine and a ribose sugar molecule (ribofuranose). Adenosine is naturally present in mammals and plays a crucial role in several biochemical processes, including energy transfer (as adenosine triphosphate and adenosine monophosphate) and signal transduction (as cyclic adenosine monophosphate). Adenosine also functions in vasodilation-related processes, including cardiovasodilation, and acts as a neuromodulator (e.g., thought to be involved in promoting sleep). In addition to its involvement in these biochemical processes, adenosine is used, for example, as a therapeutic antiarrhythmic agent to treat supraventricular tachycardia. As will be further discussed herein, tumors evade host responses by inhibiting immune function and promoting tolerance, and adenosine has been shown to play a crucial role in mediating tumor evasion by the immune system. A is expressed on various immune cell subsets and endothelial cells. 2A R and A 2BAdenosine signaling via R is established to play a crucial role in protecting tissues during inflammatory responses. Thus, under certain conditions, adenosine protects tumors from immune destruction (see, for example, Fishman, P et al. (2009) HandbExp Pharmacol 193:399-441).

[0005] Adenosine receptors are a class of purinergic G protein-coupled receptors that have adenosine as their endogenous ligand. In humans, there are four types of adenosine receptors: A1, A2, A3 2A , A 2B And also called A3. Modification of A1 has been proposed, for example, for the management and treatment of neurological disorders, asthma, and cardiac and renal failure. 2A Antagonists have been proposed, for example, for the management and treatment of Parkinson's disease, A 2B Modification of A3 has been proposed, for example, for the management and treatment of chronic lung diseases, including asthma, and modification of A3 has been proposed, for example, for the management and treatment of asthma and chronic obstructive pulmonary disease, glaucoma, cancer, and stroke.

[0006] Historically, adenosine receptor modulators have been non-selective. This may be acceptable in certain indications, such as when endogenous agonist adenosine, which acts on all four adenosine receptors in cardiac tissue, is administered parenterally for the treatment of severe tachycardia. However, the use of subtype-selective adenosine receptor agonists and antagonists offers the possibility of achieving desired results while minimizing or eliminating side effects.

[0007] Thus, there is a need for subtype-selective adenosine receptor agonists in this field. The present invention addresses this need and also provides related advantages. [Overview of the project]

[0008] Summary of the Invention This invention relates to adenosine A 2A Receptor (A 2AR) and / or adenosine A 2B receptor (A 2B The present invention relates to compounds that modulate receptor (A

[0009] R), and compositions (e.g., pharmaceutical compositions) containing such compounds. Such compounds, including their synthetic methods and compositions, will be described in detail below. 2A receptor (A 2A R) and / or adenosine A 2B receptor (A 2B R) for the treatment and / or prevention of various diseases, disorders and conditions mediated in whole or in part by such receptor, and the use of such compounds and compositions. Such diseases, disorders and conditions are described in detail elsewhere in this specification. Unless otherwise indicated, when the use of a compound of the present invention is described herein, it should be understood that such compound can be in the form of a composition (e.g., a pharmaceutical composition).

[0010] As described hereinafter, the compounds of the present invention affect their activities by inhibiting adenosine A 2A receptor (A 2A R) and and / or adenosine A 2B receptor (A 2B R). Although it is believed that the compounds affect their activities by inhibiting adenosine A receptor (A 2A R) and / or adenosine A receptor (A 2A R), an exact understanding of the underlying mechanism of action of the compounds is not required to practice the present invention. It is envisioned that the compounds may instead affect their activities via direct or indirect inhibition of adenylyl cyclase. The compounds may also be envisioned to affect their activities via inhibition of both A 2B receptor (A 2B R) and / or adenosine A receptor (A 2A R) as well as adenylyl cyclase. The compounds of the present invention are generally referred to herein as adenosine A 2A receptor (A 2BReceptor (A 2B R) Inhibitors, but the term "A 2A R / A 2B "R inhibitors" are A 2A R, A 2B R or Adenili Compounds that act individually through the inhibition of lucyclase, and / or A 2A R, A 2B It should be understood that this includes compounds that act through the inhibition of R and adenylyl cyclase.

[0011] A 2A and A 2B Cell surface adenosine receptors have been found to be upregulated in various tumor cells. Therefore, A 2A and / or A 2B Adenosine receptor antagonists represent a promising new class of oncological agents.

[0012] A 2A Activation of the adenosine receptor inhibits the immune response against tumors by suppressing T regulatory cell function, natural killer cell cytotoxicity, and tumor-specific CD4+ / CD8+ activity. Therefore, inhibition of this receptor subtype by a specific antagonist may enhance immunotherapy in cancer treatment. 2B Activation of adenosine receptors affects microvascular They play a role in tumor development through the upregulation of angiogenic factor expression levels in endothelial cells [e.g., P. Fishman et al., Handb ExpPharmacol (2009); 193:399-441]. [See also]. Furthermore, adenosine receptor 2A blockade has been shown to increase the potency of anti-PD-1 via an enhanced antitumor T cell response (P. Beavis et al., CancerImmunol). Res DOI:10.1158 / 2326-6066. CIR-14-0211 Published February 11, 2015). A 2A R and A 2B The role of R A more comprehensive discussion is provided below.

[0013] Adenosine 2A receptor (A 2A R) A 2A R (also known as ADORA2A) is a G protein-coupled receptor (GPCR), and its family members have seven transmembrane α-helices. Based on its crystallographic structure, A 2A R is different from other structurally determined GPCRs (e.g., β-2 adrenergic receptors). It contains distinct ligand-binding pockets.

[0014] As described elsewhere in this specification, adenosine is involved in mediating tumor evasion by the immune system. 2A R plays an important and non-redundant role in mediating the adenosine-induced anti-inflammatory response. 2A R negatively modulates the immune response, and therefore, A 2A Pharmacological inhibition of R activation is It has been demonstrated to be a viable means of enhancing immunotherapy.

[0015] As mentioned above, A 2A Activation of R affects the adaptive immune response. For example, A 2A R is T In addition to severely inhibiting cellular function, it also promotes the development of regulatory T cells in the host It protects against excessive tissue damage. 2A Since R activation is a potent inhibitor of adaptive immune responses, tumor-derived adenosine is involved in blocking anti-tumor immunity.

[0016] In addition to other roles, A 2A R selectively enhances anti-inflammatory cytokines, promotes the upregulation of PD-1 and CTLA-4, stimulates the production of LAG-3 and Foxp3+ regulatory T cells, and is involved in mediating the inhibition of regulatory T cells. It is involved in PD-1, CTLA-4, and other immune checkpoints. This will be discussed further in this specification. All of these immunosuppressive properties have been identified as mechanisms by which tumors evade host responses, A 2A Cancer immunotherapy regimens containing R antagonists may enhance tumor immunotherapy [Generally, Naganuma, M. et al. (2006) J Immunol See 177:2765-769.

[0017] A 2A R antagonists are thought to play an important role in chemotherapy and radiotherapy. Mechanistically, A during chemotherapy or radiotherapy 2A Co-administration of R antagonists has been proposed to induce tumor-specific T cell proliferation while simultaneously preventing the induction of tumor-specific regulatory T cells. Furthermore, A 2A Combining R antagonists with tumor vaccines is thought to produce at least an additive effect, considering their divergent mechanisms of action. Finally, A 2A R antagonists can be most effectively used in combination with tumor vaccines and other checkpoint blockers. For example, blocking not only PD-1 involvement but also A 2A By inhibiting R, it is possible to reduce the tumor's ability to eliminate tumor-specific effector T cells. (For example, Fishman, P et al. (2009) Handb Exp Pharmacol 193:399-441). Furthermore, A 2A R Adenosine signaling via sceptors has been shown to be a promising negative feedback loop, and in preclinical studies, A 2A Blocking R activation has been shown to significantly enhance antitumor immunity (Sitkovsky, MV et al. (2014) CancerImmun Res 2:598-605).

[0018] Adenosine 2B receptor (A 2B R) A 2b R (also known as ADORA2B) is a GPCR found in many different cell types. , requires a higher concentration of adenosine for activation than other adenosine receptor subtypes (e.g., A1R, A 2A (R and A3R) (Fredholm BB et al. (2001) BiochemPharmacol 61:4 43-448). Such conditions are seen, for example, in tumors where hypoxia is commonly observed. In contrast to other adenosine receptor subtypes, A 2B R may play a significant role in pathophysiological conditions associated with massive adenosine release. Therefore, selective blockade or stimulation of this adenosine receptor subtype would not interfere with many important physiological functions of adenosine mediated through other adenosine receptor subtypes. However, A 2B The pathways leading to R-mediated inhibition are not fully understood.

[0019] Angiogenesis represents a central mechanism of tumor growth. The angiogenic process is highly regulated by a set of angiogenic factors and is induced by adenosine under specific hypoxia-related conditions. 2B R is expressed in human microvascular endothelial cells and plays a crucial role in regulating the expression of angiogenic factors such as vascular endothelial growth factor (VEGF). In certain tumor types, hypoxia is A 2B It has been observed that this causes upregulation of R, and A 2B This suggests that R plays a crucial role in mediating the effects of adenosine on angiogenesis. Therefore, A 2B Blocking R can limit tumor growth by restricting oxygen supply to tumor cells. Furthermore, experiments involving adenylyl cyclase activation have shown that A 2B This indicates that R is the only adenosine receptor subtype in certain tumor cells, and this is A 2B This suggests that R antagonists may affect certain tumor types (e.g., Feoktistov, I. et al. (2003) Circ Res92:485-492).

[0020] Recent data shows that A 2BUnderstanding the precise role of the R modulator is complicated. As mentioned above, the data is A 2B We have confirmed that R plays a crucial role in mediating the effects of adenosine on tumor growth and progression. In fact, inhibition of angiogenesis and ERK1 / 2 phosphorylation leads to A 2B It shows the most interesting effect for potential anti-cancer therapies targeting R. However, inhibition of angiogenesis is A 2B The use of an R antagonist is required, but other clinically valid routes (e.g., MAP) are available. Inhibition of growth signaling via the enzyme pathway is A 2B This can be achieved through treatment with R agonists (e.g., Graham, S. et al. (2001) EurJ Pharmaol 420:19-26). Further developments The results of the trial may indicate that both agonists and antagonists, when used at different stages of the disease and in their treatment, offer useful therapeutic options in combination with other therapeutic means.

[0021] In one particular embodiment, the present invention relates to formula (I): [ka] (In the above formula, G 1 is N or CR 3a And, G 2 is N or CR 3b And, G 3 is N or CR 3c And, R 3a , R 3b and R 3c Each is independently H, deuterium, or C 1-3 It is alkyl, R 1a and R 1b Each is independent of the others. i) H or deuterium, ii) 1 to 3 R 5 C which may be substituted by substituents 1-8 Alkyl, iii) 1 to 3 Rs 5 -X optionally substituted by a substituent 1 -O-C 1-8 alkyl, iv) -C(O)-R 6 , v) 1 to 3 Rs 7 Y optionally substituted by a substituent, and, vi) 1 to 3 Rs 7 -X optionally substituted by a substituent 1 -Y, selected from the group consisting of, or, vii) R 1a and R 1b together with the nitrogen to which they are attached form a 5- to 6-membered heterocycloalkyl ring, the ring being optionally substituted by 1 to 3 Rs 8 the heterocycloalkyl has 0 to 2 additional heteroatom ring vertices selected from the group consisting of O, N and S , , each Y is C 3-8 cycloalkyl or a 4- to 6-membered heterocycloalkyl having 1 to 3 heteroatom ring vertices 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 is phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted by 1 to 3 Rs 9 in some cases substituted by, Ar 2 is phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted by 1 to 3 Rs 10 in some cases substituted by, Ar 1 and Ar 2 said 5- to 6-membered heteroaryl of each is independently O, N, N + -O - and S from It has 1 to 3 heteroatom ring vertices selected from the group, each X 1 is C 1-6 It is alkylene, Each R 5 is hydroxyl, C 3-8 Cycloalkyl, phenyl, -O-phenyl, -C(O)OR a and Selected independently from the group consisting of oxo, Each R 6 is C 1-8 Alkyl, or Y, each of which is hydroxyl, -O-phenyl, or phenyl. Nil and -OC 1-8 Optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups. It is done, Each R 7 is C 1-8 Alkyl, hydroxyl, -OC 1-8 Alkyl, oxo, and C(O)OR a from Selected independently from the group, Each R 8 is C 1-8 Independently selected from the group consisting of alkyl, hydroxyl, and oxo, Each R 9 is C 1-8 Alkyl, C 1-8 Deuteroalkyl, -OC 1-8 Alkyl, -OC 1-8 Du -Teroalkyl, -X 1 -OC 1-8 Alkyl, -OX 1 -OC 1-8 Alkyl, -X 1 -OX 1 -OC 1-8 Al Kill, -C(O)OR a , halogen, cyano, -NR b R c , Y, -X 1 -C 3-8 Cycloalkyl and -X 2 -Z or Selected independently from the group, where X2 is C 1-6 Alkylene, -C 1-6 Z is selected from the group consisting of alkylenes -O-, -C(O)-, and -S(O)2-, and Z is selected from the group consisting of O, N, and S, with 1 to 3 elements. It is a 4-6 member heterocycloalkyl having a heteroatom ring vertex, and the R 9 substituent Each of them has 1 to 3 R 11 It is sometimes replaced by, Each R 10 is C 1-8 Alkyl, C 1-8 Deuteroalkyl, halo, cyano, -OC 1-8 Alkyl ,-OC 1-8 Deuteroalkyl, -X 1 -OC 1-8 Alkyl, -OX 1 -OC 1-8 Alkyl, -S(O)2 -C 1-6 Alkyl, -C(O)NR d R e and 1 to 3 heteroatoms selected from the group consisting of O, N, and S Independently selected from the group consisting of 4-6 member heteroaryls having ring vertices, where R 10 Each substituent has 1 to 3 R 12 It is sometimes replaced by, or Ar 2 Adjacent vertices Two R's located 10 These can be combined in some cases to form a 5-membered heterocyclic ring, and the ring consists of 1 to 2 It is sometimes replaced by halogens. Each R 11 hydroxyl, halo, cyano, -NR d R e , -C(O)OR a phenyl, C 3-8 Cycloa Lukil and C 1-4 It is independently selected from the group consisting of alkyls, and it is C(O)OR a Depending on the case It has been replaced, Each R 12 is halo, cyano, hydroxy, -C(O)OR a They are independently selected from the group consisting of, and Each R a H, deuterium, or C 1-6 It is alkyl, Each R b and R c H, Deuterium, C 1-8 Alkyl, -S(O)2-C 1-6 Alkyl, -C(O)OR a and -X 1 -C(O)OR a Selected independently from the group consisting of, Each R d and R e H, Deuterium, C 1-8 Alkyl, -S(O)2-C 1-6 group consisting of alkyl groups Selected more independently, However, G 1 and G 2 Each of these is N, and G 3 CH is, R 2 CH3 is and R 1a and R 1b When each is H or deuterium, Ar 2 2-thienyl, phenyl, 2-, 3- (Other than 4-methoxyphenyl, 3- or 4-halophenyl, 2,4-dimethoxyphenyl, 2,4-dichlorophenyl, or 2- or 4-methylphenyl) The present invention provides compounds having [a certain characteristic] or pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0022] In some embodiments, the present invention includes the formula: [ka] Compounds having this property, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are possible candidates. As will be explained later, compound I is A2A R and A 2B It is a strong antagonist of R, and less than 10 nM It is effective on both types of receptors.

[0023] In some embodiments, the present invention relates to a method for treating or preventing cancer in a subject (e.g., a human), the method being at least one of the A's described herein. 2A R / A 2B R inhibitors This includes administering a therapeutically effective dose. In some embodiments, the present invention is A 2A R-medium The present invention includes a method for treating or preventing cancer in a subject, comprising administering at least one of the compounds described herein to the subject in an amount effective in reversing or halting the progression of mediated immunosuppression. In some embodiments, A 2A R-mediated immunosuppression is caused by antigen-presenting cells (APCs).

[0024] Examples of cancers that can be treated with the compounds and compositions described herein include, but are not limited to, cancers of the prostate, colorectal, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovaries, testes, head, neck, skin (including melanoma and basal carcinoma), mesothelial wall, 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, kidney or bone, glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, cutaneous basal cell carcinoma, and testicular seminoma. 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 Kaposi's sarcoma. Cancers that are candidates for treatment with the compounds and compositions of the present invention are discussed further below.

[0025] The present invention provides a therapeutically effective amount of A sufficient to increase delayed-type hypersensitivity reactions to tumor antigens, delay the time to recurrence of malignant tumors after transplantation, extend recurrence-free survival after transplantation, and / or extend long-term survival after transplantation. 2A R / A 2BBy administering R inhibitors, bone marrow transplantation Alternatively, the aim is to devise a method of treating patients who are candidates for peripheral blood stem cell transplantation.

[0026] In certain embodiments, the present invention envisions a method for treating or preventing an infectious disorder (e.g., a viral infection) in a subject (e.g., a human), wherein the method involves at least one A in a therapeutically effective amount. 2A R / A 2B This includes administering an R inhibitor (e.g., a novel inhibitor of the present invention) to a target. In some embodiments, the infectious disease is a viral infection (e.g., a chronic viral infection), a bacterial infection, a fungal infection, or a parasitic infection. In certain embodiments, the viral infection is human immunodeficiency virus or cytomegalovirus.

[0027] In yet another embodiment, the present invention is intended to provide a method for treating or preventing an immune-related disease, disorder, or condition in a subject (e.g., a human), wherein the method involves a therapeutically effective amount of at least one A as described herein. 2A R / A 2B This includes administering R inhibitors as the target. Examples of immune-related diseases, disorders, and conditions are listed below.

[0028] A 2A R / A 2B Other conditions that can be treated or prevented, either entirely or partially, by regulating R activity Diseases, disorders and conditions are defined in the present invention. 2A R / A 2B This is a candidate case for R inhibitor compounds.

[0029] The present invention further describes A as described herein. 2A R / A 2B The intention is to use an R inhibitor in combination with one or more additional drugs. One or more additional drugs may be several adenosine A 2A Receptor and / or adenosine A 2B It may have receptor regulatory activity, or separately It may function by the mechanism of action of the agent. In some embodiments, such agents include radiation (e.g., localized radiotherapy or total body radiotherapy) and / or other modes of treatment of a non-pharmacological nature. When combination therapy is used, the compounds and additional agents described herein may be in the form of a single composition or multiple compositions, and the mode of treatment may be administered simultaneously, sequentially, or in some other regimen. As an example, the present invention envisions a treatment regimen in which a chemotherapy stage follows a radiotherapy stage. Combination therapy may have additive or synergistic effects. Other advantages of combination therapy are described below.

[0030] In certain embodiments, the present invention may be used in combination with an immune checkpoint inhibitor as described herein. 2A R / A 2B The use of R inhibitors is intended. Blocking immune checkpoints that amplify antigen-specific T cell responses has been shown to be a promising approach in human cancer treatment. Examples of candidate immune checkpoints (ligands and receptors) for blockade, some of which 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 (Ig and ITIM Examples include dopamine-containing T-cell immune receptors and killer inhibitor receptors. Immune checkpoint inhibitors and combination therapies with them will be discussed in detail elsewhere in this specification.

[0031] In other embodiments, the present invention provides at least one therapeutically effective amount of A 2A R / A 2B To treat cancer in a subject, including administering an R inhibitor and at least one chemotherapy agent to the target. The present invention provides a method for which such chemotherapeutic agents include, but are not limited to, alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isoflavamide, mechloretamine, melphalan, and uracil mustard), aziridines such as thiotepa, methanesulfonic acid esters such as busulfan, nucleoside analogs (e.g., gemcitabine), nitrosoureas such as carmustine, lomustine, and streptozocin, topoisomerase 1 inhibitors (e.g., irinotecan), platinum complexes such as cisplatin, carboplatin, and oxaliplatin, bioreducing alkylating agents (e.g., mitomycin, procarbazine, dacarbazine, and altoretamine), anthracycline therapies (e.g., doxorubicin, daunorubicin, epirubicin, and idarubicin), and DNA strand cleavage agents. (e.g., bleomycin), topoisomerase II inhibitors (e.g., amsacrin, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide and teniposide), DNA supraclude binders (e.g., pricamidine), antimetabolites (e.g., (For example, folic acid antagonists such as methotrexate and trimethrexate, pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine and phloxuridine, purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine and pentostatin, asparginase and ribonucleotide reductase inhibitors such as hydroxyurea), tubulin interaction agents (e.g., vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives and paclitaxel), hormones (e.g., estrogen, conjugated estrogen, ethinylestradiol, diethylstilbesterol, chlortrianicene, Examples of the present invention include progestins such as idenestrol, hydroxyprogesterone caproate, medroxyprogesterone, and megestrol, and androgens such as testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone), corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone), luteinizing hormone-releasing agents or gonadotropin-releasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate), and anti-hormone antigens (e.g., anti-androgens such as tamoxifen and flutamide, and anti-adrenergic agents such as mitotane and aminoglutethimide). The present invention also relates to the use of other agents known in the art (e.g., arsenic trioxide) and other chemotherapeutic agents to be developed in the future. 2A R / A 2B The intention is to use R inhibitors.

[0032] In some embodiments relating to a method for treating cancer, at least one chemotherapeutic agent is used in combination with Combined with the therapeutically effective amount described herein, A 2A R / A 2B When R inhibitors are administered, the cancer survival rate increases. The cancer survival rate is greater than that observed when either is administered alone. In further embodiments relating to a method for treating cancer, the therapeutic effective amount of A as described herein 2A R / A2B Use fewer R inhibitors When administered in combination with one chemotherapy agent, it can reduce tumor size or delay tumor growth. However, the reduction in tumor size or delay in tumor growth observed with the administration of a single drug is greater than This would be considered superior.

[0033] In further embodiments, the present invention relates to at least one A described herein. 2A R / A 2B The invention envisions a method for treating or preventing cancer in a subject, comprising administering a therapeutically effective dose of a R inhibitor and at least one signaling inhibitor (STI) to the subject. In certain embodiments, the at least one STI is selected from the group consisting of bcr / abl kinase inhibitors, epidermal growth factor (EGF) receptor inhibitors, HER-2 / neu receptor inhibitors, and farnesyltransferase inhibitors (FTIs). Other candidate STI agents are described elsewhere in this specification. .

[0034] The present invention relates to the use of at least one chemotherapeutic agent and / or radiotherapy in combination with A 2A R / A 2B We also intend to explore methods to enhance the rejection response of tumor cells in a subject, including the administration of an R inhibitor, wherein the tumor cell rejection response obtained here is A 2A R / A 2B R inhibitors, chemotherapy agents, or radiotherapy This is greater than what can be achieved by administering either one individually.

[0035] In a further embodiment, the present invention relates to at least one A 2A R / A 2B R inhibitors and A 2A R / A 2B The present invention provides a method for treating a target cancer, comprising administering a therapeutically effective dose of at least one immunomodulatory agent other than an R inhibitor to the target. In certain embodiments, at least one immunomodulatory agent The drug used to stop cell carcinoma is CD4OL, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-1BB ligand, and dendritic cell carcinoma vaccine. Chin, 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 indoleamine 2,3-dioxygenate Selected from the group consisting of -ase 1 (IDO1) inhibitors. Other candidate immunomodulators are specified in this document. It is written in the section.

[0036] The present invention envisions embodiments comprising a method for treating or preventing an infectious disorder (e.g., a viral infection) in a subject (e.g., a human), wherein the method comprises at least one A as described herein in a therapeutically effective amount. 2A R / A 2B This includes administering R inhibitors and therapeutically effective doses of anti-infective agents to the target.

[0037] In some embodiments of the present invention, additional therapeutic agents are cytokines, for example, granulocyte-macrophage colony-stimulating factor (GM-CSF) or flt3 ligand. The present invention also, without limitation, addresses hepatitis C virus (HCV) and human papillomavirus (HPV). This includes cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus, coxsackievirus, and human immunodeficiency virus (HIV). The aim is to develop methods for treating or preventing viral infections (e.g., chronic viral infections). The use of the compounds described herein (alone or as components of combination therapy) for treating infections will be discussed further below.

[0038] In a further embodiment, the treatment of an infectious disorder is a therapeutically effective amount of the present invention A 2A R / A 2B R inhibition This is carried out by co-administration of a vaccine in combination with the administration of an agent. In some embodiments, the vaccine is an antiviral vaccine, such as an anti-HIV vaccine. Other implementations In terms of form, the vaccine is effective against tuberculosis or malaria. In yet another embodiment, the vaccine is a tumor vaccine (e.g., a vaccine effective against melanoma), and the tumor vaccine may contain genetically modified tumor cells or genetically modified cell lines that have been transfected to express granulocyte-macrophage-stimulating factor (GM-CSF). The vaccine comprises genetically modified tumor cells or genetically modified cell lines. In certain embodiments, the vaccine comprises one or more immunogenic peptides and / or dendritic cells.

[0039] In some embodiments, the present invention involves using one or more of the compounds described herein as inhibitors The intention is to use it in combination with other physical agents.

[0040] A 2A R / A 2B In a particular embodiment relating to the treatment of an infection by administering an R inhibitor and at least one additional therapeutic agent, A 2A R / A 2B After administering both the R inhibitor and the additional therapeutic agent The symptoms of infection observed are improved compared to the symptoms of infection observed after administering either drug alone. In some embodiments, the symptoms of infection observed are improved by a reduction in viral load and CD4 + Increased T cell count, reduced opportunistic infections, increased survival time, and the root cause of chronic infections. It could be either absolute or a combination of both.

[0041] Brief explanation of the drawing Not applicable [Modes for carrying out the invention]

[0042] Detailed description of the invention Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described herein, and that the terms used herein are for the purpose of describing only specific embodiments and not to limit them.

[0043] When a range of values ​​is provided, unless otherwise explicitly stated, each intermediary value up to one-tenth of the lower limit is between the upper and lower limits of that range, and any value within the stated range. The stated values ​​or intervening values ​​are incorporated into the present invention. The upper and lower limits of these smaller ranges may be independently included in smaller ranges and are also incorporated into the present invention, but depend on any specifically excluded limit values ​​within the stated ranges. Where a stated range includes one or both of the limit values, the range excluding one or both of the included limit values ​​is also included into the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains.

[0044] When used herein, the singular forms “a,” “an,” and “the” refer to multiple objects unless the context clearly indicates otherwise. It should be further noted that claims may be constructed to exclude any optional element. Therefore, this statement is intended to serve as a premise for the use of exclusive terms such as “exclusively,” “only,” etc., in connection with the enumeration of claim elements or the use of “negative” limitations.

[0045] The publications discussed herein are provided solely for their disclosure prior to the filing date of this application. Furthermore, the publication dates provided may differ from the actual publication dates, which should be verified independently.

[0046] general In this specification, for example, adenosine A 2A Receptor (A 2A R) and / or adenosine A 2B Re Scepter (A 2BCompounds and compositions for inhibiting R), and pharmaceutical compositions containing the same are provided. Furthermore, this specification provides, for example, adenosine A 2A Receptor (A 2A R) and / or adenosine A 2B Receptor (A 2B Diseases, disorders, or conditions mediated by inhibition of R) Methods for treating or preventing those symptoms are also provided.

[0047] definition Unless otherwise indicated, the following terms are intended to have the meanings set forth below. Other terms are defined elsewhere throughout this specification.

[0048] The term "alkyl" is used either by itself or as part of another substituent, unless otherwise specified. This refers to a linear or branched hydrocarbon group having a specified number of carbon atoms (i.e., C 1-8 ( means 1 to 8 carbon atoms). Alkyl means C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 Na It can contain any number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl.

[0049] The term "alkylene" refers to a compound having the indicated number of carbon atoms and at least two other groups. This refers to linked linear or branched saturated aliphatic groups, i.e., divalent hydrocarbon groups. The two parts bonded to the alkylene can bond to the same atom or different atoms of the alkylene group. For example, linear alkylenes are -(CH2) n - It may be a divalent group, and n is 1, 2, 3, 4, 5 or 6. Typical alkylene groups include, but are not limited to, methylene and ethylene. Examples include propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene. In this application, X 1 or X 2 The alkylene group, often simply called a group, may or may not be substituted. 1 or X 2 It is understood that when a group containing is optionally substituted, the optionally present substituent may be present on the alkylene portion of that part.

[0050] The term "cycloalkyl" refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C 3-6 This refers to a cycloalkyl group that is either completely saturated or has more than one double group between ring vertices. It does not have a bond. "Cycloalkyl" also means, for example, bicyclo[2.2.1]hepta It can also refer to bicyclic and polycyclic hydrocarbon rings such as bicyclo[2.2.2]octane. In some embodiments, the cycloalkyl compounds of the present disclosure are monocyclic C 3-6 This is the cycloalkyl portion.

[0051] The term "heterocycloalkyl" refers to a ring having an indicated number of ring vertices (or members), and N This refers to a cycloalkyl ring having 1 to 5 heteroatoms selected from O and S, wherein the heteroatoms substitute for 1 to 5 carbon vertices, where the nitrogen and sulfur atoms may be oxidized, and the nitrogen atom may be quaternized. The cycloheteroalkyl may be a monocyclic, bicyclic, or polycyclic ring system. Non-limiting examples of cycloheteroalkyls include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, and thiomorpho Phosphorus-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone Examples include tetrahydrofuran, tetrahydrothiophene, and quinuclidine. Cycloheteralkyl groups can be bonded to the remainder of the molecule via a ring carbon or heteroatom.

[0052] When used herein, the wavy lines intersect single, double, or triple bonds in any chemical structure described herein. [ka] The ∫ represents a single, double, or triple bond to the remainder of the molecule. Furthermore, a bond extending to the center of a ring (e.g., a phenyl ring) is intended to indicate a bond to any of the available ring vertices. Those skilled in the art will understand that multiple substituents shown as bonded to a ring provide a stable compound, or otherwise occupy ring vertices that are sterically compatible. This is likely the case. With respect to divalent components, the notation is intended to include both directions (forward or reverse). For example, the group "-C(O)NH-" includes bonds in either direction: -C(O)NH- or -NHC(O)-, and similarly, "-O-CH2CH2-" includes both -O-CH2CH2- and -CH2CH2-O-.

[0053] The terms "halo" or "halogen" mean, alone or as part of another substituent, a fluorine, chlorine, bromine, or iodine atom unless otherwise specified. Furthermore, terms such as "haloalkyl" include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" means that it contains trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0054] The term "aryl" refers to a polyunsaturated, typically aromatic carbon compound that can be monocyclic or polycyclic (up to three rings) fused or covalently bonded together, unless otherwise specified. This refers to a hydrogenated group. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl.

[0055] The term "heteroaryl" refers to a compound containing 1 to 5 heteroatoms selected from N, O, and S. This refers to an aryl group (or ring) where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaryl groups can be bonded to the remainder of the molecule via heteroatoms. Non-exclusive examples of heteroaryl groups include pyridyl, quinoxalinyl, quinazolinyl, sinnolinyl, phthalazinyl, benzotriazinyl, pryl, benzimidazolyl, pyridadinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, benzopyrazolyl, benzotriazolyl, benzoisoxazolyl, isobenzofuryl, isoindolyl, indolidinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranil, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, and thienyl. The substituents for the heteroaryl ring can be selected from the group of acceptable substituents listed below.

[0056] The above terms (e.g., "alkyl," "aryl," and "heteroaryl") may be substituted in some embodiments. Selected substituents for each type of group are provided below.

[0057] The substituents of any element for alkyl groups (including groups often called alkylene, alkenyl, and alkynyl) can be a variety of groups, such as halogens, -OR', and -NR'R. ”, -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C (O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN(S) ANO), -NO2, aryl, aryloxy, oxo, cycloalkyl and heterocyclo It is chosen from Lukil, and it is a number in the range of 0 to (2m'+1), where m' is such a base This is the total number of carbon atoms in the compound. R', R'', and R''' are each independently hydrogen, unsubstituted C1-8 Alkyl, unsubstituted aryl, 1-3 halogens, C1-8 alkoxy or C1-8 thioalkoxy This refers to aryl or unsubstituted aryl-C1-4 alkyl groups. When R' and R'' are bonded to the same nitrogen atom, they can combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' is 1-pyrrolidin It is intended to contain 4-morpholinyl and 4-morpholinyl.

[0058] The substituents of optional elements for cycloalkyl and heterocycloalkyl groups are optionally substituted with C(O)OR' alkyl, halogen, -OR', -NR'R'', -SR', -SiR'R''R'''. -OC(O)R', -C(O)R', -CO2R', -CONR'R”, -OC(O)NR'R”, -NR”C(O)R', -NR'-C(O)NR”R”', -NR”C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R”, -NR'S(O)2R”, -CN(cyano), -NO2, aryl, a It can be various groups selected from reeloxy and oxo. R', R'' and R'' Each of these is independently hydrogen, an unsubstituted C1-8 alkyl group, an unsubstituted aryl group, one to three halogens, an aryl group substituted with a C1-8 alkoxy or C1-8 thioalkoxy group, or an unsubstituted a This refers to the reel-C1-4 alkyl group.

[0059] Similarly, substituents on any element for aryl and heteroaryl groups are diverse, and generally include -halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -OC(O)NR'R'', -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R''', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -N3, perfluoro(C1-C4)alkoxy and perfluoro( Selected from C1-C4 alkyl groups, the number of which ranges from 0 to the total number of open valencies on the aromatic ring system, and R', R'', and R''' independently contain hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl , C 3-6 Cycloalkyl, C 2-8 Alkenyl and C 2-8 Selected from alkinyl. Other appropriate Examples of substituents include each of the above-mentioned aryl substituents bonded to the ring by an alkylene tether of 1 to 6 carbon atoms.

[0060] Two substituents on adjacent atoms of an aryl or heteroaryl ring are given by the formula -TC(O)-(CH2). q -U-( In the formula, T and U are independently -NH-, -O-, -CH2-, or a single bond, and q is an integer from 0 to 2. It may be replaced by substituents of formula -A-(CR). Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be of formula -A-(CR). f R g ) r -B-(wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, r is an integer from 1 to 3, and R f and R g (Each of these is independently H or a halogen) by substituents. It may be replaced by . One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be of formula -(CH2) s -X-(CH2) t -(In the formula, s and t are independently 0 to 3 (X is an integer such that X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-) The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or an unsubstituted C1-6 alkyl group.

[0061] As used herein, the term "heteroatom" refers to oxygen (O), nitrogen (N), sulfur (S), and It is intended to contain silicon (Si).

[0062] The term “pharmaceutically acceptable salt” is intended to encompass salts of active compounds, which are prepared using relatively non-toxic acids or bases depending on the specific substituents found in the compounds described herein. If the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a desired base, either neat or in a suitable inert solvent, in sufficient quantity. Examples of salts derived from pharmaceutically acceptable bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc. Examples of pharmaceutically acceptable salts derived from organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, and naturally occurring amines), such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, and tripropylamine. Examples include luamine and tromethamine. When the compound of the present invention contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogenic acid, dihydrogenic acid, sulfuric acid, monohydrogenic acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Examples include salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). (I want to be). The specific compounds of the present invention contain both basic and acidic functional groups, thereby combining The substance can be converted into either a base addition salt or an acid addition salt.

[0063] The neutral form of the compound can be regenerated by conventional methods, by contacting the salt with a base or acid and isolating the parent compound. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salt is equivalent to the parent form of the compound for the purposes of the present invention. In addition to the salt form, the present invention provides compounds in prodrug form. The prodrugs of the compounds described herein are compounds that readily undergo chemical transformation under physiological conditions to provide the compounds of the present invention. Furthermore, the prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment. For example, the prodrug can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. The prodrugs are described in more detail elsewhere in this specification.

[0064] In addition to salt forms, the present invention provides compounds in prodrug form. The prodrugs of the compounds described herein are compounds that readily undergo chemical transformation under physiological conditions to provide the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in an in vivo environment. For example, the prodrug can be slowly converted into the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0065] Certain compounds of the present invention can exist in solvated forms, including non-solvated and hydrated forms. In general, the solvated forms are equivalent to the non-solvated forms and are intended to be included within the scope of the present invention. Certain compounds of the present invention can exist in polycrystalline or amorphous forms. In general, all physical forms are equivalent for the uses intended by the present invention and are intended to be within the scope of the present invention.

[0066] Certain compounds of the present invention have an asymmetric carbon atom (optical center) or a double bond. Racemic mixtures, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separated enantiomers) are all intended to be included within the scope of the present invention. When a stereochemical description is given, one isomer is present and the other is substantially absent. It is intended to refer to a hybrid. "Substantially does not contain" other isomers. This indicates that the ratio is at least 80 / 20, more preferably 90 / 10 or 95 / 5 or higher. In some embodiments, one of the isomers will be present in an amount of at least 99%. .

[0067] The compounds of the present invention also have one or more atoms constituting such compounds in an unnatural proportion. It may contain atomic isotopes. An unnatural proportion of isotopes can be defined as ranging from the amount found in nature to the amount that constitutes 100% of the atom in question. For example, a compound may contain: For example, tritium ( 3 H), Iodine-125( 125 I) or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13 Non-radioactive isotopes such as C) may be included. Such isotopic variants may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the present invention may find additional uses as diagnostic and / or imaging reagents or as cytotoxic / radiotoxic therapeutic agents, though not limited to these. Furthermore, isotopic variants of the compounds of the present invention may have modified pharmacokinetic and pharmacodynamic properties that can contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, whether radioactive or non-radioactive, are intended to be included within the scope of the present invention.

[0068] The terms "patient" or "subject" are used interchangeably to refer to humans or non-human animals (e.g., mammals).

[0069] For example, when applied to subjects, cells, tissues, organs, or biological fluids, terms such as "administer" or "administer" can be interpreted as, for example, A 2A R / A 2B Inhibitors of R, pharmaceutical compositions containing the same, or This refers to the contact of a diagnostic agent with a target, such as cells, tissues, organs, or biological fluids. In relation to cells, administration refers to the contact of the reagent with cells (e.g., in vitro or ex vivo), as well as the contact of the reagent with fluids that are in contact with cells.

[0070] Terms such as "to treat," "to treat," and "treatment" refer to actions initiated after a disease, disability, or condition has been diagnosed or observed. 2A R / A 2B Inhibitors of R or This refers to the administration of a pharmaceutical composition containing it, etc., thereby eliminating at least one of the underlying causes of the disease, disorder, or condition that is causing the subject to distress, or the disease, disorder, To temporarily or permanently eliminate, reduce, suppress, or alleviate at least one symptom related to the condition. This will improve. Therefore, treatment (procedure) includes inhibiting the active disease (e.g., preventing the onset or further progression of the disease, disorder or condition or the associated clinical symptoms).

[0071] As used herein, the term “requiring treatment” refers to a determination made by a physician or other caregiver that the subject requires treatment or would benefit from treatment. This determination is based on a variety of factors within the physician's or caregiver's area of ​​expertise.

[0072] The terms "prevent," "prevention," and "prevention" refer to a series of actions initiated (for example, before the onset of the disease, disability, condition, or their symptoms) to temporarily or permanently prevent, suppress, inhibit, or reduce the risk to an object of developing a disease, disability, condition, etc. (for example, determined by the absence of clinical symptoms). 2A R / A 2B R inhibitor or pharmaceutical composition containing the same This term refers to (for example, giving) or, more generally, to delaying the onset of a particular disease, disorder, or condition in relation to a person who is predisposed to having such a condition. In specific cases, this term may also refer to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to an adverse or undesirable condition.

[0073] As used herein, the term “prevention is needed” refers to a judgment made by a physician or other caregiver that a person needs or would benefit from preventive care. This judgment is based on a variety of factors within the physician's or caregiver's area of ​​expertise.

[0074] The term "therapeutic dose" means that when a drug is administered to a subject, either alone or as part of a pharmaceutical composition, and in a single dose or a series of doses, it has a detectable positive effect on any symptom, condition, or characteristic of any of the diseases, disorders, or conditions at the time of administration to the subject. This refers to the amount that can be effective. The therapeutically effective dose can be determined by measuring the relevant physiological effects and can be adjusted in relation to the administration regimen and diagnostic analysis of the control state, etc. For example, A at a specific time after administration. 2A R / A 2B R inhibitors (or, for example, that Measuring serum levels of metabolites can be an indicator of whether a therapeutically effective dose has been administered.

[0075] The phrase "enough to produce a change" means that there is a detectable difference between the levels of an indicator measured before (e.g., baseline level) and after administration of a particular therapy. Indicators may be objective parameters (e.g., serum concentration) or subjective parameters (e.g., subject's perceived health).

[0076] The term "small molecule" refers to a molecule with a molecular weight of less than approximately 10 kDa, less than approximately 2 kDa, or less than approximately 1 kDa. This refers to compounds. Small molecules are not limited to inorganic molecules, organic molecules, organic molecules containing inorganic components, molecules containing radioactive atoms, and synthetic molecules. Therapeutically, small molecules tend to be more permeable to cells, more difficult to degrade, and less likely to induce an immune response than larger molecules.

[0077] The term "ligand" refers to a peptide, polypeptide, membrane-bound molecule, or membrane-binding molecule, or a complex thereof, that can act as an agonist or antagonist of a receptor, for example. Ligands include natural and synthetic ligands, such as cytokines, cytokine variants, analogs, mutant proteins, and antibody-derived binding compositions, as well as small molecules. The term also includes drugs that are neither agonists nor antagonists but can bind to receptors without significantly affecting their biological properties, such as signal transduction or adhesion. Furthermore, the term includes membrane-bound ligands in soluble forms, such as membrane-bound ligands modified by chemical or recombinant methods. Ligands or receptors can be entirely intracellular, i.e., they can reside in the cytosol, nucleus, or some other intracellular compartment. The complex of a ligand and a receptor is called a "ligand-receptor complex."

[0078] "Inhibitors" and "antagonists" or "activators" and The term "agonist" refers to a molecule that inhibits or activates, for example, a ligand, receptor, cofactor, gene, cell, tissue, or organ. Inhibitors are molecules that reduce, block, prevent, delay, inactivate, desensitize, or downregulate, for example, a gene, protein, ligand, receptor, or cell. Activators are molecules that increase, activate, promote, enhance, sensitize, or upregulate, for example, a gene, protein, ligand, receptor, or cell. Inhibitors can also be defined as molecules that reduce, block, or inactivate constitutive activity. An "agonist" interacts with a target to cause or promote increased activation of that target. An antagonist is a molecule that acts in opposition to the action of an agonist. Antagonists prevent, reduce, inhibit, or neutralize the activity of an agonist, and antagonists can also prevent, inhibit, or reduce the constitutive activity of a target, such as a target receptor, even in the absence of the identified agonist.

[0079] Terms such as "modulate" and "modulation" are used in A 2A R / A 2B R's functions and This refers to the ability of a molecule (e.g., an activator or inhibitor) to directly or indirectly increase or decrease activity. Modulators may act alone or with cofactors, such as proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bioorganic molecules. Numerous libraries of small molecule compounds (e.g., combinatorial libraries) are commercially available and can serve as a starting point for identifying modulators. Those skilled in the art will know that to identify one or more compounds with desired properties, such libraries may be used. A compound library can be screened, and then a person skilled in the art of medicinal chemistry can, for example, synthesize and evaluate its analogs and derivatives to determine which of these compounds is most effective. One or more assays that can be optimized (e.g., biochemical or cell-based assays) This can be developed. Synthetic and / or molecular modeling studies can also be used to identify activators. It can also be used.

[0080] The “activity” of a molecule can describe or refer to its binding ability to ligands or receptors, catalytic activity, ability to stimulate gene expression or cell signaling, differentiation or maturation, antigenic activity, or modulation of the activity of other molecules. The term “proliferative activity” encompasses normal cell division, as well as activity that promotes, requires, or is particularly associated with, cancer, tumor, dysplasia, cell transformation, metastasis, and angiogenesis.

[0081] When used herein, the terms "comparable," "comparable activity," "activity comparable to," and "comparable effect" are used interchangeably. "effect)", "effect comparable to", etc., are quantitative and / or qualitative. These are relative terms that can be seen in the context in which they are frequently used. The meaning of the term depends on the context in which it is used. For example, two drugs that activate receptors have comparable effects from a qualitative standpoint. It can be considered that, however, if, as determined in an assay accepted in the art (e.g., a dose-response assay) or an animal model accepted in the art, one drug can only achieve 20% of the activity of the other drug, then the two drugs are quantitatively equivalent. From that perspective, it can be seen that there is no comparable effect. When comparing one result to another... In (for example, comparing one result to a reference standard), "comparable" often means (even if not always) (Even if not), if one result is less than 35%, less than 30%, less than 25%, less than 20%, or 15% of the reference standard. The deviation is less than %, less than 10%, less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. In certain embodiments, one result is considered comparable to the reference standard if it deviates from the reference standard by less than 15%, less than 10%, or less than 5%. Examples, not limited to, However, activity or effect may refer to efficacy, stability, solubility, or immunogenicity.

[0082] "Substantially pure" indicates that the component constitutes more than approximately 50% of the total composition, and typically more than approximately 60% of the total polypeptide content. More typically, "substantially pure" refers to a composition in which the component of interest constitutes at least 75%, at least 85%, at least 90%, or more of the total composition. In some cases, the polypeptide will constitute more than approximately 90% or more than approximately 95% of the total composition.

[0083] The terms "specifically bind" or "selectively bind" refer to ligand / receptor When referring to antibodies / antigens or other binding pairs, in heterogeneous populations of proteins and other biological products It exhibits a binding reaction that determines the presence of the protein. Therefore, under specified conditions, a particular ligand binds to a specific receptor and does not bind in significant amounts to other proteins present in the sample. The antibody or binding composition derived from the antigen-binding site of the antibody in the intended method binds with affinity to its antigen, or its variant or mutant protein, and this affinity is at least twice as high as the affinity to any other antibody or binding composition derived therefrom. Larger, at least 10 times larger, at least 20 times larger, or at least 100 times larger In certain embodiments, the antibody is determined, for example, by Scatchard analysis (Munsen et al., 1980 Analyt. Biochem. 107:220-239) to be approximately 10 9 It has an affinity greater than liter / mol. ru.

[0084] For example, the term “response” of a cell, tissue, organ, or organism encompasses changes in biochemical or physiological behavior, such as concentration, density, adhesion, or migration within a biological compartment, the rate of gene expression, or the state of differentiation, where such changes correlate with internal mechanisms such as activation, stimulation, treatment, or genetic programming. In certain contexts, terms such as “activation” and “stimulation” are used. This refers to cell activation regulated by internal mechanisms and external or environmental factors. On the other hand, "inhibition" and "downregulation" refer to the opposite effect.

[0085] 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 amino acids or derivatized amino acids, and polypeptides having a modified polypeptide backbone. The terms include, but are not limited to, fusion proteins having heterologous amino acid sequences, having or not having an N-terminal methionine residue, heterologous and homologous This includes fusion proteins with leader sequences, immunologically labeled proteins, and others.

[0086] As used herein, the terms “variants” and “homlog” are used in a manner in which the terms “variants” and “homlog” are used. To refer to an amino acid sequence or DNA sequence that is similar to a reference amino acid or nucleic acid sequence, respectively. These terms are used interchangeably. This term encompasses naturally occurring and non-naturally occurring variants. Naturally occurring variants are homologs (polypeptides and nucleic acids in which the amino acid or nucleotide sequence differs between one species and another) and allelic variants (individuals within a species that have different amino acid or nucleotide sequences). Therefore, variants and homologs are the naturally occurring DNA sequences and the tangents encoded therein. This term encompasses proteins and their isoforms, as well as conjugated variants of proteins or genes. It also includes nucleic acid sequences in which one or more bases are altered from a naturally occurring DNA sequence, but which are still translated into amino acid sequences corresponding to naturally occurring proteins due to degeneracy of the genetic code. Non-naturally occurring variants and homologs include polypeptides and nucleic acids, respectively, that involve changes in amino acid or nucleotide sequences, where the sequence changes are artificially introduced (e.g., mutant proteins). For example, the changes are produced in the laboratory by human intervention ("human hands"). Therefore, non-naturally occurring variants and homologs are derived from natural proteins by one or more conserved substitutions and / or tags and / or conjugates. It can also refer to an array that is different from the one already present.

[0087] As used herein, the term “muteins” broadly refers to recombinant proteins that have undergone mutation. These proteins typically have one or more amino acid substitutions and often originate from cloned genes subjected to site-directed, random, or total mutagenesis, or from completely synthesized genes.

[0088] Terms such as "DNA," "nucleic acid," "nucleic acid molecule," and "polynucleotide" can refer to any length. The term "polynucleotide" is used interchangeably herein to refer to a polymeric form of nucleotide, which may be a deoxyribonucleotide, a ribonucleotide, or an analogue thereof. Non-limiting examples of polynucleotides include linear and cyclic nucleic acids, messenger RNA (mRNA), complementary DNA (cDNA), recombinant polynucleotides, vectors, probes, primers, and the like.

[0089] Adenosine A 2A Receptor and adenosine A 2B Receptors and their inhibition As described above, a precise understanding of the underlying mechanism of action of the compound that the compound of the present invention acts upon is not required for the implementation of the present invention, and the compound (or a subset thereof) is adenosine A 2A Receptor (A 2A R) and / or adenosine A 2B Receptor (A 2B It is thought to inhibit R). Alternatively, the compound (or a subset thereof) can inhibit adenylyl cyclase function. The compound (or a subset thereof) also inhibits A 2A Receptor (A 2A R), A Denosine A 2B Receptor (A 2B It has inhibitory activity against R) and adenylyl cyclase. It is possible. The compounds of the present invention are, in this specification, generally adenosine A2A Receptor (A 2A R) and / or adenosine A 2B Receptor (A 2B R) Inhibitors, but the term "A 2A R / A 2B "R inhibitors" are A 2A R, A 2B Compounds that act individually via the inhibition of R or adenylyl cyclase, and / or A 2A R, A 2B It should be understood that this includes compounds that act through the inhibition of R and adenylyl cyclase.

[0090] Adenosine A with desirable properties 2A Receptor and adenosine A 2B Identification of receptor inhibitors The present invention, in part, has at least one characteristic or feature that is appropriate for treatment. Denosine A 2A Receptor and / or adenosine A 2B This invention relates to the identification of receptor inhibitors. Candidate inhibitors can be identified, for example, using assays or models accepted in the art, examples of which are described herein.

[0091] After identification, candidate inhibitors can be further evaluated using techniques that provide data on the inhibitor's characteristics (e.g., pharmacokinetic parameters, solubility, or means of determining stability). Comparison of candidate inhibitors with reference standards ("best in class" of current inhibitors) serves as an indicator of the potential of such candidates.

[0092] The compound of the present invention Formula (I) [ka] (In the above formula, G 1 is N or CR 3a And, G 2 is N or CR3b And, G 3 is N or CR 3c And, R 3a , R 3b and R 3c Each is independently H, deuterium, or C 1-3 It is alkyl, R 1a and R 1b Each is independent of the others. viii) H or deuterium, ix) 1 to 3 R 5 C which may be substituted by substituents 1-8 Alkyl, x) 1 to 3 R 5 -X which may be substituted by substituents 1 -OC 1-8 Alkyl, xi)-C(O)-R 6 , xii) 1 to 3 R 7 Y, which may be substituted by substituents, xiii) 1 to 3 R 7 -X which may be substituted by substituents 1 -Y, Selected from the group consisting of, xiv)R 1a and R 1b Along with the nitrogen to which they are bound, they are 5-6 member heterocycloalkyl groups. A ring is formed, and the ring has 1 to 3 R 8 The heterocyclic The r-alkyl group has 0 to 2 additional heteroatom ring vertices selected from the group consisting of O, N, and S. , Each Y is C 3-8 Cycloalkyl or 1 to 3 heteroatoms selected from the group consisting of O, N, and S It is a 4-6 member heterocycloalkyl having a ring vertex, R 2 and R 4 Each is independently H, deuterium, or C 1-3It is alkyl, Ar 1 It is a phenyl or 5-6 member heteroaryl, each of which has 1-3 R 9 In the case of It has been replaced by, Ar 2 It is a phenyl or 5-6 member heteroaryl, each of which has 1-3 R 10 In the case of It has been replaced by, Ar 1 and Ar 2 The aforementioned 5-6 member heteroaryls are each independently O, N, N + -O - and from S It has 1 to 3 heteroatom ring vertices selected from the group, each X 1 is C 1-6 It is alkylene, Each R 5 is hydroxyl, C 3-8 Cycloalkyl, phenyl, -O-phenyl, -C(O)OR a and Selected independently from the group consisting of oxo, Each R 6 is C 1-8 Alkyl, or Y, each of which is hydroxyl, -O-phenyl, or phenyl. Nil and -OC 1-8 Optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl groups. It is done, Each R 7 is C 1-8 Alkyl, hydroxyl, -OC 1-8 Alkyl, oxo, and C(O)OR a from Selected independently from the group, Each R 8 is C 1-8 Independently selected from the group consisting of alkyl, hydroxyl, and oxo, Each R 9 is C 1-8 Alkyl, C 1-8 Deuteroalkyl, -OC 1-8 Alkyl, -OC1-8 Du -Teroalkyl, -X 1 -OC 1-8 Alkyl, -OX 1 -OC 1-8 Alkyl, -X 1 -OX 1 -OC 1-8 Al Kill, -C(O)OR a , halogen, cyano, -NR b R c , Y, -X 1 -C 3-8 Cycloalkyl and -X 2 -Z or Selected independently from the group, where X 2 is C 1-6 Alkylene, -C 1-6 Z is selected from the group consisting of alkylenes -O-, -C(O)-, and -S(O)2-, and Z is selected from the group consisting of O, N, and S, with 1 to 3 elements. It is a 4-6 member heterocycloalkyl having a heteroatom ring vertex, and the R 9 substituent Each of them has 1 to 3 R 11 It is sometimes replaced by, Each R 10 is C 1-8 Alkyl, C 1-8 Deuteroalkyl, halo, cyano, -OC 1-8 Alkyl ,-OC 1-8 Deuteroalkyl, -X 1 -OC 1-8 Alkyl, -OX 1 -OC 1-8 Alkyl, -S(O)2 -C 1-6 Alkyl, -C(O)NR d R e and 1 to 3 heteroatoms selected from the group consisting of O, N, and S Independently selected from the group consisting of 4-6 member heteroaryls having ring vertices, where R 10 Each substituent has 1 to 3 R 12 It is sometimes replaced by, or Ar2 Adjacent vertices Two R's located 10 These can be combined in some cases to form a 5-membered heterocyclic ring, and the ring consists of 1 to 2 It is sometimes replaced by halogens. Each R 11 hydroxyl, halo, cyano, -NR d R e , -C(O)OR a phenyl, C 3-8 Cycloa Lukil and C 1-4 It is independently selected from the group consisting of alkyls, and it is C(O)OR a Depending on the case It has been replaced, Each R 12 is halo, cyano, hydroxy, -C(O)OR a They are independently selected from the group consisting of, and Each R a H, deuterium, or C 1-6 It is alkyl, Each R b and R c H, Deuterium, C 1-8 Alkyl, -S(O)2-C 1-6 Alkyl, -C(O)OR a and -X 1 -C(O)OR a Selected independently from the group consisting of, Each R d and R e H, Deuterium, C 1-8 Alkyl, -S(O)2-C 1-6 group consisting of alkyl groups Selected more independently, However, G 1 and G 2 Each of these is N, and G 3 CH is, R 2 CH3 is and R 1a and R 1b When each is H or deuterium, Ar 2 2-thienyl, phenyl, 2-, 3- (Other than 4-methoxyphenyl, 3- or 4-halophenyl, 2,4-dimethoxyphenyl, 2,4-dichlorophenyl, or 2- or 4-methylphenyl) Compounds having or pharmaceutically acceptable salts, hydrates, or solvates thereof are provided.

[0093] In one selected group of embodiments, formula (I)(Ar 1 1 to 3 R 9 Depending on the circumstances Compounds (which are substituted 5-6 member heteroaryls) are provided.

[0094] In another group of selected embodiments, formula (I)(Ar 1 1 to 3 R 9 Depending on the circumstances, Compounds are provided that are replaced (selected from the group consisting of pyridyl, pyridyl N-oxide, imidazolyl, pyrazolyl and thiazolyl). In some selected embodiments, Ar 1 1 to 3 R 9 It is a pyridyl or pyridyl N-oxide substituted by [the specified agent].

[0095] In some selected embodiments, formula (I)(G 3 CR 3c The compound (is) is provided.

[0096] In some selected embodiments, the compound of formula (I) is of formula (Ia) [ka] This can be expressed as follows (where n is an integer between 0 and 2).

[0097] In some selected embodiments, the compound of formula (I) is of formula (Ib) [ka] It is represented by [this].

[0098] In some selected embodiments, formulas (I), (Ia), and (Ib) (wherein Ar 2 1 to 3 R 10 It is replaced by. In some embodiments, at least one R 10 is cyano be.

[0099] In some selected embodiments, the compound of formula (I) is of formula (Ic) [ka] This can be expressed as follows (where m is an integer between 0 and 2).

[0100] In some selected embodiments, the compound of formula (I) is of formula (Id) [ka] It is represented by [this].

[0101] In some selected embodiments, compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) ( Each R 9 is C 1-8 Alkyl, C 1-8 Deuteroalkyl, -OC 1-8 Alkyl, -OC 1-8 Due Telolalkyl, -X 1 -OC 1-8 Alkyl, -OX 1 -OC 1-8 Alkyl, -X 1 -OX 1 -OC 1-8 Alki Selected independently from R, where R 9 Each substituent has 1 to 3 R 11 Compounds (which may be substituted in some cases) are provided.

[0102] In several selected embodiments, formulas (I), (Ia), (Ib), (Ic), and (Id) (each R9 is -C(O)OR a , -NR b R c , Y, -X 1 -C 3-8 Cycloalkyl and -X 2 Selected independently from the group consisting of -Z Here, X 2 is C 1-6 Alkylene, -C 1-6 A group consisting of alkylenes -O-, -C(O)-, and -S(O)2- Z is a 4- to 6-membered heterocycloalkyl having 1 to 3 heteroatom ring vertices selected from the group consisting of O, N, and S, and R 9 Each substituent has 1 to 3 R 11 by Compounds (substituted by a compound) are provided.

[0103] In some selected embodiments, the compound of formula (I) is of formula (Ie) [ka] It is represented by [this].

[0104] In several selected embodiments, formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) (G 2 A compound of (where is N) is provided.

[0105] In several selected embodiments, formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) (G 1 A compound of (where is N) is provided.

[0106] In several selected embodiments, formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) (G 1 CR 3a The compound (is) is provided.

[0107] In several selected embodiments, formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) (R 2 Compounds of (where is H or deuterium) are provided.

[0108] In several selected embodiments, formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie)(R 4 Compounds of (where is H or deuterium) are provided.

[0109] In several selected embodiments, formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie)(R 1b Compounds of formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) are provided. (R 1b teeth: i) H or deuterium, ii) 1 to 3 R 5 C which may be substituted by substituents 1-8 Alkyl, and iii) 1 to 3 R 5 -X which may be substituted by substituents 1 -OC 1-8 Alkyl, A compound (selected from the group consisting of) is provided. In several selected embodiments, formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie)(R 1b teeth: i) H or deuterium, iv)-C(O)-R 6 , v) 1 to 3 R 7 Y, which may be substituted by substituents, vi) 1 to 3 R 7 -X which may be substituted by substituents 1 -Y, (Selected from a group consisting of) The compound is provided.

[0110] In several selected embodiments, formulas (I), (Ia), (Ib), (Ic), (Id), and (Ie) (each R 10 is C 1-8 Alkyl, halo, cyano, -OC 1-8 Alkyl, -X 1 -OC 1-8 Alkyl, -OX 1 -O -C 1-8 Independently selected from the group consisting of alkyls, the R 10 Each substituent has 1 to 3 R 12 to Compounds (which are more often substituted) are provided.

[0111] In some embodiments, formulas (I), (Ia), (Ib), (Ic), (Id), and (Ie) (each R 10 is independent And, C 1-8 Alkyl, halo, cyano, -OC 1-8 Independently selected from the group consisting of alkyl groups The compounds of ) are provided.

[0112] In some selected embodiments, formula (Ic)(m is at least 1, and at least One R 10 Compounds (which are cyano) are provided. In some selected embodiments, And, equation (Id) and (Ie) (at least one R 10 A compound (which is cyano) is provided.

[0113] In several selected embodiments, any one compound from Table 1 is provided.

[0114] In some selected embodiments, any one of the following group of compounds: [ka] It will be provided.

[0115] In several selected implementation methods, Compound I [ka] It will be provided.

[0116] In several selected embodiments, the chemical formulas (I), (Ia), (Ib), (Ic), (Id), and (Ie) The deuteriumized form of the compound is provided. Deuterium exists independently of hydrogen. It can substitute for hydrogen at any point.

[0117] Synthesis method Generally, the compounds provided herein can be prepared by conventional methods as described in the following examples.

[0118] Prodrugs and other means for drug delivery and / or half-life extension In some aspects of the present invention, the compounds described herein are administered in prodrug form.

[0119] To extend therapeutic activity, drug molecules may be engineered to utilize carriers for delivery. Such carriers can be used in a non-covalent manner, with the drug moiety being physicochemically incorporated into the solvent-carrier mixture, or by permanently covalently bonding the carrier reagent to one of the functional groups of the drug moiety (see WO20150202317 in general).

[0120] Several non-covalent approaches are preferred. For example, but not limited to, in certain embodiments, depot formulations are used that include non-covalent drug capsule encapsulations in a polymer carrier. In such formulations, the drug molecule is combined with the carrier material and processed so that the drug molecule is distributed within the bulk carrier. An example is a microparticle polymer-drug aggregate administered as an injectable suspension (e.g., Degradex (Registered Microspheres (Phosphorex, Inc.), a gel administered as a single bolus injection. Polymer-drug formulations (e.g., LupronDepot® (AbbVie Inc.)) Liposome formulations can include molecular aggregates, and the carrier can be a polymer or nonpolymeric substance capable of solubilizing the drug (e.g., DepoCyt® (Pacira Pharmaceuticals)). In these formulations, the release of the drug molecule occurs when the carrier swells or This can occur through physical decomposition. In other cases, chemical decomposition allows for the diffusion of the drug into the biological environment. Such chemical decomposition processes can be catalyzed by autohydrolysis or enzymes. Among other limitations, non-covalent drug encapsulation requires prevention of uncontrolled drug release, and the dependence of the drug release mechanism on biodegradation can lead to inter-patient variability.

[0121] In certain embodiments, drug molecules, including both small and large molecules, are bound to a carrier by permanent covalent bonds. Certain small molecule therapeutic agents exhibiting low solubility in aqueous fluids can be solubilized by binding to hydrophilic polymers, examples of which are described elsewhere in this specification. With respect to large molecule proteins, extension of half-life can be achieved, for example, by permanent covalent modification by palmitoyl moieties and by permanent covalent modification by other proteins having extended half-lives (e.g., Albuferon®). In general, Drug molecules exhibit reduced biological activity when a carrier is covalently bound to the drug.

[0122] In some cases, limitations associated with drug molecules containing non-covalent polymer mixtures or permanent covalent bonds can be successfully addressed by employing a prodrug approach to chemically bond the drug to a polymer carrier. In this context, inactive or less active therapeutic agents than the drug moiety itself are predictably converted into active molecular substances. The reduced biological activity of the prodrug compared to the released drug is advantageous when sustained or controlled release of the drug is desired. In such cases, drug release occurs over time, thereby reducing the need for repeated and frequent administration of the drug. The prodrug approach can also be advantageous when the drug moiety itself is not absorbed or is absorbed below optimal levels in the gastrointestinal tract. In these cases, the prodrug facilitates the absorption of the drug moiety, which is then cleaved at a later time (e.g., via first-pass metabolism). Drug molecules are typically linked to the polymer carrier moiety by a transient bond formed between the carrier moiety and the hydroxyl, amino, or carboxyl group of the drug molecule.

[0123] The above approach is associated with several limitations. Prodrug activation can occur by enzymatic or non-enzymatic cleavage of a transient bond between the carrier and the drug molecule, or by a sequential combination of both (e.g., an enzymatic step followed by a non-enzymatic modification). In an enzyme-free in vitro environment (e.g., aqueous buffer solution), transient bonds such as esters or amides may undergo hydrolysis, but the corresponding hydrolysis rates are outside the therapeutically useful range. In contrast, in an in vivo environment, esterases or amidases are typically present, and esterases and amidases significantly increase the reaction rate of hydrolysis by two to several orders of magnitude. This can lead to catalytic acceleration (e.g., Greenwald et al., (1999) J Med Chem 42(18):3857-67).

[0124] As described herein, prodrugs are i) biological precursors and ii) carriers. It can be classified as a prodrug. The biological precursor does not contain a carrier group and is activated by the metabolic production of a functional group. In contrast, in a carrier-bound prodrug, the active substance is bound to the carrier moiety via transient bonding at the functional group of the biologically active substance. Preferred functional groups are hydroxyl or amino groups. Both the bonding chemistry and hydrolysis conditions depend on the type of functional group used. The carrier may be biologically inert (e.g., PEG), or The prodrug may also have targeting properties (e.g., antibodies). Cleavage of the carrier portion of the carrier-bound prodrug yields the desired bioactive substance, and the properties of the deprotected functional groups of the bioactive substance often contribute to its bioactivity.

[0125] Patents and scientific literature describe many polymeric prodrugs in which the transient bond is an unstable ester bond. In these cases, the functional group of the bioactive substance is either a hydroxyl group or a carboxylic acid (see, for example, Cheng et al. (2003) BioconjugateChem 14:1007-17). Furthermore, biomacromolecules and certain small molecule drugs often bind a carrier to the amino group of the bioactive substance (e.g., the N-terminus of a protein or a lysine amino group). This is often advantageous. During the preparation of prodrugs, amino groups can be handled more chemoselectively than hydroxyl or phenol groups due to their greater nucleophilicity. This is particularly relevant to proteins and peptides containing a wide variety of different reactive functional groups, where nonselective binding reactions result in an undesirable mixture of products requiring extensive characterization or purification, thus reducing the reaction yield and therapeutic efficiency of the active ingredient.

[0126] Generally, amide bonds are more stable to hydrolysis than ester bonds, and the cleavage rate of amide bonds may be too slow for therapeutic utility in carrier-bound prodrugs. Therefore, it may be advantageous to add structural chemical components to control the cleavage potential of prodrug amide bonds. These additional cleavage-controlling chemical components, not provided by the carrier itself or the drug, are commonly called "linkers." Prodrug linkers can significantly influence the hydrolysis rate of the transient bond, and changes in the chemical properties of the linker often result in specific characteristics. Prodrug activation of an amine-containing bioactive moiety by a specific enzyme for targeted release requires the linker structure to exhibit a structural motif recognized as a substrate by the corresponding endogenous enzyme. In these cases, cleavage of the transient bond occurs in a one-step process catalyzed by the enzyme. For example, the enzymatic release of cytarabine is carried out by relatively high levels of protease plasmin in various types of tumor masses.

[0127] Inter-patient variability is a major drawback of dominant enzymatic cleavage. Enzyme levels may differ significantly among subjects, leading to biological variability in prodrug activation by enzymatic cleavage. Enzyme levels can also vary depending on the administration site (e.g., in the case of subcutaneous injection, depending on the body). (The region yields more predictable therapeutic effects than other regions.) Furthermore, establishing in vivo-in vitro correlations of the pharmacokinetic properties of enzyme-dependent carrier-bound prodrugs is difficult. be.

[0128] Other carrier prodrugs that utilize transient bonding to an amino group in the drug moiety are based on a cascade mechanism. Cascade cleavage is enabled by a linker compound consisting of a structural combination of a masking group and an activating group. The masking group is bonded to the activating group by a first transient bond, such as an ester or carbamate. The activating group is then bonded to the amino group of the drug molecule via a second transient bond (e.g., a carbamate). The stability or susceptibility to hydrolysis of the second transient bond depends on the presence or absence of the masking group. In the presence of the masking group, the second transient bond is very stable and unlikely to release the drug molecule at a therapeutically useful reaction rate, while in the absence of the masking group, this bond becomes very unstable, leading to rapid cleavage and release of the drug moiety.

[0129] The cleavage of the first transient bond is the rate-determining step in the cascade mechanism. The first step can induce a molecular rearrangement of the activating group (e.g., 1,6-elimination as described by Greenwald et al. (1999) JMed Chem 42:3657-67), and the rearrangement further strengthens the second transient bond. The first transient bond is destabilized, thereby inducing its cleavage. Ideally, the cleavage rate of the first transient bond is identical to the desired release rate of the drug molecule in a given therapeutic scenario. Furthermore, it is desirable that the cleavage of the second transient bond occurs substantially instantaneously after its instability has been induced by the cleavage of the first transient bond.

[0130] Another embodiment includes a polymer amino-containing prodrug based on trimethylloclactonization (see, for example, Greenwald et al. (2000) JMed Chem 43(3):457-87). In this prodrug system, the substituted o-hydroxyphenyl-dimethylpropionic acid is An ester, carbonate, or carbamate group is attached to PEG as the primary temporary bond. Then, as a second transient bond, it is attached to the amino group of the drug molecule by an amide bond. The rate-limiting step in drug release is the enzymatic cleavage of the first bond, followed by rapid amide cleavage via lactonization, releasing an aromatic lactone byproduct. Greenwald et al. The main drawback of the described prodrugs is the release of highly reactive, potentially toxic aromatic small molecule byproducts, such as quinone methides or aromatic lactones, after the cleavage of their transient bonds. These potentially toxic substances are released in a 1:1 stoichiometric ratio with the drug and can reach high in vivo concentrations.

[0131] In certain 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 achieved by using a stable bond between the polymer carrier and the activating group, which does not participate in the cascade cleavage mechanism. When the carrier does not function as a masking group and the activating group is bound to the carrier by a stable bond, the release of potentially toxic byproducts (such as the activating group) is avoided. The stable bond between the activating group and the polymer also suppresses the release of drug-linker intermediates in undefined pharmacology.

[0132] The first example of the approach described in the previous paragraph includes polymer prodrug systems based on mandelic acid activating groups (see, e.g., Shabat et al. (2004) Chem Eur J10:2626-34). In this approach, the masking group is bound to the activating group by a carbamate bond. The activating group is permanently bound to the polyacrylamide polymer via an amide bond. Following enzymatic activation of the masking group by a catalytic antibody, the masking group is cleaved by cyclization, releasing the drug. The activating group remains bound to the polyacrylamide polymer after drug release. Similar prodrug systems are based on mandelic acid activating groups and enzymatically cleavable ester-bonded masking groups (see, e.g., Lee et al. (2004) Angew Chem 116:1707-10 (See reference).

[0133] When using the linker described above, the 1,6-elimination step still generates a highly reactive aromatic intermediate. Even if the aromatic moiety remains permanently bound to the polymer carrier, potentially toxic byproducts or side reactions with immunogenic effects may occur. Therefore, it is advantageous to develop linker techniques for forming polymer prodrugs of amine-containing activators using aliphatic prodrug linkers that are not enzyme-dependent and do not generate reactive aromatic intermediates during cleavage. One such example is the tissue-type plasminogen activator and PEG5000-maleic anhydride is used for the reversible modification of the amino group in biurokinase (see, for example, Garman et al., (1987) FEBSLett 223(2):361-65). The regeneration of functional enzymes from PEG-uPA conjugates during incubation in pH 7.4 buffer by cleaving the maleamide bond follows a first-order kinetic model with a half-life of approximately 6 hours. The drawback of the maleamide bond is that... The problem lies in the lack of stability of the conjugate at lower pH values.

[0134] A further approach is N,N-bis-(2-hydroxyethyl)glycinamide (bicine) This includes linker-based PEG cascade prodrug systems (e.g., (2004) JMed Chem 47 (See 726-34). In this system, the two PEG carrier molecules are bound to the bicine molecule, which is attached to the amino group of the drug molecule, via transient binding. The first step of prodrug activation is to bind both PEG carrier molecules to the hydroxyl group of the bicine activating group. This involves enzymatic cleavage of transient binding. Different bindings between PEG and bicine result in different product development. This leads to a rapid activation reaction. The second step in prodrug activation involves the cleavage of a second transient bond, which attaches the bicin-activating group to the amino group of the drug molecule. The drawback of this system is the slow hydrolysis rate of this second transient bicin-amide bond, resulting in the release of a bicin-modified prodrug intermediate that exhibits different pharmacokinetic, immunogenicity, toxicity, and pharmacodynamic properties compared to the original parent drug molecule.

[0135] In certain embodiments, dipeptides are substrates for enzymes or biological transport systems and are therefore used in the development of prodrugs for targeted or targeted transport. Non-enzymatic pathways for dipeptide prodrug formation, i.e., the ability to undergo intramolecular cyclization to form the corresponding diketopiperazine (DKP) and release the active drug, are not clearly defined.

[0136] In some embodiments, the dipeptide is bound to the drug moiety via an ester bond, as described for the dipeptide ester of the drug paracetamol (Gomes et al. (2005) Bio & Med Chem Lett). In this case, the cyclization reaction occurs on the ester carbon atom. Nucleophilic attack of the N-terminal amine of the tide forms a tetrahedral intermediate, followed by the amine This method involves proton transfer to the leaving group oxyanion, simultaneous formation of a peptide bond, and provision of a cyclic DKP product and a free drug. While applicable to contained drugs, it was found that the corresponding dipeptide ester releases paracetamol at a much faster rate than in buffer, thus competing with enzymatic hydrolysis of the ester bond in vivo (Gomes et al. (Molecules 12 (2007) 2484-2506). Dipeptide-based drugs The sensitivity of the dipeptidase to the peptidase is due to the presence of at least one non-natural compound in the dipeptide motif. This can be addressed by incorporating a mino acid. However, endogenous enzymes capable of cleaving ester bonds are not limited to peptidases, and the enzyme dependence of such prodrug cleavage still results in unpredictable in vivo performance.

[0137] In some embodiments, enzyme dependence is intentionally manipulated in the DKP prodrug. For example, a dipeptide ester prodrug is formylated at the amino terminus of the dipeptide, and then enzymatic deformylation is used to initiate diketopiperazine formation, followed by cleavage of the ester dipeptide, and subsequently release of the drug molecule (see, for example, U.S. Patent No. 7,163,923). As a further example, octapeptides are 4 of vinblastine. -The hydroxyl group is bonded by an ester bond, and the ester bond is cleaved by DKP formation after specific enzymatic removal of the N-terminal hexapeptide (Brady et al. (2002) JMedChem 45:4706- 15).

[0138] The scope of DKP formation reactions has also been extended to amide prodrugs. For example, U.S. Patent Specification No. 5,952,294 describes diketopiper, a dipeptidylamide prodrug of cytarabine. The text describes prodrug activation using din formation. In this case, a temporary bond is formed between the carbonyl group of the dipeptide and the aromatic amino group of cytarabine. However, it appears that sustained-release effects cannot be achieved in conjugates that lack a carrier or other half-life extension moieties or functional groups.

[0139] Dipeptide prodrugs containing bioactive peptides such as GLP-1, which can release the peptide via diketopiperazine formation of dipeptide elongation, have also been described (see, for example, WO2009 / 099763). The bioactive peptide moiety may contain an additional PEG chain in one of its amino acid side chain residues to achieve an extended cycle of the bioactive peptide. However, this approach is associated with several significant drawbacks. Firstly, the PEG chain is... Secondly, the pegylated peptide must be bound to the peptide without impairing its biological activity, which can be difficult to achieve for many peptide-based bioactivators. Secondly, since the pegylated peptide itself is biologically active, the dipeptidic pro-molecule can affect the biological activity of the peptide and adversely impact its receptor binding properties.

[0140] Specific exemplary techniques that can be used with the compounds of the present invention include those developed by ProLynx (San Francisco, CA) and AscendisPharma (Palo Alto, CA). The ProLynx technology platform is pre-programmed to disconnect at different speeds. By utilizing a series of novel linkers, controlled, predictable, and sustained release of small molecules and peptides from circulating semi-solid polymer conjugates is enabled. This technology allows for the maintenance of steady-state serum levels of desired therapeutic agents over weeks to months.

[0141] The Ascendis technology platform combines the advantages of prodrugs and sustained-release technologies to enhance the properties of small molecules and peptides. During circulation, the rightsed prodrug releases the unmodified active parent therapeutic agent at a predetermined rate governed by physiological pH and temperature conditions. Since the therapeutic agent is released in its unmodified form, it retains its original mechanism of action.

[0142] Modifications to enhance the properties of inhibitors Improving one or more physical properties of the therapeutic modes disclosed herein and / or the modes in which they are applied is often beneficial, and sometimes essential. Improvements to physical properties include, for example, increasing water solubility, bioavailability, serum half-life, and / or therapeutic half-life. Methods for causing and / or regulating biological activity are mentioned.

[0143] Modifications known in this field include pegylation, Fc fusion, and albumin fusion. While generally associated with large molecule drugs (e.g., polypeptides), such modifications have recently been evaluated for specific small molecules. For example, see Chiang, M. et al. (J. Am. Chem. Soc., 2014, 136) (9):3370-73) describes a small molecule agonist of the adenosine 2α receptor bound to the immunoglobulin Fc domain. The small molecule Fc conjugate maintains a strong interaction between the Fc receptor and the adenosine 2α receptor and exhibits superior properties compared to the unbound small molecule. Covalent binding of PEG molecules to small molecule therapeutics is also described (Li, W. et al., Progressin Polymer Science). (2013 38:421-44).

[0144] Other known modifications include deuteration to improve pharmacokinetics, pharmacokinetics, and toxicity profiles. Due to the large atomic mass of deuterium, carbon- Breaking a deuterium bond requires more energy than breaking a carbon-hydrogen bond. These strong bonds are more difficult to break, so the rate of drug metabolism is slower compared to the undeuterated form, which can lead to fewer doses and further reduced toxicity (Charles Schmidt, Nature Biotechnology, 2017, 35(6):493-494; Harbeson, S. and Tung, R., MedchemNews, 2014(2):8-22).

[0145] Therapeutic and prophylactic use The present invention relates to the treatment or prevention of a wide range of diseases, disorders and / or conditions and / or symptoms thereof, as described herein. 2A R / A 2B The use of R inhibitors is intended. The following describes specific applications. While we will explain in detail below, please understand that the present invention is not limited thereto. Furthermore, while general categories of specific diseases, disorders, and conditions are described below, some diseases, disorders, and conditions may be components of more than one category, and others are not disclosed. It may not be a component of any of the categories being considered.

[0146] In some embodiments, the diseases, disorders and / or conditions described herein are at least Partially, adenosine A 2A Receptor (A 2A Mediated by R) in some embodiments Therefore, the diseases, disorders and / or conditions described herein are at least in part due to adenosine A 2B Receptor (A 2B In some embodiments, the diseases, disorders and / or conditions described herein are mediated by R). 2A R and A 2B Mediated by both R ru.

[0147] In some embodiments, A as described herein 2A R / A 2B R inhibitors are, 2A R-mediated immunosuppression It is administered in a dose effective in reversing or halting the progression of the disease.

[0148] Tumor-related disorders According to the present invention, A 2A R / A 2B R inhibitors are used to treat cancers such as uterine, cervical, breast, and prostate cancers. The present invention may be used to treat or prevent proliferative conditions or disorders, including cancers of the testes, gastrointestinal tract (e.g., esophagus, oral pharynx, stomach, small or large intestine, colon or rectum), kidneys, kidney cells, bladder, bone, bone marrow, skin, head and neck, liver, gallbladder, heart, lungs, pancreas, salivary glands, adrenal glands, thyroid gland, brain (e.g., glioma), ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and hematopoietic and immune systems (e.g., 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, quiescent tumors, virus-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma and papillomavirus), adenocarcinoma, lymphoma, carcinoma, melanoma, leukemia, myeloma, sarcoma, teratoma, chemically induced cancer, metastasis and angiogenesis. The present invention relates, for example, to regulatory T cells and / or CD8+ T cells. The aim is to reduce resistance to tumor cells or cancer cell antigens by regulating cell activity (e.g., Ramirez-Montagut et al. (2003) Oncogene 22:3180-87; and Sawaya et al. (2003) NewEngl. J. Med. 349:1501-09). In certain embodiments, the tumor or cancer is These include colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. The use of the term cancer-related diseases, disorders, and conditions is intended to broadly refer to conditions directly or indirectly related to cancer, including, for example, precancerous conditions such as angiogenesis and dysplasia.

[0149] In certain embodiments, cancer may be metastatic or at risk of becoming metastatic, or may be present in radiating tissues, and may include cancers of the blood or bone marrow (e.g., leukemia). In some further embodiments, the compounds of the present invention are used to overcome T cell resistance. It can be used.

[0150] In some embodiments, the present invention is A 2A R / A 2BThe present invention provides a method for treating a proliferative state, cancer, tumor, or precancerous condition using an R inhibitor and at least one additional therapeutic or diagnostic agent (examples of which are described elsewhere in this specification).

[0151] Immune and inflammation-related disorders When used herein, terms such as “immune disease,” “immune state,” “immune disorder,” “inflammatory disease,” “inflammatory state,” and “inflammatory disorder” are used in accordance with the A definitions set forth herein. 2A R / A 2B R-blocking The term is intended to broadly encompass immune-related conditions (e.g., autoimmune diseases) or disorders that have inflammatory components that can be treated with harmful agents, thereby providing some therapeutic benefit. Such conditions are often closely intertwined with other diseases, disorders, and conditions. For example, "immune conditions" can refer to proliferative conditions such as cancer, tumors, and angiogenesis. This includes (acute and chronic) infections, tumors, and cancers that are resistant to curative treatment by the immune system.

[0152] A of the present invention 2A R / A 2B R inhibitors increase or enhance the immune response, thereby increasing the effectiveness of the vaccine. It can be used to improve vaccinations, including those that enhance inflammation, and to increase inflammation. Immunodeficiency associated with immunodeficiency diseases, immunosuppressive therapy, acute and / or chronic infections, and aging. This can be treated using the compounds disclosed herein. 2A R / A 2B R inhibitors also It can be used to stimulate the immune system of patients suffering from iatrogenically induced immunosuppression, including those who have undergone bone marrow transplantation, chemotherapy, or radiotherapy.

[0153] In certain embodiments of this disclosure, A 2A R / A 2B R inhibitors provide adjuvant activity. It is used to increase or enhance the immune response to an antigen. In certain embodiments, at least one antigen or vaccine is used to increase or enhance the immune response to the antigen or vaccine. To extend the answer, at least one A of the present invention 2A R / A 2B It is administered to the target in combination with an R inhibitor. While not limited to, it may include at least one antigen or vaccine, including viruses, bacteria and fungi, or parts thereof, proteins, peptides, tumor-specific antigens and nucleic acid vaccines. The tin component is part of at least one A of the present invention. 2A R / A 2B Therapeutic compositions containing an R inhibitor in combination are also provided.

[0154] An unspecified list of immune and inflammation-related diseases, disorders, and conditions that can be treated or prevented with the compounds and compositions of the present invention includes arthritis (e.g., rheumatoid arthritis), renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., when 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 stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), allergic contact dermatitis and other eczema, systemic sclerosis, transplantation, and multiple sclerosis.

[0155] Among other immune-related disorders, A 2A R / A 2B Inhibition of R function leads to immunological tolerance and fetal development in the womb. It is also conceivable that this could play a role in preventing rejection.

[0156] In some embodiments, A described herein 2A R / A 2B R inhibitors are immune effectors - It can be combined with immunosuppressants to reduce the number of cells.

[0157] A2A R / A 2B The aforementioned R inhibitors may be particularly effective (for example, due to limitations of current treatments). Some of the diseases, disorders, and conditions are described in more detail below.

[0158] Rheumatoid arthritis (RA), generally characterized by chronic inflammation in the synovial membrane (the inner layer of the joints), affects approximately 1% of the US population (about 2.1 million people). It involves TNF-α and IL-1 in the inflammatory process. Further understanding of the role of cytokines will lead to new developments in disease-modifying anti-rheumatic drugs (DMARDs). This has enabled the development and introduction of a new class of drugs. These include ENBREL (etanercept), REMICADE (infliximab), HUMIRA (adalimumab), and KINERET (anakinra), some of which overlap with treatments for RA. Some of these drugs alleviate symptoms. While it inhibits the progression of structural damage and improves physical function, particularly in patient populations, alternative drugs with improved efficacy, complementary mechanisms of action, and fewer / milder side effects still exist. It is needed as such.

[0159] Psoriasis, a common group of immune-mediated chronic skin diseases, affects more than 4.5 million people in the United States. The disease has developed, and it is estimated that 1.5 million of those affected have moderate to severe symptoms. Furthermore, more than 10% of psoriasis patients develop psoriatic arthritis, which damages the bone and connective tissue around the joints. A better understanding of the underlying physiological functions of psoriasis has led to the introduction of drugs that target the activity of T lymphocytes and cytokines, which are the inflammatory causes of the disease. Examples of such drugs include TNF-α inhibitors (which are also used to treat rheumatoid arthritis (RA), and include ENBREL (etanercept), REMICADE (infliximab), and HUMIRA (adalimumab)), and T-cell inhibitors such as AMEVIVE (alephate) and Rapiva (efalizumab). While some of these drugs are somewhat effective in certain patient populations, they have not been shown to effectively treat all patients.

[0160] Microbial-related disorders This invention is A 2A R / A 2B Treatment with R inhibitors may be beneficial for any viral or bacterial infection. In the treatment and / or prevention of fungal, parasitic, or other infectious diseases, disorders, or conditions, this purpose A as described in the details 2A R / A 2B The use of R inhibitors is planned.

[0161] Examples of viral diseases, disorders, and conditions to be considered include, but are not limited to, B Hepatitis B1 virus (HBV), Hepatitis C virus (HCV), Human papillomavirus (HPV), HIV, AIDS (including symptoms such as cachexia, dementia, and diarrhea), Herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, coxsackie virus Examples include viruses and cytomegalovirus (CMV).

[0162] Further examples of such diseases include staphylococcal and streptococcal infections (e.g., Staphylococcus aureus and Streptococcus sangnis, respectively), leishmania, toxoplasmosis, trichomoniasis, giardiasis, candida albicans, anthrax, and Pseudomonas aeruginosa. In some embodiments, the disease or disorder may be a mycobacterium infection (e.g., Mycobacterium repei or Mycobacterium tuberculosis) or an infection caused by Listeria monocytogenes or Toxoplasma gondii. The compounds of the present invention can be used to treat sepsis, reduce or inhibit bacterial growth, and reduce or inhibit inflammatory cytokines.

[0163] Further embodiments include, but are not limited to, Donovan's Leishmania (Leishmania donovani), tropical Leishmania (Leishmania tropica), and large Leishmania (Lei Leishmania major, Leishmania aethiopica, Mexican Leishmania Leishmaniamexicana, Plasmodium falciparum (Plasmodium falciparum) The treatment aims to eliminate parasitic infections, including those caused by Plasmodium vivax, Plasmodium ovale, or Plasmodium malariae. Often, antiparasitic therapy is administered prophylactically (for example, before the subject moves to an area with a high incidence of parasitic infection).

[0164] CNS-related and neurological disorders A 2A R / A 2B Inhibition of R also affects the nervous system, including impairments related to cognitive and motor function. This can be an important treatment strategy for patients with other neuropsychiatric, neurodegenerative, or central nervous system-related diseases, disorders, and conditions. Examples include Parkinson's disease, extrapyramidal syndrome (EPS), extrapyramidal syndrome (EPS), dystonia, stranding syndrome, tardive dyskinesia, restless limb syndrome (RLS), epilepsy, periodic limb movement during sleep (PLMS), and attention deficit disorder. These include cerebral infarction, depression, anxiety, dementia, Alzheimer's disease, Huntington's disease, multiple sclerosis, cerebral ischemia, hemorrhagic stroke, subarachnoid hemorrhage, and traumatic brain injury.

[0165] Subjects suffering from multiple sclerosis (MS), a severe debilitating autoimmune disease involving multiple areas of myelin inflammation and scarring in the brain and spinal cord, are subject to the A treatment described herein, as current treatments only alleviate symptoms or slow the progression of the disability. 2A R / A 2B R inhibitors are particularly helpful It is possible to do so.

[0166] Similarly, A 2A R / A 2B R inhibitors are used to treat brain diseases that significantly impair patients' thinking, memory, and language processes. The subjects are those suffering from Alzheimer's disease (AD), and neurodegenerative diseases such as Parkinson's disease (PD), which is a progressive disorder of the central nervous system characterized by abnormal movement, rigidity, and tremor. This can be particularly advantageous for them. These disorders are progressive, debilitating, and there is no cure.

[0167] Other disabilities Embodiments of the present invention are at least some level A 2A R / A 2B Benefiting from R inhibition For the treatment or prevention of other disorders that can be caused, as described herein. 2A R / A 2B Targeting R inhibitors The administration of the drug is intended. Such diseases, disorders and conditions include, for example, cardiovascular (e.g., cardiac ischemia), gastrointestinal (e.g., Crohn's disease), metabolic (e.g., diabetes), liver (e.g., hepatic fibrosis, NASH and NAFLD), lung (e.g., COPD and asthma), and eye diseases (e.g., diabetic dysplasia). These include retinopathy and kidney damage (e.g., renal failure).

[0168] Pharmaceutical composition A of the present invention 2A R / A 2B R inhibitors can be in the form of a composition suitable for administration to the target. Generally, such compositions are A 2A R / A 2B A "pharmaceutical composition" comprising an R inhibitor and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers, or excipients. In certain embodiments, A 2A R / A 2B R inhibitors are present in therapeutically acceptable amounts. The pharmaceutical composition It can be used in the methods of the present invention. Therefore, for example, the pharmaceutical composition can be administered to a subject ex vivo or in vivo to carry out the therapeutic and preventive methods and uses described herein.

[0169] The pharmaceutical compositions of the present invention can be formulated to suit an intended method or route of administration. Exemplary routes of administration are described herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds described herein to treat or prevent the diseases, disorders and conditions targeted by the present invention.

[0170] Active ingredient (for example, A 2A R / A 2B A pharmaceutical composition containing an inhibitor of R function is suitable for oral use. Pharmaceutical compositions may be in the form of tablets, capsules, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives. This allows for the provision of formulations that are elegant and palatable. Tablets, capsules, etc., contain the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may include, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as gelatin or acacia; and lubricants such as magnesium stearate, stearic acid, or talc.

[0171] Tablets, capsules, etc., suitable for oral administration do not need to be coated, or They may be coated by known techniques, thereby delaying disintegration and absorption in the gastrointestinal tract and providing a sustained effect. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used. These can also be coated by techniques known in the art to form permeable therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or polymers, such as polyester, polyamine acid, hydrogel, polyvinylpyrrolidone, polyacid anhydride, polyglycolic acid, ethylene-vinyl acetate, and methyl Cellulose, carboxymethylcellulose, protamine sulfate, or lactide / glycolide Copolymer, polylactide / glycolide copolymer, or ethylene vinyl acetate copolymer Examples include microcapsules, which allow for control over the delivery of the administered composition. For example, oral formulations may be delivered using coacervation technology or interfacial polymerization, hydroxymethylcellulose or gelatin microcapsules, or poly(methyl methacrylate) microcapsules. Each formulation can be used or encapsulated in microcapsules prepared in a colloidal drug delivery system. Examples of colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads, and lipid-based systems, and include oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the above formulations will be obvious to those skilled in the art.

[0172] Formulations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0173] The aqueous suspension contains the active material as a mixture with excipients suitable for its preparation. Such excipients may be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersants or wetting agents, such as naturally derived phosphatides (e.g., lecithin); or condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate); or condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol); or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives.

[0174] The oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspension may contain a thickener, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings as described above can be added to provide an oral formulation with a pleasant mouthfeel.

[0175] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients as mixtures of a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspension agents are exemplified herein.

[0176] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as acacia gum or tragacanth gum; naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydride, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyglycerides. It can be ethylene sorbitan monooleate.

[0177] A pharmaceutical composition typically contains a therapeutically effective amount of A as intended by the present invention. 2A R / A 2B R inhibitors and one or more pharmaceutically and physiologically acceptable combination preparations. Examples of pharmaceutically acceptable diluents, carriers, or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl p-hydroxybenzoate, or n-propyl), emulsifiers, suspending agents, dispersants, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be physiological saline or citrate-buffered saline, which may be supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize the various buffers that may be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffering component can be a water-soluble material such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and their salts. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), and 2-(N-morpholino)ethane. Sulfonic acid (MES), 2-(N-morpholino)ethanesulfonate sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-A Minopropanesulfonic acid (TAPS) is one example.

[0178] After formulation, pharmaceutical compositions can be stored in sterile vials as solutions, suspensions, gels, emulsions, solids, or dehydrated or lyophilized powders. Such formulations can be stored in any of the following forms: ready-to-use, lyophilized, requiring reconstitution before use, liquid, or other acceptable forms. In some embodiments, pharmaceutical compositions are provided in single-use containers (e.g., single-use vials, ampoules, syringes, or auto-injectors (e.g., similar to EpiPen®)), while multi-use containers (e.g., multi-use vials) are provided in other embodiments.

[0179] The formulation may also include a carrier to protect the composition from rapid degradation or removal from the body, such as a controlled-release formulation, including liposomes, hydrogels, prodrugs, and microencapsulation delivery systems. For example, a time-delaying material such as glyceryl monostearate or glyceryl stearate can be used alone or in combination with a wax. Using any drug delivery device, A 2A R / A 2B To deliver R inhibitors This can include implants (e.g., implantable pumps) and catheter systems, slow infusion pumps and devices, all of which are well known to those skilled in the art.

[0180] Depot injections, which are generally administered subcutaneously or intramuscularly, also contain the A information disclosed herein for a specified period of time. 2A R / A 2B It can be used to release R inhibitors. Depot injections are usually solid or It is oil-based and generally contains at least one of the formulation components described herein. He is familiar with the use of available formulations and depot injections.

[0181] The pharmaceutical composition may be in the form of a sterile aqueous or oily suspension for injection. This suspension may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents as described herein. The sterile injection formulation may be a sterile injection solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable diluents, solvents and dispersions that may be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL (trademark) (BASF, Parsippany, NJ), or phosphoric acid solution. Swallowing saline (PBS), ethanol, polyols (e.g., glycerol, propylene Examples include glycols and liquid polyethylene glycol, and suitable mixtures thereof. Furthermore, sterile non-volatile oils have conventionally been used as solvents or suspensions. For this purpose, any non-irritating fixative oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid find applications in the preparation of injectable formulations. Sustained absorption of certain injectable formulations can be achieved by including absorption-delaying agents (e.g., aluminum monostearate or gelatin).

[0182] This invention relates to a suppository form for rectal administration. 2A R / A 2B We are planning to administer an R inhibitor. The preparation can be made by mixing a drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus dissolves in the rectum to release the drug. Examples of such materials, though not limited to them, include cocoa butter and polyethylene glycol.

[0183] A intended by the present invention 2A R / A 2B R inhibitors are currently known or will be developed in the future. It may be in the form of any other suitable pharmaceutical composition (e.g., a spray for nasal or inhalation use).

[0184] Route of administration This invention is A 2A R / A 2B The administration of R inhibitors and their compositions is to be attempted in any appropriate manner. Appropriate routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracapsular, intra-articular, intraperitoneal, intracerebral (intraparenchymal) and intraventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., perdermal), buccal and inhalation. Depot injections, generally administered subcutaneously or intramuscularly, are also available for administration over a specified period of time as disclosed herein. 2A R / A 2B It can be used to release R inhibitors.

[0185] Certain embodiments of the present invention are intended for oral administration.

[0186] Combination therapy This invention is A 2A R / A 2B The R inhibitor is intended for use alone or in combination with one or more active therapeutic agents. Additional active therapeutic agents include small chemical molecules, proteins, antibodies, peptide bodies, peptides, and DNA. , macromolecules such as RNA or fragments of such macromolecules, or in cell therapy or gene therapy It is possible. In such combination therapies, various active agents often have different complementary mechanisms of action. Such combination therapies allow for a reduction in the dose of one or more drugs. This reduces or eliminates adverse effects associated with one or more drugs. This may be advantageous. Furthermore, such combination therapies may have a synergistic therapeutic or preventive effect on the underlying disease, disorder, or condition.

[0187] As used herein, “combination” includes therapies that may be administered separately and may be formulated separately for separate administrations (e.g., as may be provided in a kit), and therapies that may be administered together in a single formulation (i.e., a “co-prescription”).

[0188] In a particular embodiment, A 2A R / A 2B R inhibitors are, for example, drugs that contain one or more other drugs. When administered before the agent, it is administered or applied sequentially. In other embodiments, A 2A R / A 2B R inhibitors, for example, when two or more drugs are administered simultaneously, are administered at the same time, and two The above drugs may be present in two or more separate formulations, or in a single formulation (i.e., May be combined in a co-prescription. Two or more drugs may be administered sequentially or simultaneously. Regardless of whether they are administered separately, they are considered to be administered in combination for the purposes of the present invention.

[0189] A of the present invention 2A R / A 2B R inhibitors are administered in any manner appropriate to the situation, along with at least one other (active) ) Can be used in combination with drugs. In one embodiment, at least one The active agent and at least one A of the present invention 2A R / A 2B Treatment with an R inhibitor is maintained over a period of time. In another embodiment, A of the present invention 2A R / A 2B Treatment with R inhibitors involves a certain amount of medication. While the regimen is being maintained, treatment with at least one activator is reduced or discontinued. (For example, when the object is stable). In a further embodiment, the present invention A 2A R / A 2B While treatment with R inhibitors is reduced (e.g., lower dose, lower frequency or (A shorter treatment regimen), treatment with at least one activator is reduced or discontinued (for example) (If the target is stable). In yet another embodiment, at least one active agent Treatment with the agent may be reduced or discontinued (for example, if the subject is stable), and according to the present invention, A 2A R / A 2B Treatment with R inhibitors will increase (e.g., higher doses, more frequent administration or (Longer treatment regimens). In yet another embodiment, at least one active agent The treatment is maintained, and the present invention A 2A R / A 2B Treatment with R inhibitors is reduced or discontinued (e.g.) For example, lower doses, lower frequency administration, or shorter treatment regimens. In yet another embodiment, treatment with at least one active agent and A of the present invention. 2A R / A 2B Treatment with R inhibitors is reduced or discontinued (e.g., lower dose, less frequent administration, or shorter treatment regimen).

[0190] Tumor-related disorders This invention is A 2A R / A 2B The present invention provides a method for treating and / or preventing a proliferative state, cancer, tumor, or precancerous disease, disorder, or condition using an R inhibitor and at least one further therapeutic or diagnostic agent. In some embodiments, the additional therapeutic or diagnostic agent is a radioactive, immunomodulatory, or chemotherapeutic agent, or a diagnostic agent. Suitable immunomodulatory agents that may be used in the present invention include CD4OL, B7 and B7RP1, anti-CD40, anti-CD38, anti-ICOS and 4-1BB ligands, and other stimulating receptors. Activated monoclonal antibodies (mAbs) against dendritic cells, dendritic cell antigen loading (in vitro or Examples include in vivo anticancer vaccines such as dendritic cell carcinoma vaccines, cytokines / chemokines such as ILL IL2, IL12, IL18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / β, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10, bacterial lipopolysaccharides (LPS), indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, and immunostimulatory oligonucleotides. It can be done.

[0191] In one embodiment, the present invention, in combination with a signaling inhibitor (STI), as described herein, achieves additive or synergistic inhibition of tumor growth. 2A R / A 2B The present invention provides a method for suppressing tumor growth, comprising administering an R inhibitor. When used herein, the term "signaling inhibitor" means selectively inhibiting one or more steps in a signaling pathway. This refers to drugs that inhibit signal transduction. Examples of signal transduction inhibitors (STIs) of the present invention include (i) bcr / abl (ii) Epidermal growth factors including kinase inhibitors (e.g., GLEEVEC), kinase inhibitors and antibodies (EGF) receptor inhibitors, (iii) HER-2 / neu receptor inhibitors (e.g., HERCEPTIN), (iv) Akt family kinase or Akt pathway inhibitors (e.g., rapamycin), (v) Examples include (vi) cyst cycle kinase inhibitors (e.g., flavopyridol) and phosphatidylinositol kinase inhibitors. Immunomodulatory agents are also used to suppress tumor growth in cancer patients as described herein. 2A R / A 2B It can be used in combination with R inhibitors. ru.

[0192] Examples of chemotherapeutic agents, though not limited to these, include alkylating agents such as thiotepa and cyclophosphamide, alkyl sulfonates such as busulfan, improsulfan and piposulfan, aziridines such as benzodopa, carbocone, metredopa and uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine, ethyleneimines and methylamines, thiorambucil, chlornafadin, chlorophosphamide, estramustine, ifosphamide, mechloretamine, mechloretamine oxide hydrochloride, and melphalan. Nitrosoureas such as nobembitin, fenestrine, prednimystine, troposphamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, acrasinomycin, actinomycin, outramycin, azaserin, bleomycin, kakutinomycin, calichemycin, carabicin, kaminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, deorubicin, 6-diazo-5-oxo-L-norleucine, doxo Antibiotics such as rubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, and surubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; and fludarabi Purine analogs such as 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, phloxuridine, and 5-FU; androgens such as carotestron, dromostanolone propionate, epithiostanol, metipithiostan, and testactone; anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; acegraton and aldofamide glycosylation. D, aminolevulinic acid, amsacrine, bestlovesil, bisanthrene, edatrexate, defofamin, demecolsin, diazinon, erlothimicin, erliptinium acetate, etoglucide, gallium nitrate, hydroxyurea, lentinan, ronidamin, mitoglucon, mitoxantrone, mopidamol, nitracrine, pentostatin, fenameto, pirarubicin, podophyllic acid, 2-ethylhydrazide, procarbazine, razoxane, schizophyllan, spirogermanium, tenuazonic acid, triazicnon, 2,2',2"-tri Chlorotriethylamine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitractol, pipobromane, gasitosine, arabinoside (Ara-C), Cyclophosphamide, thiotepa, taxoids, e.g., paclitaxel and docetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum and platinum-coordinated complexes, e.g., cisplatin, carboplatin and oxaliplatin, vinblastine, etoposide (VP-16), ifosfamide, mitomycin C, mitoxantrone, vincristine, vinorelbine, navelbine, novantrone, teniposide, daunomycin, aminopterin, xeloda, ibandronate, CPT11, topoisomer Examples include enzyme inhibitors, difluoromethylornithine (DMFO), retinoic acid, esperamicin, capecitabine, anthracyclines, and any pharmaceutically acceptable salts, acids, or derivatives of the above.

[0193] Other chemotherapeutic agents include tamoxifen, raloxifen, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxoxin, keoxyfen, Examples include anti-hormone agents that act to modulate or inhibit the hormonal effects on tumors, such as anti-estrogens including onapristone and toremifene, and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin, and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy comprises a chemotherapy regimen comprising one or more chemotherapeutic agents. In certain embodiments, Oral therapy includes the administration of hormones or related hormonal agents.

[0194] A 2A R / A 2B Further treatment options that can be used in combination with R inhibitors include radiotherapy. monoclonal antibodies against tumor antigens, complexes of monoclonal antibodies and toxins, T cells TLR agonis used as an adjuvant, in bone marrow transplantation, or to stimulate antigen-presenting cells. Examples include cell-presenting cells (e.g., dendritic cell therapy), which include [specific cells].

[0195] In certain embodiments, the present invention intends to use the compounds described herein in combination with adoptive cell therapy, a novel and promising form of personalized immunotherapy in which immune cells having antitumor activity are administered to cancer patients. Adoptive cell therapy involves tumor-infiltrating phosphate cells engineered to express, for example, chimeric antigen receptors (CARs) or T cell receptors (TCRs). This is being explored using pocytes (TILs) and T cells. Adoptive cell therapy generally involves the development of T cells from an individual. This involves collecting cells, genetically modifying them to target specific antigens, or enhancing their antitumor effects, amplifying them to a sufficient number, and injecting the genetically modified T cells into cancer patients. T cells are collected from patients whose expanded cells are later reinjected (e.g., autologous). It can be collected from donor patients (e.g., allogeneic individuals).

[0196] In certain embodiments, the present invention combines a therapy based on RNA interference that suppresses gene expression with a therapy based on RNA interference. In addition, the use of the compounds described herein is intended. RNAi compresses long double-stranded RNA into smaller units. It begins with cleaving into interfering RNA (siRNA). One strand of siRNA is RNA-induced silence It is incorporated into a ribonucleoprotein complex known as the RISC complex, which is then used to identify mRNA molecules that are at least partially complementary to the incorporated siRNA chain. RISC can either bind to or cleave mRNA, both of which inhibit translation.

[0197] Immune checkpoint inhibitors The present invention, in combination with an immune checkpoint inhibitor, is described herein as A 2A R / A2B R The use of inhibitors of the function is planned.

[0198] The vast number of genetic and epigenetic alterations characteristic of all cancers provide the immune system with a diverse range of antigens that it can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the final amplitude of the response (e.g., cytocytocytosis) is initiated by antigen recognition by the T cell receptor (TCR). The level (or proliferation) and quality (e.g., the type of immune response produced, such as the pattern of cytokine production) of immune checkpoints are regulated by the balance between co-stimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are important for preventing autoimmunity (i.e., maintaining self-tolerance) and for protecting tissues from damage when the immune system is responding to pathogen infection. The expression of immune checkpoint proteins can be dysregulated by tumors as an important immune resistance mechanism.

[0199] T cells possess several advantages: i) their ability to selectively recognize peptides derived from proteins in all cellular compartments; ii) their ability to directly recognize and kill antigen-expressing cells (by CD8+ effector T cells, also known as cytotoxic T lymphocytes (CTLs)); and iii) the diversification of CD4+ helper T cells by integrating adaptive and innate effector mechanisms. Due to its ability to modulate immune responses, endogenous antitumor immunity has been a major focus of efforts to therapeutically manipulate it.

[0200] In clinical settings, blocking immune checkpoints that lead to amplification of antigen-specific T cell responses. Diagnosis has been shown to be a promising approach in the treatment of human cancer.

[0201] T cell-mediated immunity counteracts stimulating and inhibitory signals to optimize the response. It involves multiple sequential steps, each regulated by the process. Almost all inhibitory signals in the immune response ultimately regulate intracellular signaling pathways, many of which are initiated via membrane receptors, and their ligands are either membrane-bound or soluble (cytokines). Costimulatory and inhibitory receptors and ligands that regulate T cell activation are found in normal tissue. Compared to other factors, it is often not overexpressed in cancer, but it modulates T cell effector function. Inhibitory ligands and receptors are commonly overexpressed on tumor cells or on non-transformed cells associated with the tumor microenvironment. Soluble and membrane-bound receptor-ligand immunocheckpoints The function of the inhibitor is either an agonist antibody (due to the co-stimulatory pathway) or an antagonist antibody (due to the inhibitory pathway). It can be regulated using (for the pathway). Therefore, in contrast to most antibodies currently approved for cancer treatment, antibodies that block immune checkpoints do not directly target tumor cells, but rather target lymphocyte receptors or their ligands to enhance endogenous antitumor activity [Pardoll, (April 2012) Nature Rev. Cancer 12 See pages 252-64.

[0202] Examples of immune checkpoints (ligands and receptors) that are selectively upregulated in various types of tumor cells, some of which are candidates for blockade, include PD1 (programmed cell death protein 1), PDL1 (PD1 ligand), and BTLA (B and T lymphocytes). Atenuators), CTLA4 (cytotoxic T lymphocyte-associated antigen 4), TIM3 (T cell membrane protein 3), LAG3 (lymphocyte activation gene 3), TIGIT (T cell immune receptor having Ig and ITIM domains), and i) killer cell immunoglobulin-like receptors (KIRs) and ii) type C receptors The tin receptor (a component of the type II transmembrane receptor family) has two structural classes. Killer inhibitor receptors can be distinguished by their characteristics. Other less well-defined immune checkpoints include both receptors (e.g., the 2B4 receptor, also known as CD244) and ligands (e.g., specific B7 family inhibitory ligands such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)), as described in the literature [Pardoll, (April 2012) Nature Rev. Cancer 12]. See pages 252-64.

[0203] The present invention, in combination with the above-mentioned immune checkpoint receptor and ligand inhibitors and immune checkpoint receptor and ligands not described herein, is described in the A 2A R / A 2B The use of R-function inhibitors is intended for specific modules of immune checkpoints. While the PTLA4 is currently available, others are in late-stage development. To illustrate, when the treatment for melanoma was approved in 2011, the fully humanized CTLA4 monoclonal antibody PTLA4 was available. Limumab (YERVOY; Bristol-Myers Squibb) was the first immunotherapy to receive regulatory approval in the United States. It became a checkpoint inhibitor. Fusion proteins containing CTLA4 and antibodies (CTLA4-Ig; abatcept (ORENCIA; Bristol-MyersSquibb)) are used in the treatment of rheumatoid arthritis, and other The fusion protein has been shown to be effective in kidney transplant patients and sensitizes them to the Epstein-Barr virus. PD1 antibodies are under development (e.g., nivolumab (Bristol-Myers Squibb) and lambrolizumab (Merck)), and anti-PDL1 antibodies are also being developed. It has been evaluated (e.g., MPDL3280A (Roche)). Nivolumab has shown promise in patients with melanoma, lung, and kidney cancer.

[0204] In one aspect of the present invention, claimed A 2A R / A 2B R inhibitors are (i) irritant (co-stinging) (ii) Receptor agonists (including highly reactive ones), or (ii) Inhibitory agents on T cells (including co-inhibitory ones). These are combined with immunotumor agents that are signaling antagonists, and both amplify antigen-specific T cell responses. Certain stimulant and inhibitory molecules belong to the immunoglobulin superfamily. It is a component of (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory 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. Co-stimulatory or Another family of membrane-bound ligands that bind to co-inhibitory receptors includes CD40 and CD4OL, OX-40, OX-40L, CD70, CD27L, CD30, CD3OL, 4-1BBL, CD137(4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, and BA. Congeneral TNF receptors including FFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT13R, LIGHT, DcR3, HVEM, VEGI / TLL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin a / TNF13, TNFR2, TNFa, LT13R, lymphotoxin a1132, FAS, FASL, RELT, DR6, TROY, and NGFR It is a TNF family molecule that binds to the components of the TNF family.

[0205] In another embodiment, immunotumor agents are cytokines that stimulate T cell activation (e.g., IL-6) These are cytokines that stimulate T cell activation to stimulate an immune response (such as IL-10, TGF-B, VEGF, and other immunosuppressive cytokines).

[0206] In one embodiment, the T cell response is disclosed A 2A R / A 2B R inhibitors and (i) T cell activation Protein antagonists that inhibit (e.g., immune checkpoint inhibitors), e.g., CTAC-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and (ii) TIM-4 and / or (ii) agonists of proteins that stimulate T cell activation, e.g., B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX4OL, GITR, GITRL, It can be stimulated in combination with one or more of the following: CD70, CD27, CD40, DR3, and CD2. Cancer treatment For the present invention A 2A R / A 2B Other drugs that can be combined with R inhibitors include NK cell inhibitors. Examples include antagonists of inhibitory receptors on cells, or agonists of activating receptors on NK cells. For example, the compounds herein are antagonists of KIRs, such as liri It can be used in combination with lumab.

[0207] Further drugs for combination therapy include, but are not limited to, drugs that inhibit or deplete macrophages or monocytes, including CSF-1R antagonists, and CSF-1R antagonist antibodies including RG7155 (W011 / 70024, WO11 / 107553, WO11 / 131407, W013 / 87699, W013 / 119716, W013 / 132044) or FPA-008 (W011 / 140249; W013169264; W014 / 036357). include.

[0208] In another embodiment, disclosed A 2A R / A 2B R inhibitors link to positive co-stimulatory receptors. Agonists, inhibitory receptor-mediated signaling blockers, antagonists, and one or more agents that systemically increase the frequency of antitumor T cells, overcoming distinct immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor involvement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab)) or by ex vivo anti-CD25 bead depletion), or T cell It can be used in conjunction with drugs that reverse / prevent cystic anergy or fatigue, and drugs that activate innate immunity and / or cause inflammation at the tumor site.

[0209] In one embodiment, the immunotumor agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0210] In another embodiment, the immunotumor agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; W02012 / 145493). Although its specificity is questionable, pizilizumab (CT-011) may also be included among immunotumors. Another approach targeting the PD-1 receptor is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1. .

[0211] In another embodiment, the immunotumor agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. A suitable PD-L1 antibody is, for example, MPDL3280A (RG7446;W02010 / 077634). Examples include duvalmab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO02013 / 79174).

[0212] In another embodiment, the immunotumor agent is a LAG-3 antagonist, such as an antagonist LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO04 / 08218), or IMP-731 or IMP-321 (W008 / 132601, W009 / 44273).

[0213] In another embodiment, the immunotumor agent is a CD137(4-1BB) agonist, for example, agonist CD137 It is an antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0214] In another embodiment, the immunotumor agent is a GITR agonist, such as an agonist GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (W006 / 105021, W009 / 009116), and MK-4166 (W011 / 028683).

[0215] In another embodiment, the immunotumor agent is an OX40 agonist, such as an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0216] In another embodiment, the immunotumor agent is an OX4OL antagonist, for example, an OX40 antagonist. It is a suitable OX4OL antagonist, for example, RG-7888 (W006 / 029879). It can be done.

[0217] In another embodiment, the immunotumor agent is a CD40 agonist, such as an agonist CD40 antibody. In yet another embodiment, the immunotumor agent is a CD40 antagonist, such as an antagonist CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0218] In another embodiment, the immunotumor agent is a CD27 agonist, such as an agonist CD27 antibody. A suitable CD27 antibody is, for example, valirumab.

[0219] In another embodiment, the immunotumor agent is MGA271 (against B7H3) (W011 / 109400).

[0220] The present invention encompasses any of the above-mentioned pharmaceutically acceptable salts, acids, or derivatives.

[0221] Metabolic and cardiovascular diseases This invention is A 2A R / A 2B Using R inhibitors and at least one additional therapeutic or diagnostic agent, certain cardiovascular and / or metabolic diseases, disorders and conditions, and related disorders can be treated. To provide methods for treatment and / or prevention.

[0222] Examples of therapeutic agents useful in combination therapy for the treatment of hypercholesterolemia (and atherosclerosis) include statins that inhibit the enzymatic synthesis of cholesterol (e.g., CRESTOR, LESCOL, LIPITOR, MEVACOR, PRAVACOL, and ZOCOR), bile acid resins that block cholesterol and inhibit its absorption (e.g., COLESTID, LO-CHOLEST, PREVALITE, QUESTRAN, and WELCHOL), ezetimibe (ZETIA) that blocks cholesterol absorption, and agents that reduce triglycerides. Examples include fibrinic acid (e.g., TRICOR) which moderately increases HDL, niacin (e.g., NIACOR) which moderately reduces LDL cholesterol and triglycerides, and combinations of the above (e.g., VYTORIN (symvastatin and ezetimibe)). 2A R / A 2B Potential alternative cholesterol treatments that could be used in combination with R inhibitors include various adjuvants and herbs (e.g., garlic, policosanol, and gugul).

[0223] The present invention encompasses any of the above-mentioned pharmaceutically acceptable salts, acids, or derivatives.

[0224] Immune and inflammation-related disorders The present invention relates to immune-related diseases, disorders and conditions, as well as diseases, disorders and conditions having inflammatory components, A 2A R / A 2B Treatment with an R inhibitor and at least one further therapeutic or diagnostic agent To provide a method for treating / preventing the disease.

[0225] Examples of therapeutic agents useful in combination therapy include, but are not limited to, the following: nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and other propionic acids. Derivatives (aluminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, cri Examples of concomitant use include danac, diclofenac, fenclofenac, fenclodic acid, fentiazac, firofenac, ibufenac, isoxepak, oxpinac, sulindac, thiopinac, tolmetine, didomethacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflamic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicam (isooxicam, pyrooxicam, sudooxicam, and tenooxicam), salicylates (acetylsalicylic acid, sulfasalazine), and pyrazolones (apazon, bezpiperilone, feprazon, mofebutazone, oxyfenbutazone, and phenylbutazone). Other concomitant use includes cyclooxygenase-2 (COX-2) inhibitors.

[0226] Other active agents for concomitant use include steroids such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, or hydrocortisone. Such concomitant use may cause one or more adverse effects of the steroid to gradually reduce the required steroid dose. This can be particularly advantageous because it can be reduced or eliminated.

[0227] For example, further examples of active agents that may be used in combination to treat rheumatoid arthritis include cytokine-suppressing anti-inflammatory drugs (CSAIDs), TNF, LT, IL-10, IL-2, IL-6, IL-7, and IL-8. , other human cytokines such as IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, or PDGF. Alternatively, antibodies or antagonists against growth factors may be used.

[0228] Certain combinations of activators can interfere with autoimmunity and the subsequent inflammatory cascade in various ways, including TNF antagonists such as chimeric, humanized or human TNF antibodies, REMICADE, anti-TNF antibody fragments (e.g., CDP870), and soluble p55 or p75 TNF receptors. Its derivatives, p75TNFRIgG (ENBREL.) or p55TNFR1gG (LENERCEPT), soluble IL-13 receptor Examples include TNFα-converting enzyme (TACE) inhibitors, and similarly, IL-1 inhibitors (e.g., interleukin-1-converting enzyme inhibitors) may also be effective. Other combinations include interleukin-11, anti-P7, and P-selectin glycoprotein ligands (PSGLs). A as described herein 2A R / A 2B Other examples of drugs useful in combination with R inhibitors include interferon-131a (AVONEX), interferon-13b (BETASERON), copaxone, hyperbaric oxygen, and intravenous immunosuppression. Examples include antibodies against epidemic globulin, clavulorbin, and other human cytokines or growth factors, or their antagonists (e.g., antibodies against CD40 ligand and CD80).

[0229] microbial disease This invention is A 2A R / A 2B R inhibitors and at least one additional therapeutic or diagnostic agent (e.g., 1 The present invention provides methods for treating and / or preventing viral, bacterial, fungal, and parasitic diseases, disorders, and conditions, as well as related disorders, using one or more other antiviral agents and / or one or more agents unrelated to viral therapy.

[0230] Such combination therapies include, but are not limited to, antiviral agents that target various stages of the viral life cycle and have different mechanisms of action, the following: These include: virus uncoating inhibitors (e.g., amantadine and rimantidine), reverse transcriptase inhibitors (e.g., acyclovir, zidovudine and lamivudine), integrase-targeting drugs, drugs that block the binding of transcription factors to viral DNA, and drugs that affect translation. The drug that affects (e.g., antisense molecule) (e.g., formylcene), translation / ribozyme Drugs that modulate function, protease inhibitors, viral construct modulators (e.g., rifampicin), nucleoside analog reverse transcriptase inhibitors (e.g., azidothymidine (AZT)) Examples include antiretroviral agents such as ddl, ddC, 3TC, and d4T, non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz and nevirapine), nucleotide analog reverse transcriptase inhibitors, and agents that prevent the release of viral particles (e.g., zanamivir and oseltamivir). Treatment and / or prevention of certain viral infections (e.g., HIV) often involves the use of a group of antiviral agents ("cocktails").

[0231] A as described in this specification 2A R / A 2B Other antiviral agents intended for use in combination with R inhibitors While not limited to fusion inhibitors, the following are examples of fusion inhibitors: abacavir, adefovir, amantadine, amprenavir, amprigen, arbidol, atazanavir, atripra, boceprevir, cidofovir, combivir, darunavir, delavirdin, didanosine, docosanol, edoxdin, emtricitabine, enfuvirtide, entecavir, famoprenavir, fosprenavir, foscarnet, phosphonet, ganciclovir, ivacitabine, immunovir, idoc Suridine, imiquimod, indinavir, inosine, various interferons (e.g., pegylated interferon alpha-2a), lopinavir, roviride, maraviloc, moloxi Examples include din, mesizazone, nelfinavir, nexavir, penciclovir, peramivir, preconalil, podophyllotoxin, raltegravir, ribavirin, ritonavir, pyramidine, saquinavir, stabudine, telaprevir, tenofovir, tipranavir, trifluridine, trizivir, trontadine, truvada, valacyclovir, valganciclovir, bicribiloc, vidarabine, viramidine, and zalcitabine.

[0232] The invention, as described herein 2A R / A 2B Use R-function inhibitors in combination with antiparasitic agents. The aim is to achieve this. Examples of such drugs, though not limited to them, include thiabendazole, pyrantel pamoate, mebendazole, praziquantel, nicolosamide, bithionol, oxamnicin, metrifonate, ivermectin, albendazole, eflornithine, melarsoprol, pentamidine, benznidazole, nifurtimox, and nitroimidazole. Those skilled in the art are aware of other drugs that may prove useful in treating parasitic diseases.

[0233] Embodiments of the present invention are used in combination with agents useful for treating or preventing bacterial infections, as described herein. 2A R / A 2B The intention is to use R inhibitors. Antibacterial agents have a mechanism of action based on their chemical structure. Antibacterial agents can be classified in various ways, including based on their composition and activity spectrum. Examples of antibacterial agents include those that target the bacterial cell wall (e.g., cephalosporins and penicillins), those that target the cell membrane (e.g., polymyxins), or those that interfere with essential bacterial enzymes (e.g., sulfonamides, rifamycin, and quinolines). Most antibacterial agents that target protein synthesis (e.g., tetracyclines and macrolides) are bacteriostatic, while those such as aminoglycosides are bactericidal. Another means of classifying antibacterial agents is based on their target specificity; "narrow-spectrum" agents target specific types of bacteria (e.g., Gram-positive bacteria such as streptococci), while "broad-spectrum" agents are active against a wide range of bacteria. Those skilled in the art recognize the type of antibacterial agent appropriate for use in a particular bacterial infection.

[0234] Embodiments of the present invention are used in combination with agents useful for treating or preventing fungal diseases, as described herein. 2A R / A 2B The intention is to use R inhibitors. As antifungal agents, polyenes (for example) Examples include amphotericin, nystatin, and pimaricin, azoles (e.g., fluconazole, itraconazole, and ketoconazole), allylamines (e.g., naphthifine and terbinafine), morpholines (e.g., amorolphine), and antimetabolites (e.g., 5-fluorocytosine).

[0235] The present invention encompasses pharmaceutically acceptable salts, acids, or derivatives of the above-mentioned agents (and components of the class of agents).

[0236] dosage A of the present invention 2A R / A 2B R inhibitors, for example, are administered according to the target of the administration (e.g., the desired degree of resolution), and are manufactured The dosage of the drug may depend on the age, weight, sex, health and physical condition of the subject, the route of administration, and the nature of the disease, disorder, condition, or its symptoms. The dosage regimen may also take into account the presence, nature, and degree of any adverse effects associated with the administered drug. Effective dosages and dosage regimens can be readily determined, for example, from safety and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0237] Generally, drug parameters are defined as the amount of drug administered being less than the maximum tolerable dose (MTD) which is irreversibly toxic to the subject, and less than the amount necessary to produce a measurable effect on the subject. This indicates that the amount is above. Such amounts are determined by pharmacokinetic and pharmacodynamic parameters related to ADME, taking into account, for example, the route of administration and other factors.

[0238] The effective dose (ED) is the dose or amount of a drug that produces a therapeutic response or desired effect in a certain proportion of the population receiving it. The "median effective dose" or ED50 of a drug is the dose or amount of a drug that produces a therapeutic response or desired effect in 50% of the population being administered. While ED50 is commonly used as a measure of a reasonable expectation of the drug's effect, it is not necessarily the dose that a physician deems appropriate after considering all relevant factors. Therefore, in some situations the effective dose may be greater than the calculated ED50, in other situations the effective dose may be less than the calculated ED50, and in yet other situations the effective dose may be the same as the calculated ED50.

[0239] Furthermore, A of the present invention 2A R / A 2B The effective dose of an R inhibitor may be the amount that produces the desired result when administered to a subject once or multiple times, compared to a healthy subject. For example, in a subject experiencing a particular disorder, the effective dose may be at least approximately 5%, at least approximately 10%, at least approximately 20%, at least approximately 25%, or less than approximately 5% of the diagnostic parameters, measurements, markers, etc., of that disorder. The dose can be 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% improvement, where 100% is the diagnostic parameter, measurement value shown by a normal subject. Defined as a marker, etc.

[0240] In certain embodiments, A intended by the present invention 2A R / A 2B R inhibitors are used in the desired treatment To achieve the desired effect, the drug is administered once or more times per day (e.g., orally) at a dose of approximately 0.01 mg / kg to approximately 50 mg / kg, or approximately 1 mg / kg to approximately 25 mg / kg of the patient's body weight per day.

[0241] For oral administration, the composition is a tablet containing 1.0 to 1000 milligrams of the active ingredient, particularly 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 milligrams of the active ingredient. It can be provided in the form of capsules or other similar preparations.

[0242] In a particular embodiment, desired A 2A R / A 2B The dosage of an R inhibitor is included in the "unit dosage form." The term "unit dosage form" refers to a predetermined amount of A sufficient to produce the desired effect. 2A R / A 2B R inhibitors , contained alone or in combination with one or more additional drugs, physically distinct This refers to the unit. It will be understood that the parameters of the unit dosage form depend on the specific drug and the effect to be achieved.

[0243] kit The present invention also envisions a kit comprising the compounds described herein and their pharmaceutical compositions. The kit generally takes the form of a physical structure containing various components, as described below, and can be used, for example, in the implementation of the above method.

[0244] The kit comprises one or more of the compounds disclosed herein (for example, provided in a sterile container). The compounds may be in the form of a pharmaceutical composition suitable for administration to a target. The compounds described herein may be provided in a ready-to-use form (e.g., tablets or capsules) or in a form requiring reconstitution or dilution (e.g., powder) before administration. If the compounds described herein are in a form that needs to be reconstituted or diluted by the user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, etc., packaged together with or separately from the compounds described herein. When combination therapy is intended, the kit may contain several drugs separately or they may already be combined in the kit. Each component of the kit may be sealed in an individual container, and all of the various containers may be in a single package. The kits of the present invention may be designed for conditions necessary to properly maintain the components contained therein (e.g., refrigeration or freezing).

[0245] The kit may include labels or packaging inserts containing identification information for its components and instructions for their use (e.g., clinical pharmacology of the active components including drug parameters, mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The labels or inserts may also include manufacturer information such as lot number or expiration date. The labels or packaging inserts may be incorporated into the physical structure containing the components, housed separately within the physical structure, or affixed to the components of the kit (e.g., ampoules, tubes, or vials).

[0246] Labels or inserts are used for computers such as disks (e.g., hard disks, cards, memory disks), optical discs (e.g., CDs or DVD-ROMs / RAMs, DVDs, MP3s, magnetic tapes, etc.) Data-readable media, or electrical storage media such as RAM and ROM, or hybrids thereof, for example, magnetic / optical storage media, flash media, or memory cards, further including or This can be incorporated into the kit. In some embodiments, the actual instructions are not present in the kit, but means are provided for obtaining the instructions from a remote source, for example, via the internet. [Examples]

[0247] experiment The following examples are provided to give a complete disclosure and explanation of how the present invention is manufactured and used, and are not intended to limit the scope of the invention to the inventor, nor to indicate that the inventor has performed or can perform all of the following experiments. Illustrative descriptions written in the present tense are not necessarily performed, and it should be understood that the descriptions can be performed to obtain the types of data, etc., described herein. While efforts have been made to maintain accuracy with respect to the numbers used (e.g., quantity, temperature, etc.), some degree of experimental error and deviation should be taken into consideration.

[0248] Unless otherwise specified, parts are measured in parts by weight, molecular weight is the weight-average molecular weight, and temperature is measured in degrees Celsius. The temperature is in degrees Celsius (°C), and the pressure is atmospheric pressure or close to it. The following standard abbreviations are used: wt = wild type, bp = base pair, kb = kilobase, nt = nucleotide, as = amino acid, s or sec = second min = minute, h or hr = hour, ng = nanogram, tg = microgram, mg = milligram, g =gram, kg =kilogram, dl or dL =deciliter, pl or 1AL =microliter, m l or mL = milliliter, 1 or L = liter, [iM = micromolar concentration, mM = millimolar concentration] M = molar concentration, kDa = kilodalton, im = intramuscular, ip = intraperitoneal, SC or SQ = subcutaneous, QD = Daily, BID = Twice a day, QW = Weekly, QM = Monthly, HPLC = High-Performance Liquid Chromatography, BW = Body weight, U = unit, ns = not statistically significant, PBS = phosphate-buffered saline, IHC = immunohistochemistry DMEM = Dulbecco's modification of Eagle medium, EDTA = ethylenediaminetetraacetic acid.

[0249] Materials and methods The following general materials and methods may be used (if indicated) or may be used in the following embodiments.

[0250] Standard methods in molecular biology are described in scientific literature (e.g., Sambrook and Russell (2001) Molecular Cloning, 3 rd ed., Cold Spring Harbor Laboratory Pres. s, 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 (This document contains bacterial details) Cloning and DNA mutagenesis in cells (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), expression of complex carbohydrates and proteins (Vol. 3), and bioinformatics. This document describes Matics (Vol. 4).

[0251] Scientific literature describes methods for protein purification, including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization, as well as chemical analysis, chemical modification, post-translational modification, fusion protein production, and protein glycosylation (e.g., Coligan et al. (2000), Current Protocols in Protein Science, Vol. 1-2, John Wiley and Sons, Inc., NY).

[0252] For example, software packages and databases are available for determining antigen fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments (e.g., GCGWisconsin Package (Accelrys, Inc.)). San Diego, CA and DeCypher™ (TimeLogic Corp., Crystal Bay, NV).

[0253] The literature contains a wealth of assays and other experimental techniques that can serve as a basis for evaluating the compounds described herein. For example, there are ligand-binding assays based on mass spectrometry (e.g., Massink, A. et al., Purinergic Signaling (2015) 11:581, https: / / doi.org / 10.1007 / s113). 02-015-9477-0; Dionisotti S. et al., J Pharmacol Exp Ther. (1996) 298:726-732) By using this method, various properties of the compound of the present invention can be confirmed.

[0254] Functional assays can also be used to evaluate the compounds of the present invention. The specific compounds described herein were evaluated using the cAMP assay, which is described in detail below.

[0255] An alternative, exemplary functional assay for evaluating IFN-γ secretion is provided by Yuan, G. et al. (Int J Med Chem; Volume 2017(2017),Article ID 4852537; https: / / doi.org / 10.1155 / 2017 / 4852537) It is described as follows: In short, CD3 ligand-mediated T cell receptor (TCR) activity. During incubation, C57BL / 6 mouse splenocyte T cells were incubated with a receptor agonist to inhibit IFN-γ secretion caused by the A2AR receptor, leading to immunosuppression by intracellular cAMP. It induces a response. Effective receptor antagonists block receptor activation signals, thereby restoring cytokine secretion and enhancing and prolonging the immune response.

[0256] A 2A Measurement of adenosine receptor activity of compound I using the R / TRExCHOcAMP functional assay. The dose-response of NECA (5-N-ethylcarboxamide adenosine), a non-selective adenosine receptor agonist, was investigated using the EC of NECA in a cAMP function assay. 80 Measurements were taken daily. 1000-2500 cells / well of stably expressed A 2A RTRexCHO cells in 384 well OptiPlat Seeds were sown in Perkin Elmer, then incubated at 37°C for 30 minutes at various concentrations (ranging from 10 μM to 0 μM). NECA was incubated. After incubation for 30 minutes, cells were stimulated with 5 μL of Ulight anti-cAMP (1:150 dilution with conjugate and lysis buffer provided by Perkin Elmer) and 5 μL of EucAMP tracer (1:50 dilution with conjugate and lysis buffer provided by Perkin Elmer). The FRET signal was added and incubated for 1 hour. The FRET signal was collected on an Envision multi-label plate. Using a leader (PerkinElmer), Eu-cAMP tracer excitation at 615 nm and emission at 665 nm Detected in light. NECA EC 80 To determine this, we will use GraphPad Prism to perform data analysis. went.

[0257] The cAMP antagonist function assay (PerkinElmer) was performed using A 2A The procedure was performed using the R TRex CHO stable cell line. . 1x10 6 The cells were seeded in a T75 flask and cultured overnight at 37°C and 5% CO2. 2A RTR ex CHO at a concentration of 1 μg / mL tetracycline for at least 16 hours at approximately 70%-80% confluence. Induction was performed using Clin. Subsequently, stable expression of A was observed in 1,000-2,500 cells / well. 2A R TREx CHO cells were seeded in a white 384-well Opti plate, and then compound 1 was incubated at 37°C for 1 hour at varying concentrations (ranging from 10 μM to 0 μM). EC of NECA 80 (SigmaAldrich) The stimulating mixture was added and incubated at 37°C for 30 minutes. After 30 minutes of incubation, 5 μL of Ulight-anti-cAMP and 5 μL of Eu-cAMP tracer were added to the cell stimuli and incubated for 1 hour. The FRET signal was observed at Eu-cAMP tracer excitation at 615 nm and emission at 665 nm. It was detected.

[0258] Data analysis was performed using GraphPadPrism, and the K of compound I was analyzed. B (Less than 10 nM) was measured.

[0259] example General method: Those skilled in the art will recognize that there are various methods available for preparing the molecules described in the claims. Generally, a useful method for synthesizing the compounds described in the claims consists of four parts: linking of fragments a and b (or cyclization of ring b to form abc parts) The formation of the ring, linking of fragments b and c (or formation of the abc moiety by cyclization of the b ring), linking of fragments c and d, and modification of the functional groups present in all fragments can be carried out in any order. The retrosynthetic cleavage of the compound of the present invention into fragments a-d, which is useful for constructing the compound, is shown below: [ka]

[0260] Some methods for preparing the claimed compounds are illustrative (Formulas 1-7). Formula 1 shows one method for forming a bond between fragments c and d by the Suzuki reaction. In combination, Z may be selected from suitable groups such as Cl, Br, I, OTf, etc., -B(OR)2 is a boronic acid or ester, and the coupling has a transition metal catalyst, preferably a suitable ligand. It is platinum. [ka]

[0261] Coupling may be assisted by the use of organic or inorganic bases, and various conditions for facilitating Suzuki coupling are known in the art. The functionalization of the coupling partners may be reversed, as illustrated in Formula 2. Those skilled in the art will be able to obtain the desired product. They will realize that other possible combinations exist. [ka]

[0262] Equation 3 shows another way to form the cd fragment. In the case of Equation 3, a suitable aryl acid and meldra Condensation with muic acid, along with a suitable accelerator (other agents such as EDCI and DMAP also yield the desired product), yields the corresponding aryl keto ester. The keto ester is then condensed with guanidine to form the corresponding 2-amino-3-hydroxy-5-arylpyrimidine, which can be converted to the corresponding chloride by treatment with POCl3 or other suitable reagents. [ka]

[0263] The formation of the bond between fragment c and fragment b can occur before or after the formation of the linkage between fragment c and fragment d, and the base can be further modified before or after the linkage between fragment c and fragment b. Formula 4 is, One method for linking fragments c and b by Zuki coupling is shown. [ka]

[0264] In formula 4, Z is selected from appropriate groups such as Cl, Br, I, OTf, and -B(OR)2 is a boronic acid or The compound is an ester, and the coupling is mediated by a transition metal catalyst, preferably palladium with a suitable ligand. The coupling can be assisted by the use of an organic or inorganic base. Various conditions for facilitating Suzuki coupling are known in the art. The functionalization of the ring partner may also be reversed, as illustrated in Equation 5. Those skilled in the art will know You will realize that there are other possible combinations that produce the desired product. [ka]

[0265] Alternatively, fragment b is a 1,3-dipolar cycloaddition of azido-alkyne huisgen ( It can be formed by ring addition between fragment a and fragment c according to formula 6). In the case of formula 6, appropriately functionalized fragments a and c can be combined together in a cycloaddition reaction between an azide and an alkyne. This reaction can be accelerated by the use of a copper catalyst or other catalysts. [ka]

[0266] If fragment b is a triazole, the ring is also palladium-mediated sodium azide Addition of ammonium compounds to alkenyl halides (Barluenga et al., Angew. Chem. Int. Ed., 2006, 45, 6893-6896), Amberlyst-15 catalyzed addition of azides to nitroalkenes (Zhang et al., Synthesis, (2016, 48, 131-135), I2 / TBPB-mediated oxidative cycloaddition of N-tosylhydrozone by aniline (Cai et al., Org. Lett., 2014, 16, 5108-5111) and many other methods (www.organic-chemis "Synthesis of 1,2,3-triazoles" at try.org / synthesis / heterocycles / 1,2,3-triazoles.shtm It can be synthesized by (see "..."). Those skilled in the art will understand that there are many different methods available for performing this conversion.

[0267] Equation 7 shows one method of forming a bond between fragments a and b by alkylation. In Figure 7, Z is a suitable electrophilic reagent such as Cl, Br, I, or OTf, and the coupling is mediated by an organic or inorganic base. For the most efficient preparation of any particular compound of the present invention, those skilled in the art will know that the timing and order of linking the fragments, and the modification of the functional groups present in the fragments, can be altered in the preparation of any given compound. [ka]

[0268] The compounds of the present invention were prepared using the various methods described above, some of which are illustrated in the examples. The deuterated forms of the following examples can be synthesized by using appropriate deuterated intermediates.

[0269] Example 1: 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridine-2-yl]methyl} Synthesis of -1H-1,2,3-triazole-4-yl)pyrimidine-4-yl]-2-methylbenzonitrile [ka]

[0270] Step 1: A 250 mL round-bottom flask equipped with a magnetic star bar was sequentially loaded with boronic acid ester (3.89 g, 16 mmol) and 2-amino-4,6-dichloropyrimidine (3.67 g, 22.4 mmol). Add anhydrous ethanol (100 mL), then add deionized water (1) of KHCO3 (4.81 g, 48 mmol). The solution in 9 mL was added. The resulting suspension was degassed with nitrogen for 5 minutes. PdCl2(PPh3)2(112 The 1 mol% mg of the solution is then added, and the mixture is heated at 78°C for 3 hours under a nitrogen atmosphere. The ethanol was evaporated under reduced pressure, and deionized water (150 mL) was added. The suspension was filtered, and the solids were washed with an additional 100 mL of water. The solids were then dissolved in acetone (220 mL) and collected in a 500 mL round-bottom flask. (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 chromatography on silica gel (dichloromethane / ethyl acetate gradient solution 0%~15%). The desired product was obtained as white solids (1.91 g, 49%). LCMS: Method A, retention time = 2.93 min, C 12 ESIMS[M+H] for H9ClN4 + Calculated value: 245.7, measured value: 245.2.

[0271] 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, 8.68 mL (62.4 mmol) of Et3N and 5.95 mL (25.0 mmol) TIPS-acetylene was added. The reaction mixture was stirred for 5 minutes, and then 219 mg (0.312 mmol) was added. PdCl2(PPh3)2 and 119 mg (0.624 mmol) of CuI were added. The reaction mixture was heated at 50°C for 5 minutes. The mixture was stirred under N2 for 2 hours. After the reaction mixture cooled to room temperature, the solvent was removed, and the crude material was resuspended in 100 mL of siRNA, from which the insoluble solids were filtered out. The filtrate was (1:1)NH4Cl / NH4. The layers were washed with OH (2 x 100 mL) and 10% Na2S2O4 (1 x 100 mL). The organic layer was dried with Na2SO4. It was dried and then sent to the next process without further purification.

[0272] Step 3: In a round-bottom flask, the crude TIPS product from the above process was dissolved in 42 mL of dry THF and cooled to 0 °C. To this, 25 mL (25.0 mmol) of TBAF (1.0 M in THF) was added. The reaction mixture was stirred at 0 °C for 15 minutes. Saturated NH4Cl (100 mL) was added, and the reaction mixture was citric acid mixed. The organic matter was extracted from the aqueous layer with SiO2 (2 x 100 mL). The combined organic layers were then mixed in (1:1) NH3. The samples were washed with 4Cl / NH4OH (2 x 100 mL) and 10% Na2S2O4 (1 x 100 mL). The organic layer was treated with Na2SO4. The mixture was dried, concentrated, and the pure product 5 was ground with 40% CH2Cl2 / hexene to obtain a light brown solid. Yield: 3.71 g (76%, 2-step process).

[0273] Step 4: In a solution of methylmagnesium bromide (3 M in Et2O, 40 mL, 120 mmol, 4.0 equiv), 0 At °C under N2, methyl 2-(hydroxymethyl)pyridine-2-carboxylate (5.0 g, The solution (29.9 mmol) in THF (70 mL, 0.4 M) was added over 30 minutes. The resulting mixture was heated in a room. The mixture was heated to a warm temperature and stirred for 3 hours. The reaction mixture was quenched with NH4Cl aqueous solution (55 mL), and then... Then HCl (50 mL) was added. The organic phase was separated, and the aqueous phase was extracted with HCl (3 x 40 mL). The combined organic extracts were washed with saturated aqueous sodium bisulfite (7 x 20 mL). Next, the mixture was dried (Na2SO4), filtered, and concentrated under vacuum to provide the compound described above as a pale yellow liquid (3.45 g, 69% yield; 96% purity, as determined by LC-MS). LC-MS: Method A, retention time = 0 0.722 and 1.06 min, C9H 13 ESI MS [M+H] for NO2 + The calculated value was 167.09, and the measured value was 167.2.

[0274] Step 5: 2-Hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (5 g, 29.9 mmol, 1. Diphenylphosphoryl (0 equiv) is dissolved in a 33 mL, 0.9 M solution of PhMe under N2 conditions at 0 °C. Add azide (7.73 mL, 35.9 mmol, 1.2 equiv.), then 1,8-diazabicyclo[5.4.0 Undes-7-ene (5.37 mL, 35.9 mmol, 1.2 equiv.) was added. The resulting mixture was heated at room temperature. The mixture was heated and stirred for 14 hours. Upon completion, it was diluted with ethyl acetate, washed with water, the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was diluted with 1N HCl aqueous solution (2 eq, 60 mmol). The mixture was dissolved and extracted with MTBE in hexane (3:7,100 mL), and the organic layer was washed with water (50 mL). Then, the combined aqueous layer was neutralized with 2N aqueous NaOH, and extracted with ethyl acetate (3 × 75 mL). The organic layer was dried (Na2SO4), filtered through a cotton plug, and the filtrate was concentrated to provide the pure compound as a pale yellow liquid (3.75 g, 75%). LCMS: Method A, retention time = 2.67 min, C9H 12ESIMS[M+H] regarding N4O + The calculated value was 193.1, and the measured value was 193.2.

[0275] Step 6: 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 a 2:1 ratio t-BuOH / H2O (158 The mixture in mL was heated at 60°C for 13 hours. The solvent was removed under vacuum, and the residue was silicified. The material is dried and loaded into a container, then purified by silica gel chromatography (0-100% acetone in hexane). The desired product was then provided as an off-white solid (6.08 g, 90%). 1 H NMR (400 MHz, DMSO-d6)δ8.69 (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). C 23 H 23 ESI MS[M+H] for N8O + , calculated value 427.2, actual Measured value: 427.3.

[0276] Example 2: Synthesis of 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridine-2-yl]methyl}-1H-1,2,3-triazole-4-yl)pyrimidine-4-yl]-2-methoxybenzonitrile [ka]

[0277] Step 1: In a round-bottom flask, add 26 g (157.5 mmol) of 3-cyano-2-fluorobenzoic acid to 315 mL of water. The suspension was suspended in (0.5 M) dry MeOH. To this suspension, 144 mL (630 mmol) of NaOMe (MeOH) was added. 25 wt%) was added. The resulting reaction mixture was refluxed under N2 for 2 hours. After cooling to room temperature, the excess MeOH was evaporated under reduced pressure to obtain a concentrated slurry. 158 mL (47 3 mmol of 3 M aqueous HCl was added. The product precipitated as a white solid, which was then filtered. The product was isolated. Residual water was removed azeotropically using toluene to obtain 26.2 g (94%) of pure product.

[0278] Step 2: Meldramic acid 43 g (297 mmol) and 3-cyano,2-methoxybenzoic acid 35 g (198 mmol) The substance was suspended in 660 mL (0.3 M) of CH2Cl2. To this suspension, 57 g (297 mmol) of N-(3-dimethyl) was added. (Tylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and 24g (198 mmo l) 4-dimethylaminopyridine (DMAP) was added. The reaction mixture was incubated under N2 at room temperature for 2 hours. The mixture was stirred. At this point, the reactants were homogeneous. Next, the reaction mixture was transferred to a separatory funnel, and 200 mL of CH2Cl2 was added. The organic layer was then treated with 1 M HCl (2 x 300 mL) and saturated NaCl (300 mL). Washed. The organic layer was dried and concentrated using MgSO4, and the crude material was obtained without further purification. It was used in the next step. The crude meldram acid adduct from the above step was suspended in 400 mL of anhydrous EtOH and refluxed for 1.5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the initial The volume was reduced to 1 / 4 (approximately 100 mL). The product β-ketoester in EtOH was further purified in the next step. It was used without performing any action.

[0279] Step 3; In a round-bottom flask, add 19 g (198 mmol) of guanidine hydrochloride to 300 mL (0.7 M). It was dissolved in EtOH. To this, 74 mL (198 mmol) of NaOEt (21 wt% in EtOH) was added. The resulting suspension solution was stirred at room temperature for 10 minutes, and then compound 4 was added to 100 mL of EtOH (pre- It was added (from the process). The reaction mixture was refluxed under N2 for 72 hours. The reaction mixture was cooled to room temperature. Subsequently, 300 mL of hexane was added. The precipitated product was obtained by filtration and used directly in the next step without further purification.

[0280] Step 4: Crude product 5 from the previous step was suspended in 200 mL of dioxane. POCl3 (186 mL, 2000 mmol) was added to this. The reaction mixture was stirred at 70°C for 1.5 hours. The mixture was then cooled to room temperature. Afterward, pour the reaction mixture over crushed ice (approximately 1000 g) and stir (Note: Stir slowly at a low temperature) The temperature rose and the excess POCl3 was quenched as the ice melted. Later, a small amount of solids K2CO3 (691 g, 5000 mmol) was added, and the resulting HCl and H3PO4 were... Quenched. The aqueous layer was extracted with CH2Cl2 (3 x 500 mL). The combined organic layer was saturated with NaCl (500 mL). The material was washed with (mL) and dried on MgSO4. The solvent was removed under reduced pressure to obtain a brown solid. The crude product was polished with 10% CH2Cl2 / hexane to obtain the pure product (28 g, 54% in 4 steps).

[0281] Step 5: In a round-bottom flask, add 7.7 g (29.3 mmol) of chloropyrimidine 6 to 60 mL (1:1 dioxide). The suspension was suspended in xane / Et3N. TMS-acetylene (20.3 mL, 146 mmol) was added to this suspension. Then, PdCl2(PPh3)2 (2.6 g, 2.93 mmol) and CuI (558 mg, 2.93 mmol) were added. The reaction mixture was stirred under N2 at 80°C for 1 hour. After the reaction mixture was cooled to room temperature, Approximately 100g of silica gel was added, and the solvent was removed under reduced pressure. The crude material was purified by chromatography using 80% (SiO₂ / hexane). 7. The percentage was found to be 5.5 g (58%).

[0282] Step 6: In a round-bottom flask, 5.1 g (15.7 mmol) of 7 was dissolved in dry THF (30 mL). To this, 16.5 mL (16.5 mmol) of TBAF (1.0 M in THF) was added. The reaction mixture was left at room temperature for 30 minutes. The mixture was stirred. Approximately 100 g of silica gel was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The crude material adsorbed onto silica gel was chromatographed using 50% (1:1 hexane:CH2Cl2 / siRNA). Purified by tography. Yield: 3.2 g (80%).

[0283] Step 7: Azide (Example 1, Step 5, 294 mg, 1.53 mmol, 1.0 equiv.) and alkyne (382 mg, 1.53 mmol) To a solution of 1.0 mol (1.0 equiv.) in 2:1 t-BuOH / H2O (5 mL, 0.3 M), add CuSO4 (7.2 mg, 0.029 m). 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 hours. Upon completion, the reaction mixture was cooled to room temperature. The solution was then diluted with CH2Cl2 (10 mL). The organic phase was separated, and the aqueous phase was diluted with CH2Cl2 (10 mL). The mixture was diluted again. The combined extract was concentrated, and the resulting residue was purified by column chromatography (CH2Cl2 → 95:5CH2Cl2:MeOH), and the compound mentioned in the title was found as a pale beige solid. It was provided as is (604 mg, 89% yield). 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J= 1.0 Hz,1 H), 8.04- 7.98 (m, 1 H), 7.92 (d, J = 0.8 Hz, 1 H), 7.78 - 7.64 (m, 2 H), 7.37 (d, J =7.9 Hz, 1 H), 7.28 (td, J = 7.8 Hz, 0.8 Hz, 1 H), 7.14 (d, J = 7.6 Hz, 1 H), 5.75(brs, 2 H), 5.15 (brs, 2 H), 4.74 (s, 1 H), 3.94 (d, J = 0.8 Hz, 3 H) , 1.54 (d, J =0.8 Hz, 6 H). C 23 H 23 The calculated ESI[M+H] value for N8O2 is 443.19, and the measured value is 443.2.

[0284] LCMS retention time: 2.8 min, method A

[0285] Example 3: Synthesis of 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridine-2-yl]methyl}-1H-1,2,3-triazole-4-yl)pyrimidine-4-yl]-2-fluorobenzonitrile [ka]

[0286] Step 1: In a solution of 3-bromo-2-fluorobenzonitrile (26 g, 130 mmol), PrMgCl was added at 0 °C. A LiCl solution (100 mL, 130 mmol, 1.3 M in THF) was added dropwise over 20 minutes. The resulting solution The mixture was stirred at 0 °C for 50 minutes, and then ZnCl2 (17.72 g, 130 mmol) was added at 0 °C. The mixture was warmed to room temperature and stirred at the same temperature for 25 minutes. Then, compound 1 (16.4 g, 100 mmol) was added and stirred for 10 minutes. Then, Pd(PPh3)4 (2.32 g, 2 mmol) was added. The mixture was added and stirred at room temperature for 12 hours. The reaction mixture was then mixed with saturated aqueous NH4Cl solution (500 mL). The combined organic layers were entrenched, extracted with toluene (3 x 300 mL), and dried over Na2SO4. The mixture was evaporated to provide 28 g of crude product 2, which was then subjected to the next step without further purification.

[0287] Step 2: To a solution of compound 3 (24 g, 96.52 mmol) stirred at room temperature, add PdCl2(PPh3)2(3.38 (g, 4.82 mmol), CuI (1.84 g, 9.65 mol), THF / Et3N (1:1, 482 mL) were added, and then N2 Degassed for 30 minutes. Then, triisopropylacetylene (130 mL, 579.15 mmol) was added for 15 minutes. The compound 2 was added dropwise over several minutes (the reaction mixture turned reddish), and the reaction mixture was refluxed for 90 minutes. LC-MS and TLC showed that compound 2 had been completely consumed. The solvent was evaporated using a rota vaporizer. Excess Et3N was removed using a toluene (2 x 200 mL) azeotrope. The crude reaction mixture was mixed with silica gel and loaded directly onto a flash column. The solvent gradient was changed in hexane from 10 to 20, then 30, then 40, and then 50% EA. Pure solids were then removed. Product 3 (15.13 g, 46% across two steps) was obtained in 40% EA in hexane.

[0288] Step 3: To a stirred solution of compound 4 (15 g, 37.97 mmol) at 0 °C, add TBAF (37.97 mL, THF The medium (1 M) solution was added dropwise over 15 minutes, and the mixture was stirred at 0°C for <30 minutes. TLC was performed. S is nBuN + It does not show (it is tricky due to the cation). The reaction mixture is saturated aqueous NH4Cl. Quench with solution (200 mL) at 0 °C, extract with alkyl (3 x 250 mL), and dry on Na2SO4. Then, it was evaporated to provide crude product 4. To this crude product, 10% siRNA in 200 ml of hexane was added and then sonicated. The upper liquid portion was separated, and EtOA was added to the solid residue. c / CH2Cl2 (200 mL, 1:1) was added. Hexane (600 mL) was added to the resulting slurry. The precipitate was then allowed to settle and sonicated for 5 minutes. The precipitate was filtered and dried under high vacuum. Compound 4 (7.2 g) was then provided in 80% yield.

[0289] Step 4: The procedure was carried out in the same manner as in Example 1.

[0290] 1¹H NMR (400 MHz, acetone-d6) 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 = 7.8Hz, 1H), 6.30 (brs, 2H), 5.86 (s, 2H), 4.62 (s, 1H), 1.48 (s, 6H) . C 22 H 19 FN8O's ESIMS [M+H] + Calculated value: 431.4, measured value: 431.2.

[0291] Example 4: 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridine-2-yl]methyl}-1H-1,2,3-triazole-4-yl)pyrimidine-4-yl]benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 2, starting with 3-cyanobenzoic acid. 1 1H NMR (400 MH) z, DMSO-d6)8.71 (d, J = 1.2 Hz, 1 H), 8.59 (q, J = 1.5 Hz, 1 H),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, 1 H), 7.11 (dt, J = 7.7, 1.1 Hz, 1 H), 6.92 (s, 2 H), 5.83 (s, 2 H), 5.23(d, J = 1.2 Hz, 1 H), 1.38 (d, J = 1.2 Hz, 6 H). C 22 H 20 N8O's ESIM S [M+H] + Calculated value: 413.2, measured value: 413.3.

[0292] Example 5: 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridine-2-yl]methyl}-1H-1,2,3-triazole-4-yl)pyrimidine-4-yl]-2-chlorobenzonitrile [ka] The compound described in the title was prepared using 2-chloro-3-cyanoboronic acid in the same manner as in Example 1. 1 HNMR (4 00 MHz, Acetone-d6)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). 22 H 19 ClN8O's ESIMS [M+H] + The calculated value was 447.9, and the measured value was 447.2.

[0293] Example 6: 2-[6-({4-[2-amino-6-(2,3-dichlorophenyl)pyrimidine-4-yl]-1H-1,2,3-to [Riazole-1-yl]methyl)pyridine-2-yl]propan-2-ol [ka] The compound described in the title was prepared in the same manner as in Example 1, starting from 2,3-dichloroboronic acid. 1 HNMR (400 MHz, acetone-d6)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); LC-MS retention time 2.96 min, method B, C 21 H 19 ESIMS[M+H] of Cl2N7O + Calculated value: 456 0.1, measured value 456.2.

[0294] Example 7: 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridine-2-yl]methyl}-1H-pyrazole-4-yl)pyrimidine-4-yl]-2-methoxybenzonitrile [ka]

[0295] Step 1: MeCN (100 mL, 0.2 M) of 2-acetyl-6-methylpyridine (3.0 g, 22.2 mmol, 1.0 equiv) In a spurged solution under N2 conditions, benzoyl peroxide (538 mg, 2.2 mmol, 0.1 (equv), followed by the addition of N-bromosuccinimide (4.7g, 26.6 mmol, 1.2 equiv). The flask was equipped with a reflux condenser, and the mixture was heated to 85 °C and stirred for 28 hours. At completion, saturated aqueous solution Na₂S₂O₃ (50 mL) was added, and the two-phase mixture was stirred for 10 minutes. The mixture was transferred to a separatory funnel containing SiO (100 mL) and 1:1 water: saturated Na2S2O3 (100 mL). The organic phase was recovered, and the aqueous phase was extracted with 2 x 50 mL of ELISA. The combined organic extracts were dried over MgSO4 and concentrated under vacuum. The resulting residue was subjected to column chromatography (hexachromatography). The compound was purified using a 9:1 hexane:SiO ratio, and the compound (2.65g, 56% yield) was diluted with dilute ethanol. It was provided as orange-colored oil.

[0296] Step 2: 1-(6-(bromomethyl)pyridine-2-yl)ethane-1-one (1.0 g, 4.7 mmol, 1.0 equiv) and 4-Pyrazolboronate pinacol ester (997 mg, 5.1 mmol, 1.1 equiv) is used in MeCN (23 It was absorbed in mL, 0.2 M, and then Cs2CO3 (1.7 g, 5.1 mmol, 1.1 equiv) was added. The mixture was stirred at room temperature for 4 hours. Upon completion, the mixture was diluted with CH2Cl2 (20 mL) and filtered through a frit-equipped funnel. The filtrate was concentrated under vacuum to yield the compound described above, which was used in the next reaction without further purification.

[0297] Step 3: 1-(6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)methyl)pyridine-2-yl)ethane-1-one (301 mg, 0.92 mmol, 1.2 equiv) and 3-(2- Amino-6-chloropyrimidine-4-yl)-2-methoxybenzonitrile (Example 2, Step 4, 200 mg, DMF (33 mL, 0.9 M) and 2.0 M aqueous K2CO3 (0.8 mL, 2.0 M) of 0.77 mmol, 1.0 equiv. The solution was spurged with N2 for 10 minutes. After this, Pd(dppf)Cl2(55.6 mg, 0.04 mmol, 0.1 Equiv) was added, and the reaction mixture was heated at 100°C for 16 hours. Upon completion, the reaction mixture The mixture was diluted with CH2Cl2 (10 mL) and H2O (10 mL). The two-phase mixture was transferred to a separatory funnel, and then... The instrument phase was recovered. The aqueous phase was extracted with 2 x 10 mL CH2Cl2, and the combined organic extract was dried over MgSO4 and concentrated under vacuum. The brown residue was subjected to column chromatography (7:3 The compound was purified by hexane (siRNA → siRNA) to obtain the compound in question (190 mg, 58% yield) in yellow oil. It was provided as such.

[0298] Step 4: 3-(6-(1-((6-acetylpyridine-2-yl)methyl)-1H-pyrazole-4-yl)-2-aminopyrimidine-4-yl)-2-methoxybenzonitrile (190 mg, 0.45 mmol, 1.0 equiv) in THF In a solution (8.2 mL, 0.05 M) under N2 conditions at °C, add MeMgBr (0.8 mL, 1.1 mmol, 2.5 equiv, 3:1TH) F (1.4 M in toluene) was added. The resulting mixture was warmed to room temperature and stirred for 21 hours. At completion, the reaction was quenched by adding saturated aqueous solution NH4Cl (10 mL). The two-phase mixture was separated using a separatory funnel. The mixture was transferred to a separate container and extracted with 3 x 10 mL of phenylethylamine. The combined organic extracts were washed with saline solution (10 mL) and then MgSO4. The mixture was dried on 4 and concentrated in a vacuum. The residue was subjected to reverse-phase HPLC (19:1 → 1:19H2O:MeCN, 0.1%). The compound is purified using CF3CO2H (including CF3CO2H), and the compound described above (10 mg, 5% yield) is provided as a white solid. Ta. 1 ¹H NMR (400 MHz, acetone-d6) δ 8.80 (d, J = 14.1 Hz, 1H), 8.35 (d, J = 6.3 Hz, 1H),8.15 - 8.07 (m, 1H), 7.97 - 7.77 (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 2.52min LC-MS, Method B, C 24 H 23 ESIMS[M+H] regarding N7O2 + Calculated value: 441.2, Measured value: 441.3.

[0299] Example 8: 2-[6-({4-[2-amino-6-(3-fluoro-2-methoxyphenyl)-4-pyrimidinyl]-1H-1, 2,3-Triazole-1-ylmethyl)-2-pyridyl]-2-propanol [ka] The compound described in the title was prepared in the same manner as in Example 1. 1 ¹H 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 H z, 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 LC-MS, Method A, C 22 H 23 ESIMS [M+H] for FN7O2 + Calculated value: 436.2, measured value: 436.3.

[0300] Example 9:2-[6-({4-[2-amino-6-(3-chloro-2-methoxyphenyl)-4-pyrimidinyl]-1H-1,2 ,3-triazole-1-yl)methyl)-2-pyridyl]-2-propanol [ka] The compound described in the title was prepared in the same manner as in Example 1. 1 HNMR (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 L C-MS, Method A, C 22 H 23 ClN7O2 ESIMS [M+H] + Calculated value: 452.2, measured value: 452.3.

[0301] Example 10: m-(2-amino-6-{1-[(2-pyridyl)methyl]-1H-1,2,3-triazole-4-yl}-4-py Limidinil Benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 4. 1 ¹H 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); C 19 H 14 N8 ESIMS [M+H] + Calculated value: 355.1, Measured value 355.2.

[0302] Example 11: m-(2-amino-6-{1-[(3-pyridyl)methyl]-1H-1,2,3-triazole-4-yl}-4- Pyrimidinyl benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 4, yielding 59 mg of brown solids. 1 1H NMR (400 MHz, DMSO-d6)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). C 19 H 14 N8 ESIMS [M+H] + Calculated value 355.1, measured value 35 5.3.

[0303] Example 12: m-(2-amino-6-{1-[(4-pyridyl)methyl]-1H-1,2,3-triazole-4-yl}-4-pyridyl) Limidinil Benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 4, yielding 66 mg of brown solids. 1 1H NMR (400 MHz, DMSO-d6)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). C 19 H 14 N8's ESIMS [M+H] + Calculated value: 355.1, measured value: 355.3.

[0304] Example 13: m-(2-amino-6-{1-[(6-methyl-2-pyridyl)methyl]-1H-1,2,3-triazole-4-I (L)-4-pyrimidinyl benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 4, yielding 14 mg of brown solids. 1 1H NMR (400 MHz, DMSO-d6)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 = 7.7 Hz, 1H), 6.92 (s, 2H), 5.78 (d, J = 2.0 Hz, 2H), 2.45 (s, 3H). C20 H 16 N8 ESIMS [M+H] + Calculated value: 369.2, measured value: 369.3.

[0305] Example 14: 3-(2-amino-6-{1-[(6-methyl-2-pyridyl)methyl]-1H-1,2,3-triazole-4-I (L)-4-pyrimidinyl-2-fluorobenzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 3, yielding 13 mg of brown solids. 1 1H NMR (400 MHz, DMSO-d6)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). C 20 H 15 FN8 ESIMS[M+H ] + Calculated value: 387.1, measured value: 387.3.

[0306] Example 15: 6-(2-amino-6-{1-[(6-methyl-2-pyridyl)methyl]-1H-1,2,3-triazole-4-yl}-4-pyrimidinyl)-2-toluonitrile [ka] The compound described in the title was prepared in the same manner as in Example 1, yielding 75 mg of brown solids. 1 1H NMR (400 MHz, DMSO-d6)8.66 (d, J = 1.3 Hz, 1H), 7.95 - 7.86 (m, 1H), 7.80 - 7.67(m, 2H), 7. 52 (t, J = 7.8Hz, 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). C2 1H 18 N8 ESI MS [M+H] + Calculated value: 383.2, measured value: 383.3.

[0307] Example 16: 3-(2-amino-6-{1-[(6-methyl-2-pyridyl)methyl]-1H-1,2,3-triazole-4-I (L)-4-pyrimidinyl-2-anisonitrile [ka] The compound described in the title was prepared in the same manner as in Example 2, yielding 84 mg of brown solids. 1 1H NMR (400 MHz, DMSO-d6)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 = 1.7 Hz, 3H), 2.45 (s, 3H). C 21 H 18 N8O's ESIMS[M+H] + Calculated value 3 99.2, actual measured value 399.3.

[0308] Example 17: m-(2-amino-6-{1-[(3-methyl-2-pyridyl)methyl]-1H-1,2,3-triazole-4-I (L)-4-pyrimidinyl benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 4. 1 HNMR (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); C 20 H 16 N8O3's ESIMS [M+H] + Calculated value: 369.2, measured value: 369.2.

[0309] Example 18: m-[2-amino-6-(1-{[6-(trifluoromethyl)-2-pyridyl]methyl}-1H-1,2,3- Synthesis of [Riazole-4-yl)-4-pyrimidinyl]benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 4, yielding 74 mg of brown solids. 1 1H 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, 1.2Hz, 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). C 20 H 13 ESIMS[M+H] of F3N8 + Calculated value 423.1, measured value 423.2.

[0310] Example 19: m-[2-amino-6-(1-{[6-(hydroxymethyl)-2-pyridyl]methyl}-1H-1,2,3-trimethyl] Azole-4-yl)-4-pyrimidinyl]benzonitrile [ka]

[0311] Process 1. Mixture of diol (696 mg, 5 mmol) and DBU (0.9 mL, 6 mmol) in dichloromethane (15 mL) The mixture was cooled to 0 °C. DPPA (1.3 mL, 6 mmol) was added dropwise, and the resulting mixture was obtained. Stir at 0°C for 15 minutes, then stir overnight at room temperature. Add Celite (5g), and The mixture was evaporated to dryness and purified by silica gel chromatography (hexane / siRNA 90:10~60:40) to provide the desired azide (83 mg, 10%).

[0312] Process 2. The compound described in the title is prepared in the same manner as in step 6 of Example 1 as an azide derivative and m-(2-amino-6-ethynyl-4-p Prepared using limidinyl benzonitrile (from Example 4). 1 1H 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), 7.8 2 (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). C 20 H 16 N8O's M S [M+H] + Calculated value: 385.2, measured value: 385.2.

[0313] Example 20: m-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-yl)-4-pyrimidinyl]benzonitrile [ka]

[0314] Step 1: Under a nitrogen atmosphere at room temperature, 12 g of sodium hydride (300 mmol) in dioxane (100 mL) , a 60% dispersion in mineral oil (1 e.q.) is mixed with 2,6-pyridinedimethanol (41.8 g, 300 mmol) It was added to a suspension in xan (600 mL). The suspension was stirred for 15 minutes. Methyl iodide (42.6 g) (300 mmol) was added, and the resulting mixture was heated at 50°C for 2 hours. TLC analysis was performed approximately 5 This suggested that 0% of the starting material was converted. The reaction was quenched with water, and then ethyl acetate was added. Extraction was performed with (500 mL x 3). The ethyl acetate layer was washed with water (200 mL) and saline solution. The liquid was dried on sodium sulfate for 1 hour, filtered, and concentrated. The resulting oil residue was Purified by silica gel column, followed by dichloromethane / methanol (2%-5% methanol). The compound was extracted, and 6.6 g of compound 1 was provided as pink oil in a 15% yield.

[0315] Step 2: The product from step 1 (3.4 g, 17.0 mmol) in SOCl2 (30 mL) was stirred overnight at 40 °C. The mixture was concentrated, and the product was obtained as a white solid (3.6 g, 100%).

[0316] Step 3: Product from step 2 in EtOH (1.16 g, 6.8 mmol, 1.0 eq) and NaN3 (1.3 g, 20.3 mmol, 3.0 eq) was heated and refluxed overnight. The mixture was concentrated to obtain the crude product, which was then subjected to FCC (PE / EA = The product was purified on 5 / 1) and provided as a white solid (0.9g, 74%).

[0317] Step 4: Using the general procedure from Example 1, the compound described in the title was synthesized to provide 64 mg of yellowish-brown solids. Ta. 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, 1 H), 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). C 21 H 18 N8O's ESIMS[M+ H] + Calculated value: 399.2, measured value: 399.3.

[0318] The compound mentioned above can be obtained as shown below. [ka]

[0319] Example 21: 6-(3-fluoro-2-methoxyphenyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl Tyl-1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] The compound described in the title was prepared in the same manner as in Example 20. 1 HNMR (400 MHz, DMSO-d6) δ 8.64 (s,1H), 7 .85 (t, J = 7.8Hz, 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). C 21 H 21 ESIMS [M+H] for FN7O2+ Calculated value: 422.2, measured value: 422.3.

[0320] Example 22: 3-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]-2-anisonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ8.82 (s, 1 H), 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, 1 H), 7.41 (d, J= 7.9 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.86 (s, 2H), 4.47 (s, 2 H), 3.88 (s,3H), 3.35 (s, 3H). C 22 H 21 N8O2 ESIMS[M+H] + Calculated value: 429.2, Measured value: 429 .3.

[0321] Example 23: 6-(3-chloro-2-methoxyphenyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1H NMR (400 MHz, CDCl3)δ8.28 (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). C 21 H 20 ClN 7O2 ESI MS [M+H] + Calculated value: 438.1, measured value: 438.3.

[0322] Example 24: 5-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]-3-toluonitrile [ka] The compounds listed in the title were prepared from azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ8.70 (s, 1H), 8.42 - 8.36 (m, 1H), 8.32 (d, J = 0.8 Hz, 1H), 7.86 (t, J = 7.8Hz, 1H), 7.83 (s, 1H), 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). C 22 H 20 N8O's ESIMS [M+H] + Calculated value: 413.2, measured value: 413.3.

[0323] Example 25: 3-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]-5-chlorobenzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ8.72 (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) . C 21 H 17 ClN8O's ESIMS [M+H] + Calculated value: 433.1, measured value: 433.2.

[0324] Example 26: m-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria [Zol-4-yl)-5-methyl-4-pyrimidinyl]benzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ8.63 (s, 1H), 8.02 (s, 1H), 7.97 - 7.92 (m, 1H), 7.88 (m, 2H) , 7.71 (t, J = 7.8Hz, 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). C 22 H 20 N8O ESI MS[M+H] + Calculated value: 413.2, measured value: 413.2.

[0325] Example 27: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(o-methoxyphenyl)-2-pyrimidinylamine [ka] Similar to step 6 of Example 1, 2-(azidomethyl)-6-(methoxymethyl)pyridine and 4-ethynyl-6-(o-methoxyphenyl)-2-pyrimidinylamine (which was prepared in the same manner as steps 1-3 of Example 1) It was synthesized using [this method]. 1 H NMR (400 MHz, CDCl3) δ8.27 (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), 7.1 1 - 6.96 (m,3H), 5.71 (s, 2H), 5.12 (s, 2H), 4.58 (s, 2H), 3.90 (s, 3H), 3.49 ( s, 3H). C 21 H 21 N7O2 ESIMS [M+H] + Calculated value: 404.2, measured value: 404.2.

[0326] Example 28: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(o-methylphenyl)-2-pyrimidinylamine [ka] It 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 in the same manner as in steps 1-3 of Example 1). 1 H NMR (400 MHz, CDCl3) δ8.29 (s, 1H), 7.70 (dd, J = 7.8,7.8 H z, 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). C 21 H 21 N7O's ESIMS [M+H] + Calculated value: 388.2, measured value: 388.3.

[0327] Example 29: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(p-fluorophenyl)-2-pyrimidinylamine [ka] The compounds mentioned in the title are 2-(azidomethyl)-6-(methoxymethyl)pyridine and 4-ethynyl-6-(p- Fluorophenyl)-2-pyrimidinylamine (which was prepared in the same manner as in steps 1-3 of Example 1) is used. Then, it was synthesized in the same manner as in step 6 of Example 1. 1 HNMR (400 MHz, CDCl3) 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). C 20 H 18 MS[M+H] of FN7O + Calculated value: 392.2, measured value: 392.2.

[0328] Example 30: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(o-fluorophenyl)-2-pyrimidinylamine [ka] 2-(azidomethyl)-6-(methoxymethyl)pyridine and 4-ethynyl-6-(o-fluorophenicol Using (L)-2-pyrimidinylamine (which was prepared in the same manner as in steps 1-3 of Example 1), the compound described above was formed. The material was prepared in the same manner as in step 6 of Example 1. 1 HNMR (400 MHz, CDCl3) δ 8.29 (s, 1H),8.00 (d dd, 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). C 20 H 18 MS[M+H] of FN7O + Calculated value: 392.2, measured value: 392.3.

[0329] Example 31: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(o-chlorophenyl)-2-pyrimidinylamine [ka] The compound described above was synthesized in the same manner as in step 6 of Example 1, using 2-(azidomethyl)-6-(methoxymethyl)pyridine and 4-ethynyl-6-(o-chlorophenyl)-2-pyrimidinylamine (which was prepared in the same manner as in steps 1-3 of Example 1). 1 HNMR(400 MHz, CDCl3) 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 = 8.0Hz, 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). C 20 H 18 MS[M+H] of ClN7O + Calculated value: 408 0.1, measured value 408.3.

[0330] Example 32: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(o-trifluoromethoxyphenyl)-2-pyrimidinylamine [ka] 2-(azidomethyl)-6-(methoxymethyl)pyridine and 4-ethynyl-6-(o-trifluoromethyl Using toxyphenyl)-2-pyrimidinylamine (which was prepared in the same manner as in steps 1-3 of Example 1) The compound described in the title was prepared in the same manner as in step 6 of Example 1. 1 H NMR (400 MHz, CDCl3) 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). C 21 H 18 MS[M+H] of F3N7O2 + Calculated value: 458.1, Measured value 458.2.

[0331] Example 33: 4-[o-(methoxymethyl)phenyl]-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl (L)-1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] Example 1 uses 2-(azidomethyl)-6-(methoxymethyl)pyridine and 6-ethynyl-4-[o-(methoxymethyl)phenyl]-2-pyrimidinylamine (which was prepared in the same manner as in steps 1-3 of Example 1). The compound described in the title was synthesized in the same manner as in step 6. 1 HNMR (400 MHz, CDCl3) 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 = 7.7 Hz 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). C 22 H 23 MS[M+H] of N7O2 + Calculated value: 418.2, measured value: Measured value.

[0332] Example 34: 4-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]-2-toluonitrile [ka] The compound described above 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 prepared in the same manner as in steps 1-3 of Example 1). 1 HNMR (400 MHz, CDCl3) 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). C 22 H 20 N8O's MS[M+H] + Calculated value: 413. 2. Measured value: 413.3.

[0333] Example 35: 6-(3,5-difluorophenyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}- 1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] Using 2-(azidomethyl)-6-(methoxymethyl)pyridine and 4-(3,5-difluorophenyl)-6-ethynyl-2-pyrimidinylamine (which was prepared in the same manner as in steps 1-3 of Example 1), The compound described in the title was synthesized in the same manner as in step 6. 1 HNMR (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). C 20 H 17 F2 N7O's MS[M+H] + Calculated value: 410.1, measured value: 410.2.

[0334] Example 36: 6-(3,5-dimethoxyphenyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}- 1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] Using 2-(azidomethyl)-6-(methoxymethyl)pyridine and 4-(3,5-dimethoxyphenyl)-6-ethynyl-2-pyrimidinylamine (which was prepared in the same manner as in steps 1-3 of Example 1), The compound described in the title was synthesized in the same manner as in step 6. 1 HNMR (400 MHz, DMSO-d6) 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). C 22 H 23 MS[M+H] of N7O3 + Calculated value: 434.2 The measured value was 434.3.

[0335] Example 37: p-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]benzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ8.68 (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). C 21 H 18 N8O MS [M+H] + Calculated value: 399.2, measured value: 399.3.

[0336] Example 38: o-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]benzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, CDCl3)δ8.34 (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, 2 H), 3.51 - 3.43 (s, 3H). C 21 H 18 N8O's MS [M+H] + Calculated value: 399.2, measured value: 399.3.

[0337] Example 39: 2-{m-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-yl)-4-pyrimidinyl]phenyl}-2-propanol [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, CDCl3)δ8.30 (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). C 25 H 25 N7O2 MS[M+H ] + Calculated value: 432.2, measured value: 432.2.

[0338] Example 40: 6-(m-cumenyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3- Riazole-4-yl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 ¹H 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 = 6.9Hz, 6H). C 23 H 25 N7O's MS [M+H] + Calculated value: 416.2, measured value: 416.4.

[0339] Example 41: Ethyl 3-{m-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-yl)-4-pyrimidinyl]phenyl}propionate [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 ¹H 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). C 25 H 27 MS[M+H] of N7O3 + Calculated value: 474.2, measured value: 474.3.

[0340] Example 42: 4-[m-(2-methoxyethoxy)phenyl]-6-(1-{[6-(methoxymethyl)-2-pyridyl] Methyl}-1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 ¹H 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). C 23 H 25 MS[M+H] of N7O3 + Calculated value: 448.2, measured value: 448.3.

[0341] Example 43: 3-{m-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-yl)-4-pyrimidinyl]phenyl}propionic acid [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ12.15 (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). C 23 H 23 MS[M+H] of N7O3 + Calculated value: 446.2 The measured value was 446.3.

[0342] Example 44: 3-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria [Zol-4-yl)-4-pyrimidinyl]-4-fluorobenzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ8.70 (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). C 21 H 17 MS of FN8O M+H] + Calculated value: 417.2, measured value: 417.3.

[0343] Example 45: 3-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria [Zol-4-yl)-4-pyrimidinyl]-2-fluorobenzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ8.66 (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). C 21 H 17 FN8O's MS [M+H] + Calculated value: 417.2, Measured value: 417.3.

[0344] Example 46: 6-(2,3-difluorophenyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}- 1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] 1 H NMR (400 MHz, DMSO-d6) δ8.69 (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). C 20 H 17 MS[M+H] of F2N7O2 + Calculated value: 410.1, measured value: Measured value.

[0345] Example 47: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(m-Tolyl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, yielding 9 mg of yellow-brown solids. 1 H NMR (400MHz, DMSO-d6) δ8.25 (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 = 7.6Hz, 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). C2 1H 21 N7O's ESI MS[M+H] + Calculated value: 388.1, measured value: 388.3.

[0346] Example 48: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(m-methoxyphenyl)-2-pyrimidinylamine [ka] Prepare the compounds listed in the title from the corresponding azides and alkynes in the same manner as in Example 20, and 37 mg of yellowish-brown Colored solids were provided. 1 H NMR (400 MHz, DMSO-d6) δ8.67 (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 (dd d, J = 8.2,2.7, 0.9 Hz, 1H), 6.80 (bs, 2H), 5.81 (s, 2H), 4.46 (s, 2H), 3.84 (s , 3H), 3.34 (s,3H). C 21 H 21 N7O2 ESIMS [M+H] + Calculated value: 404.2, measured value: 404.2.

[0347] Example 49: 6-(m-fluorophenyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1 ,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] Prepare the compounds listed in the title from the corresponding azides and alkynes in the same manner as in Example 20, and 32 mg of yellow Solids were provided. 1 H NMR (400 MHz, DMSO-d6) δ8.69 (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). C 20 H 18 FN7O's ESIMS [M+H] + Total Calculated value: 392.2, measured value: 392.2.

[0348] Example 50: 6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-4-[m-(trifluoromethyl)phenyl]-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, and orange solids were provided. 1 H NMR (400 MHz,DMSO-d6) δ8.70 (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). C 21 H 18 ESIMS[M+H] of F3N7O + Calculated value 442.2, actual Measured value: 442.2.

[0349] Example 51: 6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-4-[m-(methylsulfonyl)phenyl]-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, and yellowish-brown solids were provided. 1 H NMR (400 MHz,DMSO-d6) δ8.77 - 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). C 21 H 21 ESIMS[M+H] of N7O3S + Calculated value: 452.2, Measured value: 452 .2.

[0350] Example 52: 6-(m-chlorophenyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2 ,3-triazole-4-yl)-2-pyrimidinylamine [ka] The compounds listed in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, and 71 mg of brown Solids were provided. 1 H NMR (400 MHz, DMSO-d6) δ8.69 (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). C 20 H 18 ClN7O's ESIMS [M+H] + Calculated value 408.1, measured value 4 08.2.

[0351] Example 53: 3-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]-5-fluorobenzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, yielding 3 mg of white solids. 1 H NMR (400 MHz, CDCl3) δ8.33 (s, 1H), 8.25 (t, J = 1.2 Hz, 1H ), 8.15 - 8.05(m, 1H), 7.88 (s, 1H), 7.73 - 7.71 (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) ). C 21 H 17 FN8O's ESIMS [M+H] + Calculated value: 417.2, measured value: 417.3.

[0352] Example 54: 3-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]-5-anisonitrile [ka] The compounds listed in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, and 56 mg of white Solids were provided. 1 H NMR (400 MHz, DMSO-d6) δ8.72 (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). C 22 H 20 N8O2 ESIMS[M+H] + Calculated value: 429 0.2, measured value 429.3.

[0353] Example 55: 6-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]-2-toluonitrile [ka] The compounds listed in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, and 78 mg of brown Solids were provided. 1 H NMR (400 MHz, DMSO-d6)8.67 (d, J = 0.8 Hz,1H), 7.94 - 7.8 1 (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). C 22 H 20 N8O's ESIMS[M+H] + Calculated value: 413.2, measured value: 413.3.

[0354] Example 56: 6-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-4-(1-{[6-(methoxymethyl (Tyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] Prepare the compounds listed in the title from the corresponding azides and alkynes in the same manner as in Example 20, and 30 mg of yellow Solids were provided. 1 H NMR (400 MHz, DMSO-d6) δ8.67 (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). C 21 H 17 F2N7O3 ESI MS [M+H] + Calculated value: 454.1, measured value: 454.3.

[0355] Example 57: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(m-trifluoromethoxyphenyl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, yielding 100 mg of white solids. 1 H NMR (400MHz, DMSO-d6) δ8.70 (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). C 21 H 18 ESI of F3N7O2 MS [M+H]+ Calculated value: 458.2, measured value: 458.3.

[0356] Example 58: {m-[2-Amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazol-4-yl)-4-pyrimidinyl]phenyl}(dimethylamino)formaldehyde

Chemical Structure

[0357] Example 59: {m-[2-Amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazol-4-yl)-4-pyrimidinyl]phenylaminohydroxysulfeno}methane

Chemical Structure

[0358] Example 60: 6-(Methylphenyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazol-4-yl)-2-pyrimidinylamine

Chemical Structure

[0359] Example 61: {m-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-yl)-4-pyrimidinyl]phenyl}acetonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, yielding 103 mg of brown solids. 1 H NMR (400MHz, DMSO-d6) δ8.66 (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 = 1.2 Hz, 3H). C 22 H2 ESI MS [M+H] of 0N8O + Calculated value: 413.2, measured value: 413.3.

[0360] Example 62: 6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-4-[m-(1,3-oxazole-2-yl)phenyl]-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, yielding 110 mg of brown solids. 1H NMR (400MHz, DMSO-d6) δ8.79 (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). C 23 H 20 N8O2 ESI MS [M+H] + Calculated value: 441.2, measured value: 441.3.

[0361] Example 63: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (L)-6-(3-pyridyl)-2-pyrimidinylamine [ka] 2-(azidomethyl)-6-(methoxymethyl)pyridine and 6-ethynyl-4-(3-pyridyl)-2-pyridyl Using limidinylamine (which was prepared in the same manner as in steps 1-3 of Example 1), proceed in the same manner as in step 6 of Example 1. The compound described in the title was synthesized. 1 ¹H NMR (400 MHz, chloroform-d) δ 9.32 (d, J = 2.4 H) z, 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, J = 7.8Hz, 1H), 5.73 (s, 2H), 5.15 (s, 2H), 4.59 (s, 2H), 3.50 (s, 3H) . C 19 H 18 N8O's MS[M+H] + Calculated value: 375.2, measured value: 375.3.

[0362] Example 64: 6-(2-furyl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-trimethyl) Azole-4-yl)-2-pyrimidinylamine [ka] 2-(azidomethyl)-6-(methoxymethyl)pyridine and 6-ethynyl-4-(2-furyl)-2-pyridine The compound described in the title was synthesized using a midinylamine in the same manner as in step 6 of Example 1. 1 ¹H 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); C 18 H 17 N7O2 ESIMS[M+H] + Calculated value: 364.1, Measured value: 364.2 .

[0363] Example 65: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(1,3-thiazole-2-yl)-2-pyrimidinylamine [ka]

[0364] Step 1: To a solution of thiazole acid derivative (6.46 g, 50.0 mmol) and THF (100 mL) at 0 °C, CDI (9.72 g, 60.0 mmol) was added in a single dose. The mixture was then stirred at room temperature for 4 hours. In a Lasco, ethyl potassium malonate (25.5 g, 150 mmol), MgCl2 (14.3 g, 150 mmol), and THF (100 mL) were stirred at 75 °C for 4 hours. Upon completion of the two reactions, the activated acid derivative was... The mixture containing was added to the other flask at room temperature. The combined reaction mixture was stirred at 50 °C for 16 hours. The mixture was cooled to room temperature, and then 100 mL of 2 M HCl (aqueous solution) was added. The mixture was extracted with ethyl acetate (2 x 150 mL), washed with saturated NaHCO3 and brine, and then silica. The mixture was filtered through a gel plug to provide the desired β-ketoester product as a brown oil (9.11 g; 91%).

[0365] Step 2: Sodium ethoxide (1.36 g, 20.0 mmol) was provided in a solution of guanidine hydrochloride (1.91 g, 20.0 mmol) and ethanol (40 mL). The mixture was stirred at room temperature for 10 minutes, and then... Next, the above β-ketoester (3.98 g, 20.0 mmol) was added. The mixture was heated at 100 °C for 16 hours. The mixture was stirred. Hexane (100 mL) was added during cooling to room temperature. The precipitated solid was recovered by filtration, and the desired product was provided as a yellow solid (2.88 g, 74%).

[0366] Step 3: The dioxane (59 m) of the product from step 2 (2.88 g, 14.8 mmol) and POCl3 (13.8 mL, 148 mmol) The mixture in (L) was stirred at 70 °C for 2 hours. Then, the mixture was poured onto ice (75 g) and saturated NaH Neutralized with CO3, extracted with ethyl acetate (2 x 150 mL), and dried over Na2SO4. Crude product. The substance was purified by silica gel chromatography (0-5% MeOH in CH2Cl2), and the desired chloropyrimidine derivative was provided as a brown solid (1.29 g; 41%).

[0367] Steps 4 and 5: Product of step 3 (1.29 g; 6.07 mmol), trimethylsilylacetylene (2.59 mL, 18.2 mm) (ol), bis(triphenylphosphine)palladium chloride (428 mg; 0.61 mmol), copper iodide (I) Mixture of (116 mg, 0.61 mmol), triethylamine (3 mL), and DMF (3 mL) at 80 °C. The mixture was stirred for 12 hours. After removing volatiles, the crude product was purified by silica gel chromatography (0-100% ELISA in hexane) to provide the alkyne derivative. It was then converted to MeOH(30 Dissolve in (mL), add ammonia (4.3 mL, 7 M in MeOH), and leave the mixture at room temperature for 30 minutes. The mixture was stirred. Volatile matter was removed, and the crude product was purified by silica gel chromatography (0-50% siRNA in CH2Cl2 / hexane (1:1)) to obtain the desired product as an orange solid (254 mg; 21%).

[0368] Step 6: The product was synthesized in the same manner as in step 6 of Example 1: off-white solids content (34 mg, 30%). 1H NMR (400 MHz,DMSO-d6)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). C 17 H 17 N8OS's ESIMS [M+H] + Calculated value: 381.1, measured value: 381.2.

[0369] Example 66: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(4-methyl-1,3-thiazole-2-yl)-2-pyrimidinylamine [ka] The compound described in the title was synthesized in the same manner as in Example 65 above. 1 HNMR (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, 2 H), 3.49 (s,3H), 2.54 (s, 3H). C 18 H 18 N8OS's ESIMS [M+H] + Calculated value: 395.1, Measured value: 395 .2.

[0370] Example 67: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (l)-6-(3-methyl-2-pyradinyl l)-2-pyrimidinylamine [ka]

[0371] Steps 1~4: TMS alkyne derivatives were synthesized in the same manner as in Example 65: brown solids (193 mg, 1.3% (4 steps)).

[0372] Step 5: A solution of TMS alkyne derivative (193 mg, 0.682 mmol) in THF (3.4 mL) at 0 °C is mixed with TBAF (3. 4 mL of 0.750 mmol (1 M in THF) was added dropwise. The mixture was stirred at 0 °C for 15 minutes. The mixture was concentrated and purified by silica gel chromatography (0-5% MeOH in CH2Cl2), and the desired product was provided as a brown solid (93 mg; 65%).

[0373] Step 6: In Example 1, the product was synthesized in the same manner as in step 6: off-white solids (7 mg, 6%). 1 1H NMR (40 0 MHz, DMSO-d6)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). C 19 H 20 N9O's ESIMS [M+H] + Calculated value: 390.2, measured value value.

[0374] Example 68: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(2H-pyrazole-3-yl)-2-pyrimidinylamine [ka] Prepare the compounds listed in the title from the corresponding azides and alkynes in the same manner as in Example 20, and 92 mg of pale yellow Colored solids were provided. 1 H NMR (400 MHz, DMSO-d6) δ8.60 (s, 1H), 7.90 -7.81 (m, 2 H), 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). C 17 H 17 N 9O ESI MS [M+H] + Calculated value: 364.2, measured value: 364.3.

[0375] Example 69: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(1H-pyrazole-4-yl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, yielding 2.4 mg of yellowish-brown solids. 1 H NMR (400MHz, DMSO-d6) δ8.57 (s, 1H), 8.45 (s, 1H), 8.0 9 (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). C 17 H 17 N9O's ESIMS [M+H] + Calculated value: 364.2, measured value: 364.2.

[0376] Example 70: 6-(1H-indazole-6-yl)-4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}- 1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ9.23 (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). C 21 H 19 N9O MS [M+H] + Calculated value: 414.2, measured value: 414.3.

[0377] Example 71: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(7-Quinolyl)-2-Pyrimidinylamine [ka] The compounds listed in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, and 61 mg of brown Solids were provided. 1H NMR (400 MHz, DMSO-d6) δ8.99 (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). C 23 H 20 N8O's ESIMS[M+H] + Calculated value 425.2, Measured value: 425.3.

[0378] Example 72: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(8-quinolyl)-2-pyrimidinylamine [ka] The compounds listed in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20, and 31 mg of brown Solids were provided. 1 H NMR (400 MHz, DMSO-d6) δ8.98 (dt, J = 4.2,1.5 Hz, 1H), 8 .65 (d, J = 1.2Hz, 1H), 8.49 (dd, J = 8.4, 1.8 Hz, 1H), 8.21 - 8.09 (m, 2H), 7. 93 (d, J = 1.2Hz, 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) . C 23 H 20 N8O's ESI MS [M+H] + Calculated value: 425.2, measured value: 425.3.

[0379] Example 73: 4-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-I (Lu)-6-(1H-pyrazole-1-yl)-2-pyrimidinylamine [ka]

[0380] Step 1: NaH (60% dispersion in mineral oil, 840 mg, 21 mmol, 1.05 equiv.) was suspended in DMF (80 mL), The suspension was then cooled in an ice / water bath. (Pyrazole (1.43 g, 21 mmol, 1.05 equiv.)) The following was added. After 45 minutes, the solid component dichloropyrimidine (3.26 g, 20 mmol, 1 equiv.) was added. Then the ice bath was removed. After 2 hours, water was added, and the reaction mixture was filtered. The compound described above was provided as 2.99 g of pale yellow solids.

[0381] Steps 2 and 3: Similar to Example 1, 30 mg of yellow solid was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 8.64(s, 1 H), 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). C 17 H 17 N9O's ESIMS [M+H] + Calculated value: 364.2, measured value: 364.2.

[0382] Example 74: m-[2-amino-6-(1-{[6-(methoxymethyl)-2-pyridyl]methyl}-5-methyl-1H-1,2 ,3-triazol-4-yl)-4-pyrimidinyl]benzonitrile [ka]

[0383] Process 1. Alkynes were prepared in the same manner as in step 2 of Example 1 by using propyne as a reagent. .

[0384] Process 2. Azide derivatives (18 mg, 0.1 mmol) and alkynes (23 mg, 0.1 mmol) in toluene (1 mL) The mixture was heated in a sealed tube at 120 °C for 20 hours. The mixture was then cooled to room temperature. The solution was evaporated until dry, and then purified by silica gel chromatography (hexane / Â 70:30~0:100). The desired product (4 mg, 10%) was provided along with its positional isomer (2 mg, 5%). Ta. 1¹H 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, 1.2H) z, 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 = 7.8Hz, 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). C 22 H 20 N8O's MS[M+H] + Calculated value: 413.2, Measured value: 413.3.

[0385] Example 75: m-[2-amino-6-(1-{[6-(ethoxymethyl)-2-pyridyl]methyl}-1H-1,2,3-tria Zole-4-yl)-4-pyrimidinyl]benzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 20. 1 H NMR (400 MHz, DMSO-d6)δ8.90 (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). C 22 H 21 ESIMS of N8O [M+H + Calculated value 413.2, measured value 413.3.

[0386] Example 76: m-[2-Amino-6-(1-{[6-(Isopropoxymethyl)-2-pyridyl]methyl}-1H-1,2,3- triazol-4-yl)-4-pyrimidinyl]benzonitrile

Chemical Structure

[0387] Example 77: m-[2-Amino-6-(1-{[6-(1-Methoxyethyl)-2-pyridyl]methyl}-1H-1,2,3-tri azol-4-yl)-4-pyrimidinyl]benzonitrile

Chemical Structure

[0388] Process 1. Diol (700 mg, 4.6 mmol) was dissolved in CH2Cl2 (10 mL). Imidazole (640 mg, 9. Add 4 mmol) and TBSCl (754 mg, 5 mmol), and continue mixing until the starting material is completely converted. The mixture was stirred. The crude mixture was directly taken onto a silica gel column (Hex / Â 95:5) to provide monoprotected alcohol (794 mg, 65%). The TBS-protected alcohol (794 mg, 3 mmol) from the above process was obtained. Dissolve in THF (6 mL), then add NaH (60% of mineral oil, 144 mg, 3.6 mmol) and wait for 10 minutes. The mixture was stirred, and methyl iodide (374 μL, 6 mmol) was added. Complete conversion of the starting alcohol was performed. During the fermentation process, the mixture was quenched with saturated NH4Cl, and after the usual work-up, the residue was saturated. The ether was purified by gel chromatography (Hex / Â 95:5) to provide the desired ether (800 mg, 96%).

[0389] Dissolve the above TBS derivative (800 mg, 2.8 mmol) in THF (5 mL), and then bring the solution to 0°C. After cooling, a TBAF solution (1 M in THF, 3 mL) was added dropwise. Upon completion of the reaction, Quench the mixture with saturated NH4Cl, and after normal work-up, remove the residue from silica gel. Purified by chromatography (Hex / alkyl 90:10~60:40), the desired primary alcohol (475) is obtained. We provided the amount (in mg, quantitative).

[0390] Process 2. The alcohol (475 mg, 2.8 mmol) obtained in step 1 is dissolved in CH2Cl2 (3 mL). Then, SOCl2 (397 μL, 2 equiv., 5.6 mmol) was added. The resulting solution was then prepared using a starting alcohol. The mixture was stirred until complete inversion occurred, at which point it was evaporated to dryness. The resulting residue was used without further purification. The resulting crude material was dissolved in DMF (5 mL), and sodium azide (273 mg, 4.2 mmol) was added. The resulting mixture was stirred at 50 °C for 8 hours. Next, it was cooled to room temperature. The crude product was separated into water and dichloromethane. The organic layer was evaporated until dry, and the residue was subjected to silica gel chromatography (Hex / siRNA90:10). Further purification yielded the desired azide (200 mg, 37% in 2 steps).

[0391] Step 3: The compound described in the title was synthesized in the same manner as in step 6 of Example 1, using azide derivatives and m-(2-amino-6-ethynyl-4-pyrimidinyl)benzonitrile (from Example 4). 1 1H NMR (400 MHz, chlorophosphene) Lum-d) δ8.46 (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 Hz1H), 7.40 (d, J = 7.8 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1 H), 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). C 22 H 20 N8O's MS[M+H] + Calculated value: 413.2, measured value: 413.3.

[0392] Example 78: 4-(1-{[6-(1-methoxyethyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4- (yl)-6-(1,3-oxazol-2-yl)-2-pyrimidinylamine [ka]

[0393] Steps 1 and 2: Pyrimidine derivative (3.64 g, 10.0 mmol), 2-(tri-n-butylstanyl)oxazole (2.1 A mixture of 0 mL (10.0 mmol) and Pd(PPh3)4 (1.16 g; 1.00 mmol) in DMF (20 mL) was heated to 100°C. The mixture was stirred in C for 5 hours. The mixture was cooled to room temperature, and then ethyl acetate (200 mL) was added. The material was washed with brine (4 x 200 mL) and dried on MgSO4. The crude product was stored on silica gel. The desired product was obtained by purification using chromatography (0-30% siRNA in hexane). To this, add TFA (1 mL) and CH2Cl2 (5 mL), and stir the mixture at room temperature for 10 minutes. The mixture was neutralized with saturated NaHCO3, diluted with ethyl acetate, and dried over Na2SO4. The desired product provided a yellow solid content (322 mg; 8%).

[0394] Steps 3 and 4: Terminal alkynes were synthesized in the same manner as in Example 65: brown solids (63 mg, 21%, 2 steps).

[0395] Step 5: In Example 1, the product was synthesized in the same manner as in step 6: yellow solids (13 mg, 10%). 1 1H 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). C 18 H 19 N8O2 ES I MS [M+H] + Calculated value: 379.2, measured value: 379.3.

[0396] Example 79: m-[2-amino-6-(1-{[6-(1-methoxypropyl)-2-pyridyl]methyl}-1H-1,2,3- [Riazole-4-yl)-4-pyrimidinyl]benzonitrile [ka]

[0397] 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 (3 M in THF, 2 mL, 6 mmol, 1.5 equiv.) was added along the side of the flask. After 1.5 hours, the reaction mixture was quenched with NH4Cl and extracted with ELISA. The organic layer was Celite. Concentrated with (registered trademark), and then purified by chromatography on SiO2, alcohol B (537 mg) was provided as a white solid component.

[0398] Step 2: Alcohol B (537 mg, 1.9 mmol) in THF (8 mL) is dissolved in NaH (60% dispersion in mineral oil, 99%). (mg, 2.5 mmol, 1.3 equiv.) was added. After 30 minutes, MeI (0.18 mL, 2.9 mmol, 1.5 equiv.) was added. .) was added. The reaction mixture was stirred overnight, quenched with H2O, extracted with MTBE, dried, and then It was concentrated and supplied as ether C (559 mg) as a yellow oil.

[0399] Step 3: To a solution of ether C (1.9 mmol) in THF (2 mL), TBAF (1 M, 2 mL in THF) was added. 1.5 After a certain period, the reaction mixture was concentrated, and the crude residue was purified by flash column chromatography on SiO2 to provide alcohol D (299 mg) as a colorless oil.

[0400] Steps 4 and 5: Using the procedure in Example 1, the compound described in the title was synthesized, yielding 81 mg of brown solids. 1 1H 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). C 23 H 22 N8O's ESI MS [M+H] + Calculated value: 427.2, measured value: 427.3.

[0401] Example 80: m-[2-amino-6-(1-{[6-(1-methoxy-2-methylpropyl)-2-pyridyl]methyl}-1H [-1,2,3-triazol-4-yl)-4-pyrimidinyl]benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 79, yielding 86 mg of brown solids. 1 1H NMR (400 MHz) , DMSO-d6)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, 2 H), 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, 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). C 24 H 24 N8O's ESI MS [M+H] + Calculated value: 441.2, measured value: 441.5.

[0402] Example 81: m-[2-amino-6-(1-{[6-(cyclopropylmethoxymethyl)-2-pyridyl]methyl}-1 H-1,2,3-triazol-4-yl)-4-pyrimidinyl]benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 79, and 87 mg of brown solids were provided. 1 1H NMR (400 MHz) , DMSO-d6)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), 3.6 7 (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, 4.6 Hz, 2H). C 24 H 22 N8O's ESIMS[M+H] + calculation Value 439.2, measured value 439.3.

[0403] Example 82: m-[2-amino-6-(1-{[6-(cyclopentylmethoxymethyl)-2-pyridyl]methyl}-1 H-1,2,3-triazol-4-yl)-4-pyrimidinyl]benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 79, and 81 mg of brown solids were provided. 1 1H NMR (400 MHz) , DMSO-d6)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 - 3.9 3 (m, 1H), 3.13(s, 3H), 2.16 (q, J = 7.9 Hz, 1H), 1.60 (d, J = 8.8 Hz, 1H), 1.5 2 - 1.09 (m, 7H). C 26 H 26 N8O's ESIMS [M+H] + Calculated value: 467.2, measured value: 467.3.

[0404] Example 83: m-[2-amino-6-(1-{[6-(methoxyphenylmethyl)-2-pyridyl]methyl}-1H-1,2, [3-Triazol-4-yl)-4-pyrimidinyl]benzonitrile [ka] The compound described in the title was prepared in the same manner as in Example 79, and 90 mg of brown solids were provided. 1 1H 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 = 1.9Hz, 1H), 3.33 - 3.31 (m, 3H). C 27 H 22N8O's ESI MS[M+H] + Calculated value: 47 5.2, measured value 475.3.

[0405] Example 84: m-{6-[1-({6-[(R)-1-methoxyethyl]-2-pyridyl}methyl)-1H-1,2,3-triazol-4-yl]-2-amino-4-pyrimidinyl}benzonitrile [ka]

[0406] Step 1: Triethylamine (13.6 mL) was mixed with formic acid (8.0 mL) dropwise at 0 °C. The mixture was then degassed. Then, ketone (2.68 g, 10.0 mmol), RuCl(p-cymene)-[(R,R)-Ts-DPEN] (129 mg, 0.200 mmol) and CH2Cl2 (2.6 mL) were added. The mixture was stirred at room temperature for 14 hours, and saturated NaH was added. Quenched with CO3 (aqueous solution), diluted with alkylammonium phosphate (200 mL), washed with saline solution, and then on Na2SO4. The product was dried. The crude product was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to obtain the desired product as brown oil (896 mg; 33%).

[0407] Step 2: The product from step 2 (1.14 g, 4.26 mmol) is dissolved in THF (21 mL) and NaH (204 mg) is added at 0 °C. 5.11 mmol (60% of the oil) was added in one go. The mixture was stirred at room temperature for 15 minutes, then cooled to 0°C. The mixture was cooled, and methyl iodide (265 μL, 4.26 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and then concentrated on silica gel. The crude product was subjected to silica gel chromatography. The product was purified with HCl (0-30% butyl in hexane) to provide the desired product as a colorless oil. (803 mg; 67%).

[0408] Steps 3-4: The azide was synthesized in the same manner as in Example 79, and the product was obtained as a colorless oil (373m g, 68% (2 processes).

[0409] Step 5: In Example 1, the product was synthesized in the same manner as in step 6: off-white solids content (97 mg, 79%). The compound Example 1 was synthesized in the same manner as in step 6. 1 HNMR (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). C 22 H 21 N 8O ESI MS [M+H] + Calculated value: 413.2, measured value: 413.3.

[0410] Example 85: 3-{6-[1-({6-[(R)-1-methoxyethyl]-2-pyridyl}methyl)-1H-1,2,3-triazol-4-yl]-2-amino-4-pyrimidinyl}-2-fluorobenzonitrile [ka] Compounds were synthesized from the corresponding alkynes in the same manner as in Example 84. 1 1H NMR (400 MHz, DMSO-d6) 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). C 22 H 20 FN8O's ESIMS [M+H] + Calculated value: 431.2, measured value: 431.3.

[0411] Example 86: m-{6-[1-({6-[(S)-1-methoxyethyl]-2-pyridyl}methyl)-1H-1,2,3-triazol-4-yl]-2-amino-4-pyrimidinyl}benzonitrile [ka]

[0412] Synthesis: Azide was synthesized in the same manner as in Example 84, but RuCl(p-cymene)-[(S,S)-Ts-DPEN] was added in step 2. It was used as a catalyst.

[0413] Step 6: In Example 1, the product was synthesized in the same manner as in step 6: off-white solid content (96 mg, 78%). 1 H NM R (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, 3 H), 1.32 (d, J= 6.5 Hz, 3H). C 22 H 21 N8O's ESI MS[M+H] + Calculated value: 413.2, Measured value: 413.3 .

[0414] Example 87: 3-{6-[1-({6-[(S)-1-methoxyethyl]-2-pyridyl}methyl)-1H-1,2,3-triazol-4-yl]-2-amino-4-pyrimidinyl}-2-fluorobenzonitrile [ka] The compound was synthesized from the corresponding alkyne in the same manner as in Example 86. 1 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s,1H), 8.31 (td, J = 7.8, 1.8 Hz, 1H), 8.13 - 8.06 (m, 1H), 7.87 (t, 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). C 22 H 20 FN8O's ESIMS [M+H] + Calculated value 431.2, actual Measured value: 431.2.

[0415] Example 88: m-[2-amino-6-(1-{1-[6-(methoxymethyl)-2-pyridyl]ethyl}-1H-1,2,3-tri Azole-4-yl)-4-pyrimidinyl]benzonitrile [ka]

[0416] Process 1. A solution of aldehyde (756 mg, 5.0 mmol) in THF (10 mL) was cooled to -78°C. MeMgBr ( 3N (2 mL, 1.2 equiv.) was added dropwise to Et2O. The resulting mixture was incubated at 0°C for 2 hours. It was slowly heated to a certain temperature, and then quenched with a saturated solution of NH4Cl. After the topping (H2O / siRNA), the organic matter is dried over sodium sulfate, filtered, and then steamed until dry. The mixture was fermented. The residue was purified by silica gel chromatography (Hex / siRNA 90:10~60:40) to obtain the corresponding alcohol (635 mg, 76%).

[0417] The alcohol obtained in step 1 (600 mg, 3.6 mmol) is dissolved in CH2Cl2 (4 mL), and then S OCl2 (525 μL, 2 equiv., 7.4 mmol) was added. The resulting solution was completely dissolved in the starting alcohol. The mixture was stirred until inversion occurred, at which point it was evaporated to dryness. The resulting residue was used without further purification.

[0418] Process 2. The crude material obtained in step 1 is dissolved in DMF (7 mL), and then sodium azide ( 325 mg (5 mmol) was added. The resulting mixture was stirred at 80°C for 8 hours, and then left to room temperature. The mixture was cooled. The crude product was separated into water and dichloromethane. The organic layer was evaporated until dry, and the residue was purified by silica gel chromatography (Hex / Âi 90:10) to obtain the desired result. We provided azide (580 mg, 84% obtained through two processes).

[0419] Step 3: The compound described in the title was synthesized in the same manner as in step 6 of Example 1, using azide derivatives and m-(2-amino-6-ethynyl-4-pyrimidinyl)benzonitrile (from Example 4). 1 HNMR (400 MHz, chloroform (m-d) δ8.47 - 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). C 22 H 20 N8O's MS [M+H] + Calculated value: 413.2, measured value: 413.3.

[0420] Example 89: m-(6-{1-[(6-{[(S)-tetrahydroflu-3-yloxy]methyl}-2-pyridyl)meth [L]-1H-1,2,3-triazole-4-yl}-2-amino-4-pyrimidinyl)benzonitrile [ka]

[0421] Process 1. 3(S)-hydroxytetrahydrofuran (440 mg, 5 mmol) in 20 mL of dry THF at 0 °C NaH (60%, 400 mg, 10 mmol) was added in five separate additions to the stirred solution. The mixture was stirred at 0°C 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 step at 0°C. The reaction mixture was stirred overnight at room temperature. It was cooled to 0°C, quenched with saturated NH4Cl aqueous solution, diluted with MTBE (10 mL), the layers were separated, the aqueous layer was extracted with MTBE, the organic matter was combined, dried (Na2SO4), filtered, and concentrated by rota vaporization. The oily residue was dissolved in dichloromethane and purified by flash column (ISCO, 40 g column 5 - 60% ethyl acetate in hexane) to a pure The compound was obtained as a colorless liquid (480 mg, 42%).

[0422] Process 2. The above product (480 mg, 2.1 mmol) was dissolved in dry DMSO (2 mL), and NaN3 (164 mg, 2.53 mmol) was dissolved. (mol) was added and the mixture was stirred at room temperature for 2 hours. LC-MS indicated completion of the reaction, and it was then mixed with water (15 mmol). Dilute (mL), extract with MTBE (3 × 15 mL), dry (Na2SO4), filter, and rotava. The mixture was concentrated. The oily residue was dried under high vacuum to provide the product (455 mg, 92%).

[0423] Process 3. The compounds described in the title were prepared from the above-mentioned azides and corresponding alkynes in the same manner as in Example 1, Step 6. 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), 4.5 2 (d, J = 1.8Hz, 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); C 24 H 22 N8O2 ESIMS[M+H] + Calculated value: 455.2, measured value: 455.3.

[0424] Example 90: m-(6-{1-[(6-{[(R)-tetrahydroflu-3-yloxy]methyl}-2-pyridyl)methyl [Tyl]-1H-1,2,3-triazol-4-yl}-2-amino-4-pyrimidinyl)benzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 89. 1 1H NMR (40 0 MHz, DMSO-d6)δ 8.73 (t, J = 1.2 Hz, 1H), 8.60 (dt, J = 1.8, 1.0Hz, 1H), 8.4 8 (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), 4.31 - 4.19 (m, 1H), 3.83 - 3.58 (m, 4H), 1.97 - 1.92 (m, 2H); C 24 H 22 N8O2 ESIMS [M+H] + Calculated value: 455.2, measured value: 455.3.

[0425] Example 91: m-{2-amino-6-[1-({6-[(2-methoxyethoxy)methyl]-2-pyridyl}methyl)-1H-1,2,3-triazole-4-yl]-4-pyrimidinyl}benzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 89. 1 H NMR (400 MHz, DMSO-d6)δ8.70 (s, 1H), 8.59 (td, J = 1.8, 0.6 Hz, 1H), 8.47 (ddd, J = 8.0, 1.8, 1.2Hz, 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, 1 H), 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); C 23 H 22 N8O2 ESIMS [M+H] + Calculated value: 443.2, measured value: 443.3.

[0426] Example 92: 3-{2-amino-6-[1-({6-[(2-methoxyethoxy)methyl]-2-pyridyl}methyl)-1H-1,2,3-triazole-4-yl]-4-pyrimidinyl}-2-anisonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 89. 1 ¹H 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 = 7.7 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); C 24 H 24 N8O3's ESIMS[M+H] + Total Calculated value: 473.2, measured value: 473.3.

[0427] Example 93: 3-(2-amino-6-{1-[(6-cyclopropyl-2-pyridyl)methyl]-1H-1,2,3-triazo (4-yl)-4-pyrimidinyl)-2-anisonitrile [ka]

[0428] Step 1: 2-bromopyridine derivative (14 g, 46.4 mmol), cyclopropylboronic acid (8 g, 93 mmol) l) 210 mL of 20:1 toluene containing K3PO4 (34.5 g, 162.4 mmol) and PCy3 (1.3 g, 4.64 mmol). Pd(OAc)2 (516 mg, 2.3 mmol) was added to the mixture in H2O. The reaction mixture was heated at 100 °C for 12 minutes. The mixture was stirred under N2 for 2 hours. Saturated NH4Cl (50 mL) was added to quench the reaction, and then aqueous solution was added. The layers were extracted with ELISA (2 x 70 mL). The pooled organic layer was dried on Na2SO4 and concentrated. It was then sent to the next process without further purification.

[0429] Step 2: The crude TBS-ether from the above process was poured into 100 mL of THF, and 46.4 mL of 1 M TBAF was added dropwise to the THF. After 15 minutes, 50 mL of saturated NH4Cl was added to quench the reaction, and then The aqueous layer was extracted with HCl (2 x 70 mL). The pooled organic layer was dried on Na2SO4 and concentrated. The alcohol was then purified by silica gel chromatography to obtain the desired alcohol (6.3 g, 91% in two steps).

[0430] Step 3: Azide was synthesized in the same manner as in step 5 of Example 1: colorless oil (6.2 g, 85%).

[0431] Step 4: The compound described in the title was synthesized in the same manner as in step 6 of Example 1. 1 HNMR (400 MHz, DMSO-d6) 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). C 23 H 20 N8O's ESIMS [M+H] + Calculated value: 425.2, Measured value: 42 5.3.

[0432] Example 94: m-(2-amino-6-{1-[(6-cyclopropyl-2-pyridyl)methyl]-1H-1,2,3-triazo (Il-4-yl)-4-pyrimidinyl)benzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 93. 1 ¹H 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 3.15min LC-MS, Method A, C 22 H 19 N8 ESIMS [M+H + ] - Calculated value 395.2, Actual measured value: 395.3.

[0433] Example 95: 3-(2-amino-6-{1-[(6-cyclopropyl-2-pyridyl)methyl]-1H-1,2,3-triazo (Il-4-yl)-4-pyrimidinyl)-2-fluorobenzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 93. 1 ¹H 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 LC-MS, Method A, C 22 H 18 FN8 ESIMS [M+H + Calculated value 413.2, Measured value: 413.3.

[0434] Example 96: 4-{1-[(6-cyclopropyl-2-pyridyl)methyl]-1H-1,2,3-triazole-4-yl}6-(2,3-difluorophenyl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 93. 1 ¹H 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 0.94 (m, 4H). C 21 H 17 MS[M+H] of F2N7 + Calculated value: 406.2, measured value: 406.3.

[0435] Example 97: 4-{1-[(6-cyclopropyl-2-pyridyl)methyl]-1H-1,2,3-triazole-4-6-(m- Fluorophenyl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 93. 1 H NMR (400 MHz, CD3OD-d4)8.60(s, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.89 (d, J = 12 Hz, 1 H), 7.77(s, 1 H), 7.64 (t, J = 8 Hz, 1 H), 7.52 (q, J = 8 Hz, 1 H), 7.25 (t, J = 8 Hz, 1H), 7.17 (d, J = 4 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 5.72 (s, 1H), 2.09-2.02(m, 1H), 0.98-0.91(m, 4H). C 21 H 18 FN7's ESIMS [M+H] + Calculated value 388.4, Actual measured value: 388.3.

[0436] Example 98: 3-(2-amino-6-{1-[(6-isopropyl-2-pyridyl)methyl]-1H-1,2,3-triazone (Lu-4-yl)-4-pyrimidinyl)-2-anisonitrile [ka]

[0437] Step 1: 2-Bromo-6-({[dimethyl(2-methyl-2-propanyl)silyl]oxy}methyl)pyridine( (2.8 g, 9.2 mmol, 1.0 equiv) and isopropenylboronate pinacol ester (2.3 g, 1 3.9 mmol, 1.5 equiv) of dioxane (37 mL, 0.25 M) and 2.0 M aqueous Na2CO3 (14 mL, 3.0 The equiv) solution was spurged with N2 for 10 minutes. After this, Pd(PPh3)4(717 mg, 0.46 mmol, 0.0 5 equiv) was added, and the reaction mixture was heated at 95°C for 18 hours. After this, the reaction mixture The solution was diluted with CH2Cl2 (100 mL), transferred to a separatory funnel, and washed with H2O (100 mL). The organic phase was then... The mixture was collected, and the aqueous phase was extracted with CH2Cl2 (2 x 100 mL). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. The resulting oil was purified by column chromatography (0:1 siRNA:hexane → 1:9 siRNA:hexane) to obtain the compound described above as a colorless oil. Provided (2.2g, 90% yield).

[0438] Step 2: Isopropenylpyridine (2.2 g, 8.4 mmol, 1.0 equiv) from step 1 containing acetic acid (0.1 mL) The solution of ) in methanol (20 mL, 0.5 M) was spurged with N2 for 5 minutes, and then PtO2 (117 mg, 0.52 mmol (0.05 equiv) was added. The suspension was spurged with an H2 balloon for 10 minutes, and then... The reaction mixture was then stirred under an H2 atmosphere (balloon) for 20 hours. Upon completion, the reaction mixture was saturated. Filter the filtrate on a tray, wash the filter cake with methanol (2 x 10 mL), and then vacuum the filtrate. It was concentrated inside. The resulting oil was used in the next step without further refinement.

[0439] Step 3: The intermediate from the above process is absorbed into 1.0 M TBAF (20 mL, 2.0 equiv) in THF, and The solution was stirred at room temperature for 45 minutes. Then, the reaction mixture was directly loaded onto SiO2, and then... Purified by ram chromatography (0:1 MeOH:CH2Cl2 → 1:9 MeOH:CH2Cl2), (6-isopropyl alcohol) Ropyru-2-pyridyl)methanol (1.1g, 87% yield) was provided as a colorless oil.

[0440] Step 4: (6-isopropyl-2-pyridyl)methanol (1.1g, 7.0 mmol, 1.0 equiv) in toluene To a solution (14 mL, 0.5 M), add diphenyl phosphoryl azide (1.8 mL, 8.4 mmol, 1.2 equiv.) Add the following, then 1,8-diazabicyclo[5.4.0]undes-7-ene (1.3 mL, 8.4 mmol, 1.2 (equiv.) was added. The resulting mixture was heated at 60°C for 1.5 hours. The reaction mixture was then , loaded directly onto SiO2, and column chromatography (0:1 Depositphotos → 1:19 Depositphotos Purified by hexane, yielding 2-(azidomethyl)-6-isopropylpyridine (890 mg, 72% yield). It was provided as a colorless oil.

[0441] Step 5: The compound described in the title was synthesized in the same manner as in step 6 of Example 1. 1 HNMR (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), 7.6 3 (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). C 23 H 22 N8O's ESIMS [M+H] + Calculated value: 427.2, measured value: 427.3.

[0442] Example 99: m-(2-amino-6-{1-[(6-isopropyl-2-pyridyl)methyl]-1H-1,2,3-triazone (Lu-4-yl)-4-pyrimidinyl)benzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 98. 1 H NMR (400 MHz, CD3OD)δ8.82 (s, 1H), 8.54 (s, 1H), 8.45 (d, J = 8.1 Hz, 1H), 7.94-7.86 (m, overlap, 3H), 7.74 (dd, J = 8.0, 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1 H), 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). C 22 H 20 N8 ESIMS [M+H] + Calculated value: 397.2, measured value: 397.3.

[0443] Example 100: 6-(m-fluorophenyl)-4-{1-[(6-isopropyl-2-pyridyl)methyl]-1H-1,2,3 Triazole-4-yl-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 98. 1 H NMR (400 MHz, CD3OD-d4)8.65(s, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.73-7.78(m, 3 H), 7.53 (d, J = 8 Hz, 1 H), 7.27 (d, J = 8 Hz, 1 H), 7.16 (d, J = 4Hz, 1 H), 7.20 (dt, J = 8, 4 Hz, 1 H), 7.1 (d, J = 8.0 Hz, 1 H), 5.79 (s, 2H),3.04-3.07 (m, 1H), 1.28 (d, J = 4 Hz, 6H). C 21 H 20 FN7's ESIMS [M+H] + Calculated value: 390.4, measured value: 390.3.

[0444] Example 101: 3-(2-amino-6-{1-[(6-isopropyl-2-pyridyl)methyl]-1H-1,2,3-triazone (Lu-4-yl)-4-pyrimidinyl)-2-fluorobenzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 98. 1 ¹H NMR (400 MHz, acetone-d6) 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, 0.9Hz, 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). C 22 H 19 FN8 ESI MS[M+H] + Calculated value: 415.2, Measured value: 415.3 .

[0445] Example 102: 6-(2,3-difluorophenyl)-4-{1-[(6-isopropyl-2-pyridyl)methyl]-1H-1,2,3-triazole-4-yl}-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 98. 1 ¹H NMR (400 MHz, acetone-d6) δ 8.72 (s, 1H), 7.89 - 7.87 (s, 2H), 7.79 (t, J = 7.9 Hz, 1 H), 7.51 (q, J= 8.6 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.2 1 (d, J = 7.7Hz, 1H), 5.85 (s, 2H), 3.07 (p, J = 7.2 Hz, 1H), 1.25 (dd, J = 6.9 , 1.2 Hz, 6H). C 21 H 19 ESIMS[M+H] of F2N7 + Calculated value: 408.2, measured value: 408.3.

[0446] Example 103: 6-(2-amino-6-{1-[(6-isopropyl-2-pyridyl)methyl]-1H-1,2,3-triazone (Lu-4-yl)-4-pyrimidinyl)-2-truonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 98. 1 ¹H NMR (400 MHz, acetone-d6) 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 H z, 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). C 23 H 22 N8 ESI MS [M+H] + Calculated value: 411.2, measured value: 411.3.

[0447] Example 104: 3-(2-amino-6-{1-[(6-isopropyl-2-pyridyl)methyl]-1H-1,2,3-triazone (Lu-4-yl)-4-pyrimidinyl)-2-ethoxybenzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 98. 1 ¹H NMR (400 MHz, acetone-d6) 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, 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, 1.8Hz, 4H), 1.25 (dd, J = 6.9, 1.9Hz, 6H). C 24 H 24 N8O's ESIMS[M+H] + Calculated value: 441.2, measured value: 441.3.

[0448] Example 105: m-[2-amino-6-(1-{[6-(tert-butyl)-2-pyridyl]methyl}-1H-1,2,3-triazo [4-yl)-4-pyrimidinyl]benzonitrile [ka]

[0449] Step 1: To a suspension of CuCN (2.24 g, 25.0 mmol) in THF (50 mL), t-BuMgCl (50.0 mmol) was added at -78 °C. A 1 M solution (50.0 mmol, 1 M in THF) was added. The mixture was stirred at -78 °C for 30 minutes. Add the lysine derivative (1.51 g, 5.00 mmol) dropwise, and stir the mixture at -78 °C for 2 hours. Mixed. The mixture was heated at room temperature for 14 hours, and then NH3 (50 mL, 25% in water) and then 50 mL of ethyl acetate were added. The mixture was stirred at room temperature for 30 minutes and then filtered to remove all traces of the solution. The solid components were filtered. The organic phase was dried with brine and MgSO4, then passed through a silica gel plug and eluted with ethyl acetate. The organic phase was concentrated to provide the desired product as a yellow oil, which was used directly in the next step.

[0450] Steps 2~3: Azide was synthesized in the same manner as in Example 79: colorless oil (253 mg, 27%, 3 steps).

[0451] Step 4: The product was synthesized in the same manner as in Example 1, step 6: yellow solids (86 mg, 70%). 1 1H NMR (400 MHz, DMSO-d6)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, 0.9 Hz,1H), 5.88 (s, 2H), 1.25 (s, 9H). C 23 H 23 N8's ESIMS [M+H] + Calculated value: 41 1.2, measured value 411.3.

[0452] Example 106: 6-(3-chloro-2-methoxyphenyl)-4-(1-{[6-(tert-butyl)-2-pyridyl]methyl }-1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 105. 1 H NMR (400 MHz, CDCl3)δ8.35 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 7.8, 1.9Hz, 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). C 23 H 24 ClN7O's ESI MS[M+H] + Calculated value: 450.2, Measured value: 450.3 .

[0453] Example 107: 6-(3-fluoro-2-methoxyphenyl)-4-(1-{[6-(tert-butyl)-2-pyridyl]meth (L)-1H-1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 105. 1 H NMR (400 MHz, DMSO-d6)δ8.65 (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 = 7.4 Hz, 1H), 6.80 (s, 2H), 5. 80 (s, 2H), 3.85 (s, 3H), 1.26 (s, 9H). C 23 H 25 FN7O's ESIMS [M+H] + Calculated value 434.2, Actual measured value: 434.4.

[0454] Example 108: 3-[2-amino-6-(1-{[6-(tert-butyl)-2-pyridyl]methyl}-1H-1,2,3-triazo [4-yl)-4-pyrimidinyl]-2-anisonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 105. 1 H NMR (400 MHz, DMSO-d6)δ8.76 (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). C 24 H 25 N8O's ESIMS [M+H] + Calculated value: 441.2, measured value: 441.3.

[0455] Example 109: 3-[2-amino-6-(1-{[6-(tert-butyl)-2-pyridyl]methyl}-1H-1,2,3-triazo [4-yl)-4-pyrimidinyl]-2-fluorobenzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 105. 1 H NMR (400 MHz, DMSO-d6)δ8.75 (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). C 23 H 22 FN8's ESIMS [M+H] + Calculated value: 429.2, measured value: 429.3.

[0456] Example 110: 6-(2,3-difluorophenyl)-4-(1-{[6-(tert-butyl)-2-pyridyl]methyl}-1H -1,2,3-triazole-4-yl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 105. 1 H NMR (400 MHz, CDCl3)δ8.38 (s, 1H), 7.87 (s, 1H), 7.77 - 7.70 (m, 1H), 7.60 (dd, J = 8.0, 8.0Hz, 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). C 22 H 21 MS[M+H] of F2N7 + Calculated value: 422.2, measured value: 422.3.

[0457] Example 111: 6-[2-amino-6-(1-{[6-(tert-butyl)-2-pyridyl]methyl}-1H-1,2,3-triazo [4-yl)-4-pyrimidinyl]-2-tolunitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 105, yielding 73 mg of brown solids. 1 H NMR (400MHz, DMSO-d6)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). C 24 H 24 N8 ESIMS[M +H] + Calculated value: 425.2, measured value: 425.4.

[0458] Example 112: 6-(m-fluorophenyl)-4-(1-{[6-tert-butyl)2-pyridyl]methyl}-1H-1,2, 3-Triazole-4-yl)-2-pyrimidinylamine [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 105. 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). C 22 H 22 FN7 ESIMS [M+H] + Calculated value: 404.4, measured value: 404.4.

[0459] Example 113: 2-[6-({4-[2-amino-6-(o-fluorophenyl)-4-pyrimidinyl]-1H-1,2,3-tri Azole-1-yl(methyl)-2-pyridyl]-2-methylpropiononitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 1. 1 1H NMR (400 MHz, chloroform-d)δ 8.34 (s, 1H), 8.01 (ddd, J = 7.8, 7.8, 1.9 Hz, 1H), 7.9 2 (d, J = 2.2Hz, 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). C 22 H 17 FN8 MS[M+H] + Calculated value: 415.2, measured value: 1 / 2 The value is 415.2.

[0460] Example 114: 5-[2-amino-6-(m-cyanophenyl)-4-pyrimidinyl]-3-{[6-(tert-butyl)-2- Pyridylmethyl}-3H-1,2,3-triazole-4-carboxylic acid [ka]

[0461] Process 1. Chloride (500 mg, 2.17 mmol) and propinol (0.5 mL) in DMF (3 mL) and Et3N (5 mL) The mixture was degassed for 5 minutes. PdCl2 (dppf) (79 mg, 5 mol%) and CuI (41 mg, 10 mol%) were added. The mixture was then heated to 75°C for 1 hour. The desired alkyne (210) was obtained by a normal workup, followed by purification on silica gel ((hexane / CH2Cl2)(1:1) / siRNA100:0~0:100). We provided mg, 39%).

[0462] Process 2. A mixture of alkyne derivative (70 mg) and azide derivative (60 mg, 1.1 eq.) in toluene. The mixture was heated at 120°C for 30 hours. Excess solvent was removed under vacuum, and the residue was flushed out. Purified by column chromatography, m-{2-amino-6-[5-(hydroxymethyl)-1-{[6-(tert-butyl)-2-pyridyl]methyl}-1H-1,2,3-triazole-4-yl]-4-pyrimidinyl}benzonitrile was obtained. 1 1H 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). C 24 H 24 N8O's MS[M+H] + Calculated value: 441.2, measured value: 441.4.

[0463] Process 3. m-{2-amino-6-[5-(hydroxymethyl)-1-{[6-(tert-butyl)-2-pyridyl]methyl}-1H-1,2,3-triazol-4-yl]-4-pyrimidinyl}benzonitrile (35 mg, 0.08 mmol) The mixture was absorbed into CH2Cl2 (3 mL), and then MnO2 (1.05 g) was added. The resulting mixture was left at room temperature. The mixture was stirred for 24 hours. Filtration on Celite, followed by chromatography on silica gel (CH2Cl2 / siRNA90:10~20:80), revealed the corresponding aldehyde (15 mg, 43%) and acid (11 mg). They provided 31%. 1 HNMR (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), 7.1 3 (d, J = 7.9Hz, 1H), 6.31 (s, 2H), 1.18 (s, 9H). C 24 H 22 MS[M+H] of N8O2 + Calculated value 4 55.2, actual measured value 455.3.

[0464] Example 115: m-[2-amino-6-(1-{[6-(1-hydroxycyclobutyl)-2-pyridyl]methyl}-1H- [1,2,3-triazol-4-yl)-4-pyrimidinyl]benzonitrile [ka]

[0465] Step 1: A round-bottom flask was loaded with 2.0 g (6.7 mmol) of a commercially available 2-bromopyridine derivative. 13.0 mL of dry THF was added to the flask and cooled to -78 °C under N2. nBuLi 2.7 The cyclob solution (2.5 M in THF) was added dropwise to the reaction mixture at -78°C and stirred for 30 minutes. Then, add Tanone (0.58 mL, 7.9 mmol) in one step, and warm the reaction mixture at room temperature for 2 hours. (LCMS shows the formation of the desired addition product). The reaction mixture was cooled to 0°C and then 6.7 m L of TBAF (1M in THF) was added. The reaction mixture was stirred at 0 °C for 15 minutes, and then 50.0 mL of saturation was added. The reaction was quenched by adding aqueous NH4Cl. The aqueous layer was extracted with ELISA (2 x 50 mL). The crude material was dried on Na2SO4 and then concentrated. The crude material was analyzed by silica gel chromatography. The desired pyridine-diol (570 mg, 48%, obtained in two steps) was obtained through purification.

[0466] Step 2: A solution of the diol (570.0 mg, 3.2 mmol) from step 1 in CH2Cl2 (4.0 mL) is mixed with diphenyl Phosphoryl azide (0.8 mL, 3.8 mmol) and DBU (0.6 mL, 3.8 mmol) were added at room temperature. The reaction mixture was stirred under N2 at room temperature for 10 hours. After removing CH2Cl2, the residue was resuspended in SiO2 and then washed with H2O (2 x 25 mL). The organic layer was dried over Na2SO4. The crude material was then concentrated. The crude material was purified by silica gel chromatography to obtain the desired azide (450 mg, 69%).

[0467] Step 3: The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 1 (Step 6). 1H 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, 0.9 Hz, 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). C 23 H 20 N8O ESI MS[M+H] + Calculated value: 425.2, measured value: 425.3.

[0468] Example 116: m-[2-amino-6-(1-{[6-(1-hydroxycyclopentyl)-2-pyridyl]methyl}-1H [-1,2,3-triazol-4-yl)-4-pyrimidinyl]benzonitrile [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 115. 1 ¹H 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),7.80 - 7.69 (m, 2H), 7.61 (td, J = 7.8, 0.6 Hz, 1H), 7.39 (dd, J = 8.0, 0.9Hz, 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). C 24 H 22 N8O's ESIMS [M+H] + Calculated value: 439.2, Measured value: 43 9.3.

[0469] Example 117: 1-[6-({4-[2-amino-6-(2,3-difluorophenyl)-4-pyrimidinyl]-1H-1,2,3- Triazole-1-yl(methyl)-2-pyridyl]cyclopentanol [ka] The compounds described in the title were prepared from the corresponding azides and alkynes in the same manner as in Example 115. 1 ¹H 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, 2 H), 2.12 - 1.79 (m, 8H). C 23 H 21 MS[M+H] of F2N7O + Calculated value: 450.2, measured value: 450.3.

[0470] Example 118: 3-[2-amino-6-(1-{[6-(1-hydroxycyclopentyl)-2-pyridyl]methyl}-1H [-1,2,3-triazol-4-yl)-4-pyrimidinyl]-2-fluorobenzonitrile [...

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