TW201940169A - Compounds - Google Patents

Abstract

Compounds of formula (I): and related aspects.

Description

   Compound   

The present invention relates to a novel compound, a method for producing these compounds, related intermediates, a composition containing these compounds, and the use of these compounds as cytidine triphosphate synthase 1 inhibitors, in particular for use in Treat or prevent conditions related to cell proliferation.

Nucleotides are key building blocks of cellular metabolic processes, such as the synthesis of DNA and RNA. There are two types of nucleotides, which contain purine or pyrimidine bases, both of which are important for metabolic processes. Accordingly, many therapies have been developed to target different aspects of nucleotide synthesis, some of which can inhibit the production of purine nucleotides, some pyrimidine nucleotides, or both.

The pyrimidine nucleotide cytidine 5 'triphosphate (CTP) is an essential precursor for not only DNA and RNA, but also anabolic metabolism of phospholipids and sialylation of proteins. CTP comes from two sources: salvage pathway and de novo synthesis pathway, depending on two enzymes of CTP synthase (or synthetase) 1 and 2 (CTPS1 and CTPS2) (Evans And Guy 2004; Higgins, et al. 2007; Ostrander, et al. 1998).

CTPS1 and CTPS2 catalyze the conversion of uridine triphosphate (UTP) and glutamine to cytidine triphosphate (CTP) and L-glutamine:

These two enzymes have two functional domains, an N-terminal synthetase domain and a C-terminal glutamylase domain (Kursula, et al., 2006). The synthetase functional domain transfers the phosphate of adenosine triphosphate (ATP) to the 4-position of UTP to form the activated intermediate 4-phosphate-UTP. The glutamate functional domain causes glutamine to produce ammonia, which produces glutamine via a covalent thioester intermediate with a retained activation site. This ammonium is transferred from the glutamylase domain to the synthetase domain via a channel or can be derived from foreign ammonium. This ammonium was then used by the synthetase domain to produce CTP from 4-phosphate-UTP (Lieberman, 1956).

Although CTPS has two isoforms, CTPS1 and CTPS2, in humans and other eukaryotes, the functional differences between these two isoforms have not been fully defined (van Kuilenburg, et al., 2000).

The immune system provides protection from infection, and thus evolves to respond rapidly to many pathogens to which an individual is exposed. This response can take many forms, but the expansion and differentiation of immune populations are important elements, and are therefore closely related to rapid cell proliferation. Accordingly, CTP synthetase activity appears to play an important role in DNA synthesis and rapid expansion of lymphocytes after activation (Fairbanks, et al., 1995; van den Berg, et al., 1995).

Reliable clinical trials confirm that CTPS1 is an important enzyme for human lymphocytic proliferation, because the loss of homozygous mutations (rs145092287) identified in this enzyme results in unique and life-threatening immunodeficiency, which is characterized by response to antigen receptors. The ability to activate T- and B-cells for proliferation is impaired. Activated CTPS1-deficient cells have been shown to have reduced levels of CTP. In CTPS1-deficient cells, normal T-cell proliferation can be restored by expressing wild-type CTPS1 or adding cytidine. CTPS1 has been found to be low in resting lymphocytes, but is rapidly upregulated upon activation of these cells. CTPS1 performance in other tissues is usually low. CTPS2 seems to be commonly expressed in many cells and tissues, but the degree of expression is low, and the ability to maintain intact CTPS2 in patients still cannot compensate for the mutant CTPS1. Therefore, supporting CTPS1 is an important enzyme that affects the immune population of patients (Martin, et al., 2014).

Taken together, these results suggest that CTPS1 is an important enzyme necessary to supply the CTPs required to supply several important immune cell populations.

Generally, the immune response is closely regulated to ensure protection from infection, while controlling any response that targets the host tissue. In some cases, the process is not effectively controlled, causing immune-mediated lesions.

Many human diseases are attributable to these inappropriate reactions mediated by different elements of the immune system.

If the role of cell populations (such as T and B lymphocytes) is considered to play an important role in many autoimmune and other diseases, CTPS1 represents a new class of immunosuppressive targets. Therefore, inhibition of CTPS1 provides a new strategy to inhibit activated lymphocytes and selected other immune cell populations (such as natural killer cells, mucosa-associated constant T cells (MAIT), and constant natural killer) that are prominent in the phenotype of human mutant patients. T cells) (Martin, et al., 2014).

Cancer affects many cell types and tissues, but the root cause is the controlled breakdown of cell division.

This process is extremely complex and requires careful coordination, many of which are still not fully understood.

Cell division requires the efficient replication of cellular DNA and other components. Interfering with cell replication by targeting nucleic acid synthesis has been a core strategy in cancer therapy for many years. Examples of therapies that work in this way are 6-thioguanine, 6-hydrothiopurine, 5-fluorouracil, cytarabine, gemcitabine and pemetrexed.

As mentioned above, the pathways involved in providing key building blocks for nucleic acid replication are the purine and pyrimidine synthesis pathways, and pyrimidine biosynthesis has been observed in tumors and neoplastic cells.

The up-regulation of CTPS activity occurs in a range of tumor types (both blood-derived and non-blood-derived), but different types have also been observed between patients. The correlation between high enzyme content and resistance to chemotherapeutics was also explored.

At present, the true role of CTPS1 and CTPS2 in cancer is not fully understood. Several non-selective CTPS inhibitors have been developed for oncology indications, reaching Phase I / II clinical trials, but discontinued due to toxicity and efficacy issues.

Most of the inhibitors that have been developed are nucleoside analog prodrugs (3-deazauridine, CPEC, carbodine), which are involved in pyrimidine biosynthesis: uridine / cytidine kinase , Nucleoside monophosphate kinase (NMP-kinase) and nucleoside diphosphate kinase (NDP-kinase) are converted into active triphosphate metabolites. The remaining inhibitors (acivicin, DON) are reactive analogues of glutamine, which inhibits the glutamidase functional domain of CTPS in an irreversible manner. Gemcitibine has also been reported to have some inhibitory activity against CTPS (McClusky et al., 2016).

Therefore CTPS seems to be an important target in the field of cancer. The properties of all of the compounds mentioned above make their effects on other pathways likely to lead to their efficacy in inhibiting tumors.

Therefore selective CTPS inhibitors provide another notable tumor treatment. Compounds with different potencies against CTPS1 and CTPS2 may provide important opportunities to target different tumors, depending on their relative relevance to these enzymes.

CTPS1 is also thought to play a role in vascular smooth muscle cell proliferation after vascular injury or surgery (Tang, et al., 2013).

It is currently known that selective CTPS1 inhibitors have not been developed. Recently, the CTPS1 selective inhibitory peptide CTpep-3 has been identified. However, the inhibitory efficacy of CTpep-3 has been observed in cell-free assays, but not in cells. This is not surprising, however, because the peptide is unlikely to enter cells and therefore cannot easily develop into a medical agent (Sakamoto, et al., 2017).

In summary, the information and data available strongly suggest that inhibitors of CTPS1 will reduce the proliferation of many types of immune and cancer cell populations, and also have potential for targeting other selected cell types (such as vascular smooth muscle). It is therefore expected that inhibitors of CTPS1 can be used to treat or prevent many indications for pathologies driven by these ethnic groups.

CTPS1 inhibitors represent a selected group of suppressing the immune system in a variety of different tissues and related lesions or pathological symptoms (such as: generally, the rejection of transplanted cells and tissues, transplant-related diseases or disorders, allergies and autoimmune diseases) Share of the new strategy. In addition, CTPS1 inhibitors provide the medical potential of many cancer indications, and promote recovery from vascular injury or surgery, and reduce morbidity and mortality associated with neointimal and postoperative restenosis.

The invention provides a compound of formula (I):

Wherein A is an amidine linking group having the following structural formula: -C (= O) NH- or -NHC (= O)-; X is N or CH; Y is N or CR ₂ ; Z is N or CR ₃ ; But its limitation is that when at least one of X or Z is N, Y cannot be N; R ₁ is C _1-5 alkyl, C _0-2 alkyl, C _3-5 cycloalkyl (the cycloalkane (Optionally substituted with CH ₃ ), or CF ₃ ; R ₂ is H, halo, C _1-2 alkyl, OC _1-2 alkyl, C _1-2 haloalkyl, or OC _1-2 haloalkyl ; R ₃ is H, halo, CH ₃ , OCH ₃ , CF ₃ or OCF ₃ ; wherein at least one of R ₂ and R ₃ is H; R ₄ and R ₅ are independently H, C _1-6 alkyl, C _1-6 alkyl OH, C _1-6 haloalkyl, C _0-2 alkylalkyl C _3-6 cycloalkyl, C _0-2 alkyl alkyl C _3-6 heterocycloalkyl, C _{1- 3} alkylene OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; and when A is -NHC (= O)-: R ₄ and R ₅ may be additionally selected from the group consisting of halo, OC _1-6 haloalkyl, OC _0-2 alkyl, C _3-6 cycloalkyl, OC _0-2 alkyl C _3-6 heterocycloalkyl, OC _1-6 alkyl and NR ₂₁ R ₂₂ ; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 Relative to amidine Position; R ₁₀ is H, halo, C _1-3 alkyl, C _1-2 haloalkyl, OC _1-2 alkyl, OC _1-2 haloalkyl or CN; R ₁₁ is H, F, Cl , C _1-2 alkyl, CF ₃ , OCH ₃ or CN; R ₁₂ is attached to Ar2 in ortho or meta position relative to Ar1, and R ₁₂ is H, halo, C _1-4 alkyl, C _2-4 alkenyl, C _0-2 alkylene C _3-5 cycloalkyl, OC _1-4 alkyl, OC _0-2 alkylene C _3-5 cycloalkyl, C _1-4 haloalkyl OC _1-4 haloalkyl, hydroxyl, C _1-4 alkyl OH, SO ₂ C _1-2 alkyl, C (O) N (C _1-2 alkyl) ₂ , NHC (O) C _{1- 3} alkyl or NR ₂₃ R ₂₄ ; and when A is -NHC (= O)-: R ₁₂ may be additionally selected from: CN, OCH ₂ CH ₂ N (CH ₃ ) ₂ and C _3-6 heterocycloalkyl , which is the point of attachment position of the Ar2 contains one nitrogen, or R ₁₂ is attached thereto together form N- oxides of nitrogen ^{(N + -O -); R} 13 is H or halo; R ₂₁ is H, C _1-5 alkyl, C (O) C _1-5 alkyl, C (O) OC _1-5 alkyl; R ₂₂ is H or CH ₃ ; R ₂₃ is H or C _1-2 alkyl; and R ₂₄ is H or C _1-2 alkyl.

Conveniently, the invention provides a compound of formula (I):

Wherein R ₁ is a C _1-5 alkyl group or a C _0-2 alkylene group C _3-5 cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ ; R ₃ is H, a halogen group, or CH ₃ ; R ₄ And R ₅ are independently H, halo, C _1-6 alkyl, C _1-3 alkyl OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form C _{3 -6} cycloalkyl or C _3-6 heterocycloalkyl; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 opposite to amidine Position; R ₁₀ is H, halo, C _1-2 alkyl, OC _1-2 alkyl, OC _1-2 haloalkyl, or CN; R ₁₁ is H, F, CH ₃ or OCH ₃ ; and R ₁₂ It is attached to Ar2 in an ortho or meta position relative to Ar1, and R ₁₂ is H, halo, C _1-4 alkyl, OC _1-4 alkyl, OC _0-2 alkyl, C _3-5 ring Alkyl, CN, C _1-4 haloalkyl, OC _1-4 haloalkyl.

The invention also provides a compound of formula (I):

Wherein R ₁ is a C _1-5 alkyl group or a C _0-2 alkylene group C _3-5 cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ ; R ₃ is H, a halogen group, or CH ₃ ; R ₄ And R ₅ are independently H, C _1-6 alkyl, C _1-3 alkyl OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form a C _3-6 ring Alkyl; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 in a para position relative to amidine; R ₁₀ is H, halo, C _{1 -2} alkyl, OC _1-2 alkyl, OC _1-2 haloalkyl or CN; R ₁₁ is H, F, CH ₃ or OCH ₃ ; and R ₁₂ is attached to Ar2 in an ortho position relative to Ar1 or Meta position, and R ₁₂ is H, halo, C _1-4 alkyl, OC _1-4 alkyl, OC _0-2 alkyl, C _3-5 cycloalkyl, CN, C _1-4 haloalkyl OC _1-4 haloalkyl.

The invention also provides a compound of formula (I):

Wherein A is an amidine linking group having the following structural formula: -C (= O) NH- or -NHC (= O)-; X is N or CH; Y is N or CR ₂ ; Z is N or CR ₃ ; But its limitation is that when at least one of X or Z is N, Y cannot be N; R ₁ is C _1-5 alkyl or C _0-2 alkylene C _3-5 cycloalkyl, the cycloalkane The group may be optionally substituted by CH ₃ ; R ₂ is H, C _1-2 alkyl or C _1-2 haloalkyl; R ₃ is H, halo or CH ₃ ; wherein at least one of R ₂ and R ₃ is H ; R ₄ and R ₅ are independently H, C _1-6 alkyl or C _1-3 alkyl OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom attached to form C _{3 -6} cycloalkyl or C _3-6 heterocycloalkyl; and when A is -NHC (= O)-; R ₄ and R ₅ may be additionally selected from: halo and OC _1-6 alkyl; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl, and is attached to Ar1 in a para position relative to amidine; R ₁₀ is H, halo, C _1-3 alkyl , C _1-2 haloalkyl, OC _1-2 alkyl, OC _1-2 haloalkyl or CN; R ₁₁ is H, F, CH ₃ or OCH ₃ ; R ₁₂ is attached to Ar2 with respect to Ar1. ortho or meta position, and R ₁₂ is H, halo, C _1-4 alkyl, OC _1-4 alkyl, C _1-4 haloalkyl, OC _1-4 haloalkyl, C _0-2 Cycloalkyl C _3-5 alkyl, OC _0-2 cycloalkyl, C _3-5 alkylene, CN, or C _2-4 alkenyl group; and R ₁₃ is H.

Compounds of formula (I) may be provided in the form of their salts and / or their solvates and / or their derivatives. Conveniently, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or solvate and / or derivative thereof. In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or solvate, such as a pharmaceutically acceptable salt.

Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof and / or a solvate and / or a derivative thereof, for use in medicine, in particular, for inhibiting CTPS1 in an individual, or for preventing or treating Diseases or conditions, such as diseases or conditions that can benefit by reducing T-cell and / or B-cell proliferation.

In addition, a method for inhibiting CTPS1 for an individual, or preventing or treating a related disease or disorder, such as a disease or disorder that can benefit by reducing T-cell and / or B-cell proliferation, is provided. An individual in need thereof administers a compound of formula (I), or a pharmaceutically acceptable salt thereof and / or a formulation thereof and / or a derivative thereof.

Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof and / or a solvate and / or a derivative thereof, for use in the manufacture of a medicament for the purpose of inhibiting CTPS1 or preventing or treating related diseases for an individual. Or conditions, such as diseases or conditions that can benefit by reducing T-cell and / or B-cell proliferation.

Conveniently, the disease or condition is selected from the group consisting of: inflammatory skin diseases such as psoriasis or lichen planus; acute and / or chronic GVHD, such as: steroid-resistant acute GVHD; acute lymphoblastic syndrome (ALPS); systemic Lupus erythematosus, lupus nephritis, or cutaneous lupus; and transplantation. In addition, the disease or disorder may be selected from the group consisting of myasthenia gravis, multiple sclerosis, and scleroderma / systemic sclerosis.

Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof and / or a solvate and / or a derivative thereof, for use in treating cancer.

Further provided is a method for treating cancer in an individual, which comprises administering a compound of formula (I), or a pharmaceutically acceptable salt and / or a solvate and / or a derivative thereof to an individual in need thereof.

In addition, a compound of formula (I), or a pharmaceutically acceptable salt and / or a solvate and / or a derivative thereof, is provided for use in the manufacture of a medicament for treating cancer in an individual.

Also provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof and / or a solvate and / or a derivative thereof, for use in promoting recovery from vascular injury or surgery for an individual, and reducing neointima Mortality and mortality related to postoperative restenosis.

Further provided is a method for promoting recovery from vascular injury or surgery for an individual, and reducing the morbidity and mortality associated with neointimal and postoperative restenosis, which comprises administering a compound of formula (I) to an individual in need thereof Or its pharmaceutically acceptable salt and / or its solvate and / or its derivative.

In addition, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof and / or a solvate and / or a derivative thereof, for use in the manufacture of a medicament for promoting recovery from vascular injury or surgery for an individual. , And reduce the incidence and mortality associated with neointimal and postoperative restenosis.

Also provided is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate and / or derivative thereof, and a pharmaceutically acceptable carrier or excipient.

A method for preparing a compound of formula (I) and a glume intermediate for preparing a compound of formula (I) is also provided.

The invention provides a compound of formula (I):

Wherein A is an amidine linking group having the following structural formula: -C (= O) NH- or -NHC (= O)-; X is N or CH; Y is N or CR ₂ ; Z is N or CR ₃ ; But its limitation is that when at least one of X or Z is N, Y cannot be N; R ₁ is C _1-5 alkyl, C _0-2 alkyl, C _3-5 cycloalkyl (the cycloalkane (Optionally substituted with CH ₃ ), or CF ₃ ; R ₂ is H, halo, C _1-2 alkyl, OC _1-2 alkyl, C _1-2 haloalkyl, or OC _1-2 haloalkyl ; R ₃ is H, halo, CH ₃ , OCH ₃ , CF ₃ or OCF ₃ ; wherein at least one of R ₂ and R ₃ is H; R ₄ and R ₅ are independently H, C _1-6 alkyl, C _1-6 alkyl OH, C _1-6 haloalkyl, C _0-2 alkylalkyl C _3-6 cycloalkyl, C _0-2 alkyl alkyl C _3-6 heterocycloalkyl, C _{1- 3} alkylene OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; and when A is -NHC (= O)-When R ₄ and R ₅ can be additionally selected from: halo, OC _1-6 haloalkyl, OC _0-2 alkylalkyl C _3-6 cycloalkyl, OC _0-2 alkylalkyl C _3-6 heterocycloalkyl, OC _1-6 alkyl and NR ₂₁ R ₂₂ ; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 In amidine ; R ₁₀ is H, halo, C _1-3 alkyl, C _1-2 haloalkyl, OC _1-2 alkyl, OC _1-2 haloalkyl or CN; R ₁₁ is H, F, Cl, C _1-2 alkyl, CF ₃ , OCH ₃ or CN; R ₁₂ is attached to Ar2 in ortho or meta position relative to Ar1, and R ₁₂ is H, halo, C _1-4 alkyl, C _{2 -4} alkenyl, C _0-2 alkylene C _3-5 cycloalkyl, OC _1-4 alkyl, OC _0-2 alkylene C _3-5 cycloalkyl, C _1-4 haloalkyl, OC _1-4 haloalkyl, hydroxy, C _1-4 alkylOH, SO ₂ C _1-2 alkyl, C (O) N (C _1-2 alkyl) ₂ , NHC (O) C _1-3 Alkyl or NR ₂₃ R ₂₄ ; and when A is -NHC (= O)-: R ₁₂ may be additionally selected from: CN, OCH ₂ CH ₂ N (CH ₃ ) ₂ and C _3-6 heterocycloalkyl ( its point of attachment position of Ar2 comprises one nitrogen), or R ₁₂ is attached thereto together form N- oxides of nitrogen ^{(N + -O -); R} 13 is H or halo; R ₂₁ is H, C _1-5 alkyl, C (O) C _1-5 alkyl, C (O) OC _1-5 alkyl; R ₂₂ is H or CH ₃ ; R ₂₃ is H or C _1-2 alkyl; and R ₂₄ is H or C _1-2 alkyl; or a salt and / or a solvate and / or a derivative thereof.

Conveniently, the invention provides a compound of formula (I):

Wherein R ₁ is a C _1-5 alkyl group or a C _0-2 alkylene group C _3-5 cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ ; R ₃ is H, a halogen group, or CH ₃ ; R ₄ And R ₅ are independently H, halo, C _1-6 alkyl, C _1-3 alkyl OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form C _{3 -6} cycloalkyl or C _3-6 heterocycloalkyl; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 opposite to amidine Position; R ₁₀ is H, halo, C _1-2 alkyl, OC _1-2 alkyl, OC _1-2 haloalkyl, or CN; R ₁₁ is H, F, CH ₃ or OCH ₃ ; and R ₁₂ It is attached to Ar2 in an ortho or meta position relative to Ar1, and R ₁₂ is H, halo, C _1-4 alkyl, OC _1-4 alkyl, OC _0-2 alkyl, C _3-5 ring Alkyl, CN, C _1-4 haloalkyl, OC _1-4 haloalkyl; or salts and / or solvates and / or derivatives thereof.

The invention also provides a compound of formula (I):

Wherein R ₁ is a C _1-5 alkyl group or a C _0-2 alkylene group C _3-5 cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ ; R ₃ is H, a halogen group, or CH ₃ ; R ₄ And R ₅ are independently H, C _1-6 alkyl, C _1-3 alkyl OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form a C _3-6 ring Alkyl; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 in a para position relative to amidine; R ₁₀ is H, halo, C _{1 -2} alkyl, OC _1-2 alkyl, OC _1-2 haloalkyl or CN; R ₁₁ is H, F, CH ₃ or OCH ₃ ; and R ₁₂ is attached to Ar2 in an ortho position relative to Ar1 or Meta position, and R ₁₂ is H, halo, C _1-4 alkyl, OC _1-4 alkyl, OC _0-2 alkyl, C _3-5 cycloalkyl, CN, C _1-4 haloalkyl , OC _1-4 haloalkyl; or a salt and / or a solvate and / or a derivative thereof.

The invention also provides a compound of formula (I):

Wherein A is an amidine linking group having the following structural formula: -C (= O) NH- or -NHC (= O)-; X is N or CH; Y is N or CR ₂ ; Z is N or CR ₃ ; But its limitation is that when at least one of X or Z is N, Y cannot be N; R ₁ is C _1-5 alkyl or C _0-2 alkylene C _3-5 cycloalkyl, the cycloalkane The group may be optionally substituted with CH ₃ ; R ₂ is H, C _1-2 alkyl, or C _1-2 haloalkyl; R ₃ is H, halo, or CH ₃ ; wherein at least one of R ₂ and R ₃ is H ; R ₄ and R ₅ are independently H, C _1-6 alkyl or C _1-3 alkyl OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form C _{3 -6} cycloalkyl or C _3-6 heterocycloalkyl; and when A is -NHC (= O)-: R ₄ and R ₅ may be additionally selected from: halo and OC _1-6 alkyl; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 in a para position relative to amidine; R ₁₀ is H, halo, C _1-3 alkyl, C _1-2 haloalkyl, OC _1-2 alkyl, OC _1-2 haloalkyl or CN; R ₁₁ is H, F, CH ₃ or OCH ₃ ; R ₁₂ is attached to Ar2 adjacent to Ar1 or meta positions, and R ₁₂ is H, halo, C _1-4 alkyl, OC _1-4 alkyl, C _1-4 haloalkyl, OC _1-4 haloalkyl, C _0-2 stretch Group C _3-5 cycloalkyl, OC _0-2 cycloalkyl, C _3-5 alkylene, CN, or C _2-4 alkenyl group; and R ₁₃ is H; or a salt thereof and / or solvates and / Or its derivatives.

As used herein, the term "alkyl", such as: C _1-3 alkyl, C _1-4 alkyl, C _1-5 alkyl, or C _1-6 alkyl, whether used alone or forming one of the larger groups Some, such as: O alkyl (for example: OC _1-3 alkyl, OC _1-4 alkyl, and OC _1-5 alkyl), are straight or branched fully saturated hydrocarbon chains containing the specified number of carbon atoms. Examples of alkyl include C _1-5 alkyl: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl and n-pentyl, second pentyl And 3-pentyl, in particular, C _1-3 alkyl: methyl, ethyl, n-propyl, and isopropyl. References to "propyl" include n-propyl and isopropyl, and references to "butyl" include n-butyl, isobutyl, second butyl, and third butyl. Examples of O alkyl include OC _1-4 alkyl: methoxy, ethoxy, propoxy (which includes n-propoxy and isopropoxy) and butoxy (which includes n-butoxy, isobutyl Oxy, second butoxy and third butoxy).

As used herein, C ₆ alkyl, whether used alone or forming part of a larger group, such as OC ₆ alkyl, is a straight or branched fully saturated hydrocarbon chain containing 6 carbon atoms. Examples of C ₆ alkyl include n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

The term "alkylene" is used herein, such as: C _0-2 alkylene C _3-5 cycloalkyl, C _1-2 alkylene OC _1-2 alkyl, or OC _0-2 alkylene C _{3 -5} cycloalkyl is a bifunctional straight or branched fully saturated hydrocarbon chain containing a specified number of carbon atoms. Examples of C _0-2 alkylene are those in which the group is absent (ie, C ₀ ), methylene (C ₁ ), and ethylene (C ₂ ).

The term "alkenyl" as used herein, such as: C _2-4 alkenyl, is a straight or branched hydrocarbon chain containing a specified number of carbon atoms and a carbon-carbon double bond.

The term "cycloalkyl" as used herein, such as: C _3-5 cycloalkyl or C _3-6 cycloalkyl, whether used alone or forming part of a larger group, such as: OC _3-5 cycloalkane Or C _0-2 alkylene C _3-5 cycloalkyl, is a fully saturated hydrocarbon ring containing the specified number of carbon atoms. Examples of cycloalkyl include C _3-6 cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and specifically, C _3-5 cycloalkyl: cyclopropyl, cyclobutyl, and cyclopentyl base:

The term "heterocycloalkyl" as used herein, such as: C _3-6 heterocycloalkyl or C _0-2 alkylene C _3-6 heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms, and May include carbon atoms attached to a cycloalkyl group, where at least one carbon atom in the ring is replaced by a heteroatom, such as: N, S, or O. As required by the valence, a nitrogen atom (group) can be connected to a hydrogen atom to form an NH group. Alternatively, the nitrogen atom (group) may be substituted (eg, one nitrogen atom is substituted), for example: C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl, C (O ) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkane Aryl (such as: C (O) NHBz), Fmoc group, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _1-4 halo Alkyl substitution, such as: C (O) OtBu. When the ring heteroatom is S, the term "heterocycloalkyl" as used herein includes those in which the S atom (group) is replaced by one or two oxygen atoms (for example, one S atom is substituted) (that is, S (O) Or S (O) ₂ ). Alternatively, any sulfur atom (group) in the C _3-6 heterocycloalkyl ring is unsubstituted.

Examples of C _3-6 heterocycloalkyl include those containing one heteroatom, such as: containing one heteroatom (eg, oxygen) or two heteroatoms (eg, two oxygen atoms or one oxygen atom and one nitrogen atom) ). Specific examples of the C _3-6 heterocycloalkyl group containing one oxygen atom include ethylene oxide, oxetanyl, 3-dioxolyl, morpholinyl, 1,4-oxosulfanyl Hexane, tetrahydropiperanyl, 1,4-thioxetanyl and 1,3,5-trioxetanyl. Examples of C _3-6 heterocycloalkyl include those containing one oxygen atom (eg, containing one oxygen atom) or those containing two oxygen atoms. Specific examples of the C _3-6 heterocycloalkyl group containing one oxygen atom include ethylene oxide, oxetanyl, 3-dioxolyl, morpholinyl, 1,4-oxosulfanyl Hexane, tetrahydropiperanyl, 1,4-thioxetanyl and 1,3,5-trioxetanyl.

In one embodiment, the term "heterocycloalkyl" as used herein, such as: C _3-6 heterocycloalkyl is a fully saturated hydrocarbon ring containing a specified number of carbon atoms and may include carbon atoms attached to a cycloalkyl group, Wherein at least one carbon atom in the ring is replaced by a heteroatom, such as: N, S or O. Examples of C _3-6 heterocycloalkyl include those containing one heteroatom (eg, containing one heteroatom (eg, oxygen)) or two heteroatoms (eg, two oxygen atoms or one oxygen atom and one nitrogen atom) Atom).

Heterocycloalkyl may have the following structural formula:

Wherein each Q is a hetero atom independently selected from O, N or S. When Q is N, according to the requirements of valence, a nitrogen atom (group) can be connected to a hydrogen atom to form an NH group. Alternatively, the nitrogen atom (group) may be substituted (eg, one nitrogen atom is substituted), for example: C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl, C (O ) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkane Aryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _1-4 haloalkane Group substitution, such as: C (O) OtBu. When any Q is S, the S atom may be substituted (eg, one S atom is substituted), which is substituted by one or two oxygen atoms (ie, S (O) or S (O) ₂ ). Alternatively, any sulfur atom (group) in the C _3-6 heterocycloalkyl ring is unsubstituted.

Heterocycloalkyl may also have the following structural formula:

Each Q is independently selected from: O, N or S, such as: O or N. When Q is N, according to the requirements of valence, a nitrogen atom (group) can be connected to a hydrogen atom to form an NH group. Alternatively, the nitrogen atom (group) may be substituted (eg, one nitrogen atom is substituted), for example: C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl, C (O ) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkane Aryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _1-4 haloalkane Group substitution, such as: C (O) OtBu. When any Q is S, the S atom may be substituted (eg, one S atom is substituted), which is substituted by one or two oxygen atoms (ie, S (O) or S (O) ₂ ). Alternatively, any sulfur atom (group) in the C _3-6 heterocycloalkyl ring is unsubstituted.

When A is -C (= O) NH and R ₄ and / or R ₅ is C ₀ alkylene C _3-6 heterocycloalkyl, or when R ₄ and R ₅ are common with the carbon atom to which they are attached When forming a C _3-6 heterocycloalkyl, any heteroatom in the heterocycloalkyl cannot be directly connected to the carbon to which R ₄ and R ₅ are connected.

Conveniently, heterocycloalkyl is a completely saturated hydrocarbon ring containing a specified number of carbon atoms, at least one of which is replaced by a heteroatom (such as N, S, or O), where any nitrogen atom is connected as required by the valence A hydrogen atom, and wherein the S atom is not in an oxide state.

The term "halo" or "halogen" as used herein means fluorine, chlorine, bromine, or iodine. Specific examples of halo are fluorine and chlorine, especially fluorine.

The term "haloalkyl" as used herein, such as: when used in C _1-6 haloalkyl, such as: C _1-4 haloalkyl, whether used alone or forming part of a larger group, such as: O haloalkyl, such as: OC _1-6 haloalkyl, such as: OC _1-4 haloalkyl, are straight chain containing the specified number of carbon atoms and at least one halogen atom, such as fluorine or chlorine, especially fluorine Or branch a fully saturated hydrocarbon chain. An example of a haloalkyl group is CF ₃ . Other examples of haloalkyl are CHF ₂ and CH ₂ CF ₃ . Examples of O haloalkyl include OCF ₃ , OCHF ₂ and OCH ₂ CF ₃ .

The term "6-membered aryl" as used herein refers to a phenyl ring.

The term "6-membered heteroaryl" as used herein refers to a 6-membered aromatic ring containing at least one heteroatom (eg, nitrogen). Examples of 6-membered heteroaryl include one nitrogen atom (pyridyl), two nitrogen atoms (da Base, pyrimidinyl or pyridyl Radical) with three nitrogen atoms (trivalent base).

The phrase used in this article is "parallel to amidine", for example, when it is related to the position of Ar2. It is meant to form the compound having the following substructure:

Wherein W ₁ may be N, CH, CR ₁₀ or CR ₁₁ , and W ₂ may be N, CH or CR ₁₂ as defined by the compound of formula (I). W ₂ may also be CR ₁₃ as defined by the compound of formula (I).

The terms "adjacent" and "meta" used in this article, for example: when used to define the position of R ₁₂ on Ar2 relative to Ar1, mean that the following structural formula may be formed:

The phrase "A is an amidine linker having the following structural formula: -C (= O) NH- or -NHC (= O)-" means that the following structural formula is formed:

In one embodiment, A is -C (= O) NH-. In one embodiment, A is -NHC (= O)-.

In one embodiment, X is N. In another embodiment, X is CH.

In one embodiment, Y is N. In another embodiment, Y is CR ₂ .

In one embodiment, Z is N. In another embodiment, Z is CR ₃ .

Conveniently, X is N, Y is CR ₂ , and Z is CR ₃ . Alternatively, X is CH, Y is N, and Z is CR ₃ . Alternatively, X is CH, Y is CR ₂ , and Z is CR ₃ . Alternatively, X is CH, Y is CR ₂ , and Z is N. Alternatively, X is N, Y is CR ₂ , and Z is N.

In one embodiment of the present invention, R ₁ is C _1-5 alkyl. When R ₁ is C _1-5 alkyl, R ₁ may be methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, second butyl, or Third butyl) or pentyl (for example: n-pentyl, second pentyl or 3-pentyl).

In the second embodiment of the present invention, R ₁ is a C _0-2 alkylene group C _3-5 cycloalkyl group, and the cycloalkyl group may be substituted with CH ₃ if necessary. In some embodiments, R ₁ is C _0-2 alkylene C _3-5 cycloalkyl. In other embodiments, R ₁ is C _0-2 alkylene C _3-5 cycloalkyl, and the cycloalkyl is substituted with CH ₃ . R ₁ may be C _3-5 cycloalkyl, and the cycloalkyl may be optionally substituted with CH ₃ . R ₁ may be a C ₁ alkylene C _3-5 cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ . R ₁ may be a C ₂ alkylene C _3-5 cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ . R ₁ may be a C _0-2 alkylene C ₃ cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ .

R ₁ may be a C _0-2 alkylene C ₄ cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ . R ₁ may be a C _0-2 alkylene C ₅ cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ . Conveniently, where C _0-2 alkylene C _3-5 cycloalkyl is optionally substituted with CH ₃ , the CH ₃ is at the attachment point of C _3-5 cycloalkyl and C _0-2 alkyl .

In the third embodiment, R ₁ is CF ₃ .

Conveniently, R ₁ is cyclopropyl, cyclopropyl substituted with CH ₃ at the point of attachment, cyclobutyl, CH ₃ or CH ₂ CH ₃ .

In particular, R ₁ is cyclopropyl, cyclobutyl, CH ₃ or CH ₂ CH ₃ , especially cyclopropyl.

In one embodiment, R ₂ is H. In the second embodiment, R ₂ is a halogen group, such as: F, Cl or Br, for example: Cl or Br. In a third embodiment, R ₂ is C _1-2 alkyl. When R ₂ is C _1-2 alkyl, R ₂ may be methyl or ethyl, such as methyl. In a fourth embodiment, R ₂ is OC _1-2 alkyl. When R ₂ is OC _1-2 alkyl, it may be OCH ₃ or OEt, such as OCH ₃ . In a fifth embodiment, R ₂ is a C _1-2 haloalkyl group. When R ₂ is a C _1-2 haloalkyl group, R ₂ may be CF ₃ or CH ₂ CF ₃ , such as: CF ₃ . In the sixth embodiment, R ₂ is OC _1-2 haloalkyl. When R ₂ is OC _1-2 haloalkyl, R ₂ may be OCF ₃ or OCH ₂ CF ₃ , such as OCF ₃ .

Conveniently, R ₂ is H, CH ₃ or CF ₃ , such as: H or CH ₃ , in particular, H.

In one embodiment, R ₃ is H. In the second embodiment, R ₃ is a halogen group, specifically, chlorine or fluorine, especially fluorine. In the third embodiment, R ₃ is CH ₃ . In the fourth embodiment, R ₃ is OCH ₃ . In a fifth embodiment, R ₃ is CF ₃ . In the sixth embodiment, R ₃ is OCF ₃ .

Conveniently, R ₃ is H, halo (specifically, chlorine or fluorine, especially fluorine), CH ₃ or CF ₃ . More suitably, R ₃ is H or F, such as: H.

Conveniently, at least one of R ₂ and R ₃ is H.

In one embodiment, R ₄ and R _{5 together} with the carbon atoms to which they are attached form a C _3-6 cycloalkyl group, such as: cyclopropyl, cyclobutyl, or cyclopentyl. In particular, cyclopropyl or Cyclopentyl. In the second embodiment, R ₄ and R _{5 together} with the carbon atoms to which they are attached form a C _3-6 heterocycloalkyl group, such as: heterocyclohexyl, specifically tetrahydropiperanyl. Any nitrogen atom (eg, a nitrogen atom) in a C _3-6 heterocycloalkyl ring may be substituted, for example, via C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl , C (O) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkylaryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _{1 -4} haloalkyl substitution, such as: C (O) OtBu. Conveniently, any nitrogen atom in the C _3-6 heterocycloalkyl ring is unsubstituted. In the third embodiment, R ₄ is C _1-6 alkyl, specifically, C _1-4 alkyl, such as: methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (N-butyl, isobutyl, second butyl, or third butyl). In the fourth embodiment, R ₄ is C _1-3 alkylene OC _1-3 alkyl, in particular, C _1-2 alkylene OC _1-2 alkyl, such as: C ₁ alkylene OC ₁ alkyl, C ₂ alkyl OC ₁ alkyl, C ₁ alkyl OC ₂ alkyl, or C ₂ alkyl OC ₂ alkyl. In the fifth embodiment, R ₄ is H. In the sixth embodiment, R ₄ is a halogen group, such as: chlorine or fluorine, especially fluorine. In the seventh embodiment, R ₄ is a C _1-6 haloalkyl group, such as: CF ₃ or CH ₂ CF ₃ . In the eighth embodiment, R ₄ is C _0-2 alkylene C _3-6 cycloalkyl, such as: C _3-6 cycloalkyl, C ₁ alkylene C _3-6 cycloalkyl, C ₂ Alkylene C _3-6 cycloalkyl, C _0-2 alkylene C ₃ cycloalkyl, C _0-2 alkylene C ₄ cycloalkyl, C _0-2 alkylene C ₅ cycloalkyl or C _0-2 alkylene C ₆ cycloalkyl.

In the ninth embodiment, R ₄ is C _0-2 alkylene C _3-6 heterocycloalkyl, such as: C _3-6 heterocycloalkyl, C ₁ alkylalkyl C _3-6 heterocycloalkyl , C ₂ alkylene C _3-6 heterocycloalkyl, C _0-2 alkylene C ₃ heterocycloalkyl, C _0-2 alkylene C ₄ heterocycloalkyl, C _0-2 alkylene C ₅ heterocycloalkyl or C _0-2 alkylalkyl C ₆ heterocycloalkyl.

Conveniently, the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heteropentyl or heterohexyl ring, such as a heterocyclohexyl ring. Conveniently, the heteropentyl ring is tetrahydrofuranyl or pyrrolidinyl. Conveniently, the heterocyclohexyl ring is tetrahydropiperanyl or piperidinyl. Any nitrogen atom (eg, a nitrogen atom) in a C _3-6 heterocycloalkyl ring may be substituted, for example, via C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl , C (O) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkylaryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _{1 -4} haloalkyl substitution, such as: C (O) OtBu. Conveniently, any nitrogen atom in the C _3-6 heterocycloalkyl ring is unsubstituted. In the tenth embodiment, R ₄ is a C _1-6 alkyl OH, such as: CH ₂ OH or CH ₂ CH ₂ OH. In the eleventh embodiment, R ₄ is OC _1-6 haloalkyl, such as: OC _1-4 haloalkyl, such as: OCF ₃ or OCHF ₂ . In the twelfth embodiment, R ₄ is OC _0-2 alkylene C _3-6 cycloalkyl, such as: OC _3-6 cycloalkyl, OC ₁ alkylene C _3-6 cycloalkyl, OC ₂ alkylene C _3-6 cycloalkyl, OC _0-2 alkylene C ₃ cycloalkyl, OC _0-2 alkylene C ₄ cycloalkyl, OC _0-2 alkylene C ₅ cycloalkyl Or OC _0-2 alkylene C ₆ cycloalkyl. In the thirteenth embodiment, R ₄ is OC _1-6 alkyl, specifically, OC _1-4 alkyl, such as: methoxy, ethoxy, propoxy (n-propoxy or isopropyl) Oxy) or butoxy (n-butoxy, isobutoxy, second butoxy or third butoxy). In the fourteenth embodiment, R ₄ is OC _0-2 alkylene C _3-6 heterocycloalkyl, such as: OC _3-6 heterocycloalkyl, OC ₁ alkylalkyl C _3-6 heterocycloalkyl , OC ₂ alkylene C _3-6 heterocycloalkyl, OC _0-2 alkylene C ₃ heterocycloalkyl, OC _0-2 alkylene C ₄ heterocycloalkyl, OC _0-2 alkylene C ₅ heterocycloalkyl or OC _0-2 alkylalkyl C ₆ heterocycloalkyl. Conveniently, the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heteropentyl or heterohexyl ring, such as a heterocyclohexyl ring. Conveniently, the heteropentyl ring is tetrahydrofuranyl or pyrrolidinyl. Conveniently, the heterocyclohexyl ring is tetrahydropiperanyl or piperidinyl. Any nitrogen atom (eg, a nitrogen atom) in a C _3-6 heterocycloalkyl ring may be substituted, for example, via C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl , C (O) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkylaryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _{1 -4} haloalkyl substitution, such as: C (O) OtBu. Conveniently, any nitrogen atom in the C _3-6 heterocycloalkyl ring is unsubstituted. In the fifteenth embodiment, R ₄ is NR ₂₁ R ₂₂ .

When A is -NHC (= O)-or -C (= O) NH-, suitably R ₄ is H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl OH, C _0-2 alkylene C _3-6 cycloalkyl, C _0-2 alkylene C _3-6 heterocycloalkyl, C _1-3 alkylene OC _1-3 alkyl, or R ₄ Together with R ₅ and the carbon atom to which it is attached, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl is formed. When A is -NHC (= O)-, desirably, R ₄ may be additionally selected from: halo, OC _1-6 haloalkyl, OC _0-2 alkyl, C _3-6 cycloalkyl, OC _{0 -2} alkylene C _3-6 heterocycloalkyl, OC _1-6 alkyl or NR ₂₁ R ₂₂ .

Conveniently, R ₄ is H, fluorine, CH ₃ , ethyl, OCH ₃ or CH ₂ CH ₂ OCH ₃ , such as: fluorine, ethyl, OCH ₃ or CH ₂ CH ₂ OCH ₃ .

Conveniently, R ₄ is H, CH ₃ , ethyl or CH ₂ CH ₂ OCH ₃ , in particular CH ₃ or ethyl.

Conveniently, R ₄ and R _{5 together} with the carbon atoms to which they are attached form a cyclopropyl or cyclopentyl group, in particular, a cyclopentyl group.

Conveniently, R ₄ and R _{5 together} with the carbon atoms attached thereto form a heterocyclohexyl group, such as: tetrahydropiperanyl or piperidinyl, especially tetrahydropiperanyl. Any nitrogen atom (eg, a nitrogen atom) in a C _3-6 heterocycloalkyl ring may be substituted, for example, via C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl , C (O) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkylaryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _{1 -4} haloalkyl substitution, such as: C (O) OtBu. Conveniently, any nitrogen atom in the C _3-6 heterocycloalkyl ring is unsubstituted.

Conveniently, R ₄ and R _{5 together} with the carbon atoms to which they are attached form a heterocyclobutyl group, such as an azetidinyl group. Any nitrogen atom (eg, a nitrogen atom) in a C _3-6 heterocycloalkyl ring may be substituted, for example, via C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl , C (O) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkylaryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _{1 -4} haloalkyl substitution, such as: C (O) OtBu. Conveniently, any nitrogen atom in the C _3-6 heterocycloalkyl ring is unsubstituted.

When R ₄ is NR ₂₁ R ₂₂ , in one embodiment, R ₂₁ is H. In the second embodiment, R ₂₁ is a C _1-5 alkyl group, such as methyl, ethyl or propyl, especially methyl. In the third embodiment, R ₂₁ is a C (O) C _1-5 alkyl group, such as: C (O) CH ₃ . In the fourth embodiment, R ₂₁ is a C (O) OC _1-5 alkyl group, such as: C (O) OCH ₃ or C (O) O third butyl.

When R ₄ is NR ₂₁ R ₂₂ , in one embodiment, R ₂₂ is H. In a second embodiment, R ₂₂ is methyl.

For example: R ₄ is NH ₂ , N (CH ₃ ) ₂ , NHC (O) CH ₃ , NHC (O) OCH ₃ , NHC (O) O third butyl and CH ₂ CH ₂ OH, especially N (CH ₃ ) ₂ , NHC (O) CH ₃ , NHC (O) OCH ₃ .

Conveniently, R ₂₁ is C (O) OCH ₃ and R ₂₂ is H. Conveniently, R ₂₁ is C (O) CH ₃ and R ₂₂ is H.

Conveniently, both R ₂₁ and R ₂₂ are CH ₃ . Conveniently, both R ₂₁ and R ₂₂ are H.

In one embodiment, R ₅ is C _1-6 alkyl, specifically, C _1-4 alkyl, such as: methyl, ethyl, propyl (n-propyl or isopropyl) or butyl ( N-butyl, isobutyl, second butyl, or third butyl). In the second embodiment, R ₅ is C _1-3 alkylene OC _1-3 alkyl, specifically, C _1-2 alkyl OC _1-2 alkyl, such as: C ₁ alkyl OC ₁ alkyl, C ₂ alkyl OC ₁ alkyl, C ₁ alkyl OC ₂ alkyl, or C ₂ alkyl OC ₂ alkyl. In the third embodiment, R ₅ is H. In the fourth embodiment, R ₅ is a halogen group, such as chlorine or fluorine, especially fluorine. In the fifth embodiment, R ₅ is a C _1-6 haloalkyl group, such as CF ₃ or CH ₂ CF ₃ . In the sixth embodiment, R ₅ is C _0-2 alkylene C _3-6 cycloalkyl, such as: C _3-6 cycloalkyl, C ₁ alkylene C _3-6 cycloalkyl, C ₂ Alkylene C _3-6 cycloalkyl, C _0-2 alkylene C ₃ cycloalkyl, C _0-2 alkylene C ₄ cycloalkyl, C _0-2 alkylene C ₅ cycloalkyl or C _0-2 alkylene C ₆ cycloalkyl. In the seventh embodiment, R ₅ is C _0-2 alkylene C _3-6 heterocycloalkyl, such as: C _3-6 heterocycloalkyl, C ₁ cycloalkyl C _3-6 heterocycloalkyl , C ₂ alkylene C _3-6 heterocycloalkyl, C _0-2 alkylene C ₃ heterocycloalkyl, C _0-2 alkylene C ₄ heterocycloalkyl, C _0-2 alkylene C ₅ heterocycloalkyl or C _0-2 alkylalkyl C ₆ heterocycloalkyl. Conveniently, the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heteropentyl or heterohexyl ring, such as a heterocyclohexyl ring. Conveniently, the heteropentyl ring is tetrahydrofuranyl or pyrrolidinyl. Conveniently, the heterocyclohexyl ring is tetrahydropiperanyl or piperidinyl. Any nitrogen atom (eg, a nitrogen atom) in a C _3-6 heterocycloalkyl ring may be substituted, for example, via C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl , C (O) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) Obz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkylaryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _{1 -4} haloalkyl substitution, such as: C (O) OtBu. Conveniently, any nitrogen atom in the C _3-6 heterocycloalkyl ring is unsubstituted. In the eighth embodiment, R ₅ is C _1-6 alkyl OH, such as: CH ₂ OH or CH ₂ CH ₂ OH. In the ninth embodiment, R ₅ is OC _1-6 haloalkyl, such as: OC _1-4 haloalkyl, such as: OCF ₃ or OCHF ₂ . In the tenth embodiment, R ₅ is OC _0-2 alkylene C _3-6 cycloalkyl, such as: OC _3-6 cycloalkyl, OC ₁ alkylene C _3-6 cycloalkyl, OC ₂ Alkylene C _3-6 cycloalkyl, OC _0-2 alkylene C ₃ cycloalkyl, OC _0-2 alkylene C ₄ cycloalkyl, OC _0-2 alkylene C ₅ cycloalkyl, or OC _0-2 alkylene C ₆ cycloalkyl. In the eleventh embodiment, R ₅ is OC _1-6 alkyl, specifically, OC _1-4 alkyl, such as: methoxy, ethoxy, propoxy (n-propoxy or isopropyl) Oxy) or butoxy (n-butoxy, isobutoxy, second butoxy or third butoxy). In the twelfth embodiment, R ₅ is OC _0-2 alkylene C _3-6 heterocycloalkyl, such as: OC _3-6 heterocycloalkyl, OC ₁ alkylalkyl C _3-6 heterocycloalkyl , OC ₂ alkylene C _3-6 heterocycloalkyl, OC _0-2 alkylene C ₃ heterocycloalkyl, OC _0-2 alkylene C ₄ heterocycloalkyl, OC _0-2 alkylene C ₅ heterocycloalkyl or OC _0-2 alkylalkyl C ₆ heterocycloalkyl. Conveniently, the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heteropentyl or heterohexyl ring, such as a heterocyclohexyl ring. Conveniently, the heteropentyl ring is tetrahydrofuranyl or pyrrolidinyl. Conveniently, the heterocyclohexyl ring is tetrahydropiperanyl or piperidinyl. Any nitrogen atom (eg, a nitrogen atom) in a C _3-6 heterocycloalkyl ring may be substituted, for example, via C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl , C (O) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) Obz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkylaryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _{1 -4} haloalkyl substitution, such as: C (O) OtBu. Conveniently, all nitrogen atoms in the C _3-6 heterocycloalkyl ring are unsubstituted. In the thirteenth embodiment, R ₅ is NR ₂₁ R ₂₂ .

When A is -NHC (= O)-or -C (= O) NH-, suitably R ₅ is H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkyl OH, C _0-2 alkylene C _3-6 cycloalkyl, C _0-2 alkylene C _3-6 heterocycloalkyl, C _1-3 alkylene OC _1-3 alkyl, or R ₄ Together with R ₅ and the carbon atom to which it is attached, C _3-6 cycloalkyl or C _3-6 heterocycloalkyl is formed. When A is -NHC (= O)-, suitably, R ₅ may be additionally selected from: halo, OC _1-6 haloalkyl, OC _0-2 butanyl C _3-6 cycloalkyl, OC _{0 -2} alkylene C _3-6 heterocycloalkyl, OC _1-6 alkyl or NR ₂₁ R ₂₂ .

When R ₅ is NR ₂₁ R ₂₂ , in one embodiment, R ₂₁ is H. In the second embodiment, R ₂₁ is a C _1-5 alkyl group, such as methyl, ethyl or propyl, especially methyl. In the third embodiment, R ₂₁ is a C (O) C _1-5 alkyl group, such as: C (O) CH ₃ . In the fourth embodiment, R ₂₁ is a C (O) OC _1-5 alkyl group, such as: C (O) OCH ₃ or C (O) O third butyl.

In one embodiment, when R ₅ is NR ₂₁ R ₂₂ , R ₂₂ is H. In a second embodiment, R ₂₂ is methyl.

For example: R ₅ is NH ₂ , N (CH ₃ ) ₂ , NHC (O) CH ₃ , NHC (O) OCH ₃ , NHC (O) O third butyl and CH ₂ CH ₂ OH, especially N (CH ₃ ) ₂ , NHC (O) CH ₃ , NHC (O) OCH ₃ .

Conveniently, R ₂₁ is C (O) OCH ₃ and R ₂₂ is H. Conveniently, R ₂₁ is C (O) CH ₃ and R ₂₂ is H.

Conveniently, both R ₂₁ and R ₂₂ are CH ₃ . Conveniently, both R ₂₁ and R ₂₂ are H.

Conveniently, R ₅ is H, F, CH ₃ or ethyl, such as: H, CH ₃ or ethyl.

Conveniently, R ₄ is H, CH ₃ , ethyl or CH ₂ CH ₂ OCH ₃ , and R ₅ is H, CH ₃ or ethyl, in particular, R ₄ is CH ₃ , or ethyl, and R ₅ Is H, methyl or ethyl. For example: R ₄ and R ₅ are H, R ₄ and R ₅ are methyl, R ₄ and R ₅ are ethyl, or R ₄ is CH ₂ CH ₂ OCH ₃ and R ₅ is H.

Conveniently, R ₄ is F and R ₅ is ethyl.

Conveniently, R ₄ is F and R ₅ is F.

Conveniently, R ₄ is ethyl and R ₅ is H.

Conveniently, the R ₄ and R ₅ series are arranged in the following configurations:

In one embodiment, Ar1 is 6-membered aryl, that is, phenyl. In the second embodiment, Ar1 is a 6-membered heteroaryl group, specifically, containing one nitrogen atom (pyridyl) or two nitrogen atoms (da Base, pyrimidinyl or pyridyl base).

Specifically, Ar1 is phenyl, 2-pyridyl, or 3-pyridyl, such as phenyl or 2-pyridyl. The position of Ar1 is relative to the amidine number, and the carbon at the attachment point is set to position 1. The other numbers provide the relative position of the nitrogen atom, for example:

In one embodiment, R ₁₀ is H. In the second embodiment, R ₁₀ is a halogen group, for example, fluorine or chlorine.

In the third embodiment, R ₁₀ is C _1-3 alkyl, such as: C _1-2 alkyl, such as: CH ₃ or ethyl. In the fourth embodiment, R ₁₀ is OC _1-2 alkyl, such as OCH ₃ or ethoxy. In the fifth embodiment, R ₁₀ is OC _1-2 haloalkyl, such as OCF ₃ . In the sixth embodiment, R ₁₀ is CN. In the seventh embodiment, R ₁₀ is a C _1-2 haloalkyl group, such as CF ₃ .

Conveniently, R ₁₀ is H, fluorine, chlorine, CH ₃ , CF ₃ , OCH ₃ , OCF ₃ or CN, such as: H, fluorine, chlorine, CH ₃ , OCH ₃ , OCF ₃ or CN, in particular, H , Fluorine, chlorine, OCH ₃ , OCF ₃ or CN, especially H or fluorine.

Conveniently, R ₁₀ is H, F or CH ₃ .

In one embodiment, R ₁₁ is H. In the second embodiment, R ₁₁ is F. In the third embodiment, R ₁₁ is a C _1-2 alkyl group, such as: CH ₃ or Et, such as: CH ₃ . In the fourth embodiment, R ₁₁ is OCH ₃ . In a fifth embodiment, R ₁₁ is Cl. In the sixth embodiment, R ₁₁ is Et. In the seventh embodiment, R ₁₁ is CF ₃ . In the eighth embodiment, R ₁₁ is CN.

Conveniently, R ₁₁ is H, F, CH ₃ or OCH ₃ , such as: H, F or CH ₃ , such as: H or F, such as: H.

In one embodiment, R ₁₀ is ortho with respect to amidine. In another embodiment, R ₁₀ is meta-positioned with respect to amidine. Conveniently, R ₁₀ is ortho with respect to amidine.

In one embodiment, R ₁₁ is ortho with respect to amidine. In another embodiment, R ₁₁ is meta-positioned to amidine. Conveniently, R ₁₁ is ortho with respect to amidine.

In one embodiment, Ar2 is 6-membered aryl, that is, phenyl. In the second embodiment, Ar2 is a 6-membered heteroaryl group, specifically, containing one nitrogen atom (pyridyl) or two nitrogen atoms (da Base, pyrimidinyl or pyridyl base).

The position of Ar2 is relative to the number of attachment points of Ar1, for example:

Specifically, Ar2 is 3-pyridyl or 2,5-pyridine Base, especially 2,5-pyridine base.

In one embodiment, R ₁₂ is H. In the second embodiment, R ₁₂ is a halogen group, for example, fluorine or chlorine.

In the third embodiment, R ₁₂ is a C _1-4 alkyl group, such as: methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, second Butyl or tertiary butyl). In the fourth embodiment, R ₁₂ is OC _1-4 alkyl, such as OCH ₃ , ethoxy, isopropoxy, or n-propoxy. In the fifth embodiment, R ₁₂ is OC _0-2 alkylene C _3-5 cycloalkyl, such as: OC _3-5 cycloalkyl (for example, cyclopropoxy or cyclobutoxy), OC ₁ Aralkyl C _3-5 cycloalkyl or OC ₂ alkyl C _3-5 cycloalkyl. In the sixth embodiment, R ₁₂ is CN. In the seventh embodiment, R ₁₂ is a C _1-4 haloalkyl group, such as: CF ₃ . In the eighth embodiment, R ₁₂ is OC _1-4 haloalkyl, such as OCF ₃ , OCHF ₂ or OCH ₂ CF ₃ . In the ninth embodiment, R ₁₂ is a C _2-4 alkenyl group, such as: C (= CH ₂ ) CH ₃ . In the tenth embodiment, R ₁₂ is C _0-2 alkylene C _3-5 cycloalkyl, such as: C _3-5 cycloalkyl, C ₁ alkylene C _3-5 cycloalkyl, C ₂ Alkenyl C _3-5 cycloalkyl, C _0-2 alkenyl C ₃ cycloalkyl, C _0-2 alkenyl C ₄ cycloalkyl, or C _0-2 alkenyl C ₅ cycloalkyl. In the eleventh embodiment, R ₁₂ is a hydroxyl group. In the twelfth embodiment, R ₁₂ is a C _1-4 alkyl OH, such as: CH ₂ OH. In the thirteenth embodiment, R ₁₂ is SO ₂ C _1-2 alkyl, such as: SO ₂ CH ₃ . In the fourteenth embodiment, R ₁₂ is C (O) N (C _1-2 alkyl) ₂ , such as: C (O) N (CH ₃ ) ₂ . In the fifteenth embodiment, R ₁₂ is NHC (O) C _1-3 alkyl. In the sixteenth embodiment, R ₁₂ is NR ₂₃ R ₂₄ . In the seventeenth embodiment, R ₁₂ is OCH ₂ CH ₂ N (CH ₃ ) ₂ . In the eighteenth embodiment, R ₁₂ is a C _3-6 heterocycloalkyl group, which contains a nitrogen at the position of the attachment point to Ar ₂ . Conveniently, the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heteropentyl or heterohexyl ring, such as a heterocyclohexyl ring. Conveniently, the heteropentyl ring is pyrrolidinyl. Conveniently, the heterohexyl ring is piperidinyl or piperidinyl base. Any nitrogen atom in C _3-6 heterocycloalkyl (eg, a nitrogen atom) may be substituted, for example, via C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl , C (O) OC _1-4 alkyl, C (O) OC _1-4 alkyl aryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkylaryl (such as: C (O) NHBz), Fmoc, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl, or C (O) NHC _{1 -4} haloalkyl substitution, such as: C (O) OtBu. Conveniently, any nitrogen atom in the C _3-6 heterocycloalkyl ring is unsubstituted. A nineteenth embodiment, R ₁₂ attached thereto together form N- oxides of nitrogen (N ⁺ -O ^-).

When A is -NHC (= O)-or -C (= O) NH-, desirably, R ₁₂ is attached to Ar2 in an ortho or meta position relative to Ar1, and R ₁₂ is H, halo, C _1-4 alkyl, C _2-4 alkenyl, C _0-2 alkyl, C _3-5 cycloalkyl, OC _1-4 alkyl, OC _0-2 alkyl, C _3-5 cycloalkyl , C _1-4 haloalkyl, OC _1-4 haloalkyl, hydroxyl, C _1-4 alkyl OH, SO ₂ C _1-2 alkyl, C (O) N (C _1-2 alkyl) ₂ , NHC (O) C _1-3 alkyl or NR ₂₃ R ₂₄ .

When A is -NHC (= O)-, desirably, R ₁₂ may be additionally selected from: CN, OCH ₂ CH ₂ N (CH ₃ ) ₂ and C _3-6 heterocycloalkyl (which is attached to Ar2 contacts comprises a nitrogen position), or R ₁₂ is attached thereto together form N- oxides of nitrogen (N ⁺ -O ^-).

The present invention provides N-oxides of a compound of formula (I). Conveniently, when R ₁₂ is attached thereto together form N- oxides of nitrogen (N ⁺ -O ^-), the form of the following structural formula Example:

R _{12 is} suitably H, F, Cl, CH ₃ , OCH ₃ , OEt, O i Pr, O cyclopropyl, CN, CF ₃ , OCHF ₂ or OCH ₂ CF ₃ . Specifically, R ₁₂ is Cl, CN, CF ₃ , OCHF ₂ , OCH ₂ CF ₃ , OCH ₃ , OEt, O i Pr, O cyclopropyl, such as: CF ₃ , OCHF ₂ , OCH ₂ CF ₃ , OCH ₃ , OEt, O i Pr, O cyclopropyl, for example: OEt.

R _{12 is} suitably H, F, Cl, CH ₃ , iPr, OCH ₃ , OEt, O i Pr, O cyclopropyl, CN, CF ₃ , OCHF ₂ , OCH ₂ CF ₃ , C ₃ cycloalkyl, or C (= CH ₂ ) CH ₃ . In particular, R ₁₂ is Cl, iPr, OCH ₃ , OEt, O i Pr, O cyclopropyl, CN, CF ₃ , OCHF ₂ , OCH ₂ CF ₃ , C ₃ cycloalkyl, or C (= CH ₂ ) CH ₃ , such as: Cl, OCH ₃ , OEt, O i Pr, O cyclopropyl, CF ₃ , OCHF ₂ , OCH ₂ CF ₃ or C ₃ cycloalkyl, for example: OEt.

When A is -C (= O) NH-, desirably, R ₁₂ is CF ₃ , OEt, or OiPr, such as OEt or OiPr.

Conveniently, R ₁₂ is between Ar2. Alternatively, R ₁₂ is adjacent to Ar2.

In one embodiment, R ₁₃ is H. In another embodiment, R ₁₃ is a halogen group, such as: F or Cl, desirably, F.

In one embodiment, R ₁₃ is adjacent to Ar1. In another embodiment, R ₁₃ is in a para position relative to Ar1. In another embodiment, R ₁₃ is meta-positioned with respect to Ar1.

In one embodiment, R ₂₃ is H. In another embodiment, R ₂₃ is a C _1-2 alkyl group, such as methyl.

In one embodiment, R ₂₄ is H. In another embodiment, R ₂₄ is C _1-2 alkyl, such as: methyl.

Conveniently, R ₂₃ is H and R ₂₄ is ethyl. Conveniently, R ₂₃ is CH ₃ and R ₂₄ is CH ₃ .

Compounds of formula (I) are not intended to include 2- (6- (methylsulfonamido) pyridine 2-yl) -N- (4- (pyridin-3-yl) phenyl) acetamidamine.

In one embodiment, at least one of R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is not H.

Conveniently, at least one of R ₄ , R ₅ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is not H.

More suitably, when R ₁ is a methyl group, at least one of R ₄ , R ₅ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is not H.

Throughout this specification, Ar1 and Ar2 are explained as follows:

All descriptions about Ar1 are the same, and all descriptions about Ar2 are the same. Unless otherwise stated in the text, the description of Ar1 and Ar2 should not exclude the presence of heteroatoms or substitutions.

The invention provides a compound illustrated in any one of Examples P1 to P111.

The invention also provides compounds illustrated in any one of Examples P112 to P115.

The invention also provides compounds illustrated in any one of Examples P116 to P225.

The present invention provides the following compounds: N- (4- (5-chloropyridin-3-yl) phenyl) -2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butanamide; 1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) cyclopentanecarboxamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-methoxypyridine 2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (4- (5- (Trifluoromethyl) pyridin-3-yl) phenyl) propanamide; 2-methyl-N- (2-methyl-4- (6-methylpyridine) -2-yl) phenyl) -2- (2- (methylsulfonamido) pyrimidin-4-yl) propanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl ) -N- (2-fluoro-4- (pyridine 2-yl) phenyl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5- (trifluoromethyl) pyridine-3- ) Phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6- (trifluoromethyl) pyridine 2-yl) phenyl) acetamidamine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-isopropoxypyridine) 2-yl) pyridin-2-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxy Base -2-yl) phenyl) -2-ethylbutanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (6- ( (Trifluoromethyl) pyridine 2-yl) phenyl) acetamidamine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (6-isopropoxypyridine) 2-yl) phenyl) acetamidamine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5- (trifluoromethyl) pyridine-3- ) Phenyl) ethenylamine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5- (2,2,2-trifluoroethoxy) Pyridin-3-yl) phenyl) acetamidamine; 2- (2- (cyclopropanesulfonamido) -5-fluoropyrimidin-4-yl) -N- (4- (pyridin-3-yl) benzene Yl) acetamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (pyridin-3-yl) phenyl) acetamide; N-([1 , 1'-biphenyl] -4-yl) -2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) acetamide; 2- (2- (cyclopropanesulfenamido) pyrimidine) -4-yl) -N- (4- (6-ethoxypyridine) 2-yl) phenyl) acetamidamine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-methoxypyridine 2-yl) phenyl) acetamidamine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6- (2,2,2-trifluoroethyl (Oxy) pyridine -2-yl) phenyl) acetamidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-isopropoxypyridine) 2-yl) phenyl) acetamidamine; 2- (2- (cyclobutanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) -2-methylpropanamide; 2- (2- (cyclobutanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (6-isopropoxypyridine 2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclobutanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) -2-methylphenyl) -2-methylpropanamide; 2- (2- (cyclobutanesulfonamido) pyrimidin-4-yl) -N- (4- (6 -Methoxypyridine 2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclobutanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxypyridine -2-yl) -3-fluoropyridin-2-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5'- Ethoxy- [3,3'-bipyridine] -6-yl) -2-methylpropanamide; N-([3,3'-bipyridine] -6-yl) -2- (2- (Cyclopropanesulfonamido) pyrimidin-4-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (5- (6- (trifluoromethyl) pyridine 2-yl) pyridin-2-yl) propanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-cyclopropane Oxopyr 2-yl) pyridin-2-yl) -2-methylpropanamide; N- (2-chloro-4- (6-ethoxypyridine) -2-yl) phenyl) -2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methylpropanamide; N- (2-cyano-4- (6- Ethoxypy -2-yl) phenyl) -2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) Pyrimidin-4-yl) -N- (2-fluoro-4- (5-isopropoxypyridin-3-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonate) Amido) pyrimidin-4-yl) -N- (2-fluoro-4- (pyridin-3-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamide) ) Pyrimidin-4-yl) -N- (2-fluoro-4- (6- (trifluoromethyl) pyridine -2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine -2-yl) -2-fluorophenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (6-isopropoxypyridine -2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) -2-fluoro-5-methylphenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4 -(6-ethoxypyridine 2-yl) -2,6-difluorophenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro -4- (pyridine 2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (2-methyl- 4- (6- (trifluoromethyl) pyridine -2-yl) phenyl) propanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine -2-yl) -2,3-dimethylphenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) -5-fluoro-2-methylphenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4 -(6-ethoxypyridine -2-yl) -2,5-dimethylphenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) -2- (trifluoromethoxy) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- ( 4- (6-ethoxypyridine 2-yl) -5-fluoro-2-methoxyphenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- ( 4- (6-ethoxypyridine 2-yl) -2-methoxyphenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (4- (pyrimidin-5-yl) phenyl) propanamide; N- (4- (5-chloropyridin-3-yl) phenyl) -2- (2- (cyclopropanesulfonamido) pyrimidine 4-yl) -2-methylpropanamide; N- (4- (5-cyanopyridine-3-yl) phenyl) -2- (2- (cyclopropanesulfonamido) pyrimidine-4 -Yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5-fluoropyridin-3-yl) phenyl) 2-methylpropanamine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (4- (5-methylpyridin-3-yl) Phenyl) propanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5- (difluoromethoxy) pyridin-3-yl) phenyl ) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5-methoxypyridin-3-yl) phenyl) 2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5-ethoxypyridin-3-yl) phenyl)- 2-methylpropanamine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5-isopropoxypyridin-3-yl) phenyl)- 2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (4- (pyridin-3-yl) Propyl) propanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (3 '-(trifluoromethyl)-[1,1'- Biphenyl] -4-yl) propanamidin; N- (3'-chloro- [1,1'-biphenyl] -4-yl) -2- (2- (cyclopropanesulfonamido) pyrimidine- 4-yl) -2-methylpropanamide; N- (3'-cyano- [1,1'-biphenyl] -4-yl) -2- (2- (cyclopropanesulfonamido) Pyrimidin-4-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (3'-ethoxy- [1,1 ' -Biphenyl] -4-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (4- (6 -(Trifluoromethyl) pyridine -2-yl) phenyl) propanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-cyclopropoxypyridine -2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-isopropoxypyridine) 2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) -5-fluoropyrimidin-4-yl) -N- (4- (6-ethyl Oxopyr -2-yl) phenyl) -2-methylpropanamide; N- (4- (6-ethoxypyridine) 2-yl) phenyl) -2-methyl-2- (2-((1-methylcyclopropane) -1-sulfoamido) pyrimidin-4-yl) propanilamide; 2- (2 -(Cyclopropanesulfonamido) -5-methylpyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (4- (pyridine -2-yl) phenyl) propanamide; N- (4- (6-ethoxypyridine) -2-yl) -2-fluorophenyl) -2- (2- (ethylsulfonamido) pyrimidin-4-yl) -2-methylpropanamide; 2- (2- (ethylsulfonyl Amido) pyrimidin-4-yl) -2-methyl-N- (4- (6- (trifluoromethyl) pyridine -2-yl) phenyl) propanamide; N- (4- (6-ethoxypyridine) -2-yl) phenyl) -2- (2- (ethylsulfonamido) pyrimidin-4-yl) -2-methylpropanamide; N- (5- (6-ethoxypyridine 2-yl) -3-fluoropyridin-2-yl) -2-methyl-2- (2- (methylsulfonamido) pyrimidin-4-yl) propanamide; N- (5- ( 6-ethoxypyridine 2-yl) pyridin-2-yl) -2-methyl-2- (2- (methylsulfonamido) pyrimidin-4-yl) propanamide; N- (2-fluoro-4- ( 5-isopropoxypyridin-3-yl) phenyl) -2-methyl-2- (2- (methylsulfonamido) pyrimidin-4-yl) propanamide; N- (2-fluoro -4- (6-isopropoxypyridine -2-yl) phenyl) -2-methyl-2- (2- (methylsulfonamido) pyrimidin-4-yl) propanamide; 2-methyl-N- (2-methyl- 4- (6- (trifluoromethyl) pyridine -2-yl) phenyl) -2- (2- (methylsulfonamido) pyrimidin-4-yl) propanamide; 2-methyl-2- (2- (methylsulfonamido) Pyrimidin-4-yl) -N- (4- (6- (trifluoromethyl) pyridine -2-yl) phenyl) propanamide; N- (4- (6-ethoxypyridine) -2-yl) phenyl) -2-methyl-2- (2- (methylsulfonamido) pyrimidin-4-yl) propanamide; 2- (2-((1,1-dimethyl Ethyl) sulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) -2-methylpropanamide; 1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) cyclopropanecarboxamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5 '-(trifluoromethyl)-[3, 3'-bipyridyl] -6-yl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5 '-(2,2,2-trifluoro Ethoxy)-[3,3'-bipyridine] -6-yl) butanamide; N-([3,3'-bipyridine] -6-yl) -2- (2- (cyclopropanesulfonate) Amido) pyrimidin-4-yl) butyramide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6- (trifluoromethyl) pyridine 2-yl) pyridin-2-yl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-isopropoxypyridine) -2-yl) pyridin-2-yl) butanamide; N- (4- (5-chloropyridin-3-yl) -2-fluorophenyl) -2- (2- (cyclopropanesulfonamido) ) Pyrimidin-4-yl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (5- (2,2,2- Trifluoroethoxy) pyridin-3-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (5 -Isopropoxypyridin-3-yl) phenyl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (pyridine- 3-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (6- (trifluoromethyl) pyridine) 2-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (6-methoxypyridine) -2-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) -2-fluorophenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (6-isopropyl Oxopyr -2-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (6- (2,2,2 -Trifluoroethoxy) pyridine -2-yl) phenyl) butanamide; N- (4- (5-cyanopyridine-3-yl) phenyl) -2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl ) Butamidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5- (2,2,2-trifluoroethoxy) pyridine-3- Phenyl) phenyl) butanamine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5-isopropoxypyridin-3-yl) phenyl) Butamidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (pyridin-3-yl) phenyl) butamidine; 2- (2- (cyclo Propanesulfonamido) pyrimidin-4-yl) -N- (4- (6- (trifluoromethyl) pyridine -2-yl) phenyl) butanamide; N- (4- (6-chloropyridine) -2-yl) phenyl) -2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butanamide; 2- (2- (cyclopropanesulfoamido) pyrimidin-4-yl ) -N- (4- (6-ethoxypyridine -2-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-methoxypyridine 2-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-isopropoxypyridine) -2-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6- (2,2,2-trifluoroethyl (Oxy) pyridine -2-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (pyridine 2-yl) phenyl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) -4-methoxybutyramide; and 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (pyridin-3-yl ) Phenyl) propanilamine.

The present invention also provides the following compounds: 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) -2- ( R ) -fluorobutanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6 -Ethoxypyridine 2-yl) pyridin-2-yl) -2- ( S ) -fluorobutanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6 -Ethoxypyridine -2-yl) pyridin-2-yl) -2-fluorobutanidine; and 4- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxy Base 2-yl) pyridin-2-yl) tetrahydro-2H-piperan-4-carboxamide.

The present invention also provides the following compounds: 2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (5- (6- isopropyl-pyrazole 2-yl) pyridin-2-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxy Base -2-yl) -2-fluorophenyl) -2,2-difluoroacetamidamine; N-((2- (cyclopropanesulfonamido) pyrimidin-4-yl) methyl) -4- ( 6-ethoxypyridine 2-yl) benzamidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (5- (6- (prop-1-ene- 2-yl) pyridine 2-yl) pyridin-2-yl) propanamide; 2- (2- (cyclopropanesulfonamido) -6-methylpyrimidin-4-yl) -N- (5- (6-ethoxy Base -2-yl) pyridin-2-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) -6- (trifluoromethyl) pyrimidin-4-yl) -N -(5- (6-ethoxypyridine 2-yl) pyridin-2-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-cyclopropane Base 2-yl) pyridin-2-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (6- (6-ethoxy Base 2-yl) pyridin-3-yl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-cyclopropane Base 2-yl) -2-fluorophenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) -6-methylpyrimidin-4-yl) -N- (4 -(6-ethoxypyridine -2-yl) -2-fluorophenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) -6- (trifluoromethyl) pyrimidin-4-yl)- N- (4- (6-ethoxypyridine 2-yl) -2-fluorophenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N- (4 -(6- (prop-1-en-2-yl) pyridine 2-yl) phenyl) propanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-isopropylpyridine) -2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6- (dimethylamine ) Pyridine -2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) -6-methylpyrimidin-4-yl) -N- (4- (6- Ethoxypy -2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) -6- (trifluoromethyl) pyrimidin-4-yl) -N- (4 -(6-ethoxypyridine 2-yl) phenyl) -2-methylpropanamide; 2- (2- (cyclopropanesulfonamido) -6-methoxypyrimidin-4-yl) -2-methyl-N- (4- (pyridin-3-yl) phenyl) propanamide; 1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) cyclopentane-1-carboxamide; 4- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethyl Oxopyr 2-yl) phenyl) tetrahydro-2H-piperan-4-carboxamide; N- (5- (6-ethoxypyridine) 2-yl) pyridin-2-yl) -4- (2- (methylsulfonamido) pyrimidin-4-yl) piperidine-4-carboxamide; 4- (2- (cyclopropanesulfonyl) Amine) pyrimidin-4-yl) -4-((5- (6-ethoxypyridine 2-yl) pyridin-2-yl) carbamoyl) piperidine-1-carboxylic acid tert-butyl ester; 4- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) piperidin-4-carboxamide; 3- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -3-((5- (6-ethyl Oxopyr 2-yl) pyridin-2-yl) carbamoyl) azetidin-1-carboxylic acid third butyl ester; 4-((5- (6-ethoxypyridine 2-yl) pyridin-2-yl) carbamoyl) -4- (2- (methylsulfonamido) pyrimidin-4-yl) piperidine-1-carboxylic acid tert-butyl ester; 4- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) -2-fluorophenyl) tetrahydro-2H-piperan-4-carboxamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5 -(6-ethoxypyridine -2-yl) -3-fluoropyridin-2-yl) -4-methoxybutamidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxypyridine -2-yl) pyridin-2-yl) -4-methoxybutamidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethyl Oxopyr -2-yl) -2-fluorophenyl) -4-methoxybutanamine; N- (5- (6-ethoxypyridine) 2-yl) pyridin-2-yl) -4-methoxy-2-methyl-2- (2- (methylsulfonamido) pyrimidin-4-yl) butanamide; N- (5 '-Chloro- [3,3'-bipyridyl] -6-yl) -2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butanamide; N- (5'-chloro- [3,3'-bipyridine] -6-yl) -2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-fluorobutanidine; 2- (2- (cyclopropane Sulfonamido) pyrimidin-4-yl) -N- (5- (6-cyclopropylpyridine -2-yl) pyridin-2-yl) -2-fluorobutanamine; N- (5- (6-ethoxypyridine) 2-yl) pyridin-2-yl) -2-fluoro-2- (2- (methylsulfonamido) pyrimidin-4-yl) butanamide; 2- (2- (cyclopropanesulfonamide) ) Pyrimidin-4-yl) -N- (5- (6-ethoxypyridine) 2-yl) -3-methylpyridin-2-yl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-cyclopropyl Base 2-yl) pyridin-2-yl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6- (2,2,2- (Trifluoroethoxy) pyridine 2-yl) pyridin-2-yl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (3-fluoro-5- (6-methoxy Pyridine 2-yl) pyridin-2-yl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-methoxypyridine 2-yl) pyridin-2-yl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-cyclopropylpyridine 2-yl) -2-fluorophenyl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) -2-methylphenyl) butanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxypyridine -2-yl) -3-fluoropyridin-2-yl) butanamide; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxy Pyridine 2-yl) pyridin-2-yl) -2-methylbutamidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethoxy Base 2-yl) pyridin-2-yl) -2-fluoro-3-methylbutanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- ( 6-ethoxypyridine 2-yl) -2-fluorophenyl) -3-methylbutanidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (5- (6-ethyl Oxopyr -2-yl) pyridin-2-yl) -3-methylbutamidine; 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxy Base -2-yl) phenyl) -2-methoxyacetamidamine; N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) -2-fluoro-2- (2- (methylsulfonamido) pyrimidin-4-yl)-( R ) -butanidine; N- (5- ( 6-ethoxypyridine 2-yl) pyridin-2-yl) -2-fluoro-2- (2- (methylsulfonamido) pyrimidin-4-yl)-( S ) -butanidine; N- (4- ( 5-chloropyridin-3-yl) phenyl) -2- (6- (cyclopropanesulfonamido) pyridin-2-yl) acetamide; N- (4- (5-cyanopyridine-3- ) Phenyl) -2- (6- (cyclopropanesulfonamido) pyridin-2-yl) acetamidoamine; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N -(4- (5-fluoropyridin-3-yl) phenyl) ethanamine; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (5-methyl Oxypyridin-3-yl) phenyl) acetamidamine; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (pyridin-3-yl) phenyl) Acetylamine; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (6- (trifluoromethyl) pyridine 2-yl) phenyl) acetamidamine; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (6-methoxypyridine 2-yl) phenyl) acetamidamine; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (pyridine 2-yl) phenyl) acetamidamine; N-([3,3'-bipyridine] -6-yl) -2- (6- (cyclopropanesulfonamido) pyridin-2-yl)- 2-methylpropanamide; N- (4- (5-chloropyridin-3-yl) phenyl) -2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -2-methyl Propylpropanamine; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (5-fluoropyridin-3-yl) phenyl) -2-methylpropanil Amine; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (5-ethoxypyridin-3-yl) phenyl) -2-methylpropanamide ; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -2-methyl-N- (4- (pyridin-3-yl) phenyl) propanamidin; 2- (6- (Cyclopropanesulfonamido) pyridin-2-yl) -N- (2-fluoro-4- (pyridine 2-yl) phenyl) -2-methylpropanamide; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -2-methyl-N- (4- (6- (Trifluoromethyl) pyridine -2-yl) phenyl) propanamide; N- (4- (6-chloropyridine) -2-yl) phenyl) -2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -2-methylpropanamide; 2- (6- (cyclopropanesulfonamido) Pyridin-2-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) -2-methylpropanamide; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (6-methoxypyridine 2-yl) phenyl) -2-methylpropanamide; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -2-methyl-N- (4- (pyridine 2-yl) phenyl) propanamide; 4- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) tetrahydro-2H-piperan-4-carboxamide; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (5- (6- (trifluoromethyl) pyridine -2-yl) pyridin-2-yl) butanamide; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) butanidine; N- (4- (5-chloropyridin-3-yl) phenyl) -2- (6- (cyclopropanesulfonamido) pyridine-2 -Yl) butanidine; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (6-ethoxypyridine -2-yl) -2-fluorophenyl) butanamide; 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) -N- (4- (6-ethoxypyridine -2-yl) phenyl) butanamide; 2- (6- (cyclopropanesulfonamido) pyridine) 2-yl) -N- (4- (pyridin-3-yl) phenyl) acetamidamine; 2- (6- (ethylsulfonamido) pyridine 2-yl) -N- (4- (pyridin-3-yl) phenyl) acetamidamine; 2- (6- (methylsulfonamido) pyridine 2-yl) -N- (4- (pyridin-3-yl) phenyl) acetamidamine; 2- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) -2-methylpropanamide; 2- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (4- (6-ethoxypyridine -2-yl) phenyl) -2-methylpropanamide; 4- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) tetrahydro-2H-piperan-4-carboxamide; 2- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (5- (6-ethoxypyridine -2-yl) pyridin-2-yl) -4-methoxy-2-methylbutamidine; N- (5- (6-ethoxypyridine) 2-yl) pyridin-2-yl) -4-methoxy-2-methyl-2- (6- (methylsulfonamido) pyridine -2-yl) butanamide; 2- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (5- (6-ethoxypyridine -2-yl) pyridin-2-yl) -2-fluorobutanidine; 2- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (5- (6-ethoxypyridine -2-yl) pyridin-2-yl) butyramine; 2- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (4- (6-ethoxypyridine -2-yl) phenyl) butanamide; 2- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (5- (6-ethoxypyridine -2-yl) pyridin-2-yl) -2-methoxyacetamidamine; 2- (6- (cyclopropanesulfonamido) pyridine -2-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) -2-methoxyacetamidamine; 2- (6- (cyclopropanesulfonamido) pyridine -2-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) -2-methoxypropanamine; 2- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (5- (6-ethoxypyridine -2-yl) pyridin-2-yl) -2- ( R ) -fluorobutanamine; 2- (6- (cyclopropanesulfonamido) pyridine) -2-yl) -N- (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) -2- ( S ) -fluorobutanidine; 2- (4- (cyclopropanesulfonamido) pyrimidin-2-yl) -N- (5- (6 -Ethoxypyridine -2-yl) pyridin-2-yl) butanamide; N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) cyclopropyl) -4- (6-ethoxy Pyridine 2-yl) -2-fluorobenzamide; N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl) -5- (6-ethoxypyridine -2-yl) pyridinamide; N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl) -2-fluoro-4- (5- (trifluoromethyl) Pyridin-3-yl) benzamidine; 4- (5-chloropyridin-3-yl) -N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl)- 2-fluorobenzylamine; N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl) -4- (5- (trifluoromethyl) pyridin-3-yl ) Benzamidine; 4- (5-chloropyridin-3-yl) -N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl) benzamide; N -(1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl) -4- (6-ethoxypyridine -2-yl) -2- (trifluoromethyl) benzidine; N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl) -4- (6- Ethoxypy -2-yl) -2-fluorobenzamide; N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl) -4- (6- (trifluoromethyl Py 2-yl) benzamidine; N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl) -4- (6-isopropoxypyridine 2-yl) benzamidine; N- (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) propyl) -4- (6-ethoxypyridine 2-yl) benzamidine; N- (2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butane-2-yl) -4- (6-ethoxypyridine -2-yl) -2-fluorobenzamide; N- (2- (6- (cyclopropanesulfonamido) pyridine) pyridine -2-yl) prop-2-yl) -2-fluoro-4- (6-isopropoxypyridine 2-yl) benzamidine; N- (2- (6- (cyclopropanesulfonamido) pyridine) pyridine -2-yl) prop-2-yl) -4- (6- (trifluoromethyl) pyridine 2-yl) benzamidine; N- (1- (6- (cyclopropanesulfonamido) pyridine) pyridine -2-yl) propyl) -4- (6-ethoxypyridine -2-yl) -2-fluorobenzamide; N- (1- (6- (cyclopropanesulfonamido) pyridine) pyridine -2-yl) propyl) -4- (6-ethoxypyridine -2-yl) -2- ( R ) -fluorobenzamide; with N- (1- (6- (cyclopropanesulfonamido) pyridine) pyridine -2-yl) propyl) -4- (6-ethoxypyridine 2-yl) -2- ( S ) -fluorobenzamide.

The compounds of the invention may be provided in the form of their pharmaceutically acceptable salts and / or solvates and / or derivatives thereof. In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or solvate, such as a pharmaceutically acceptable salt.

Compounds of the present invention of particular interest are those in which the method (or a similar method) is used in the examples, and IC ₅₀ has been confirmed to be 1 uM or lower, especially 100 nM or lower in terms of CTPS1 enzyme.

The compounds of the present invention that are of particular interest are those using the methods (or similar methods) in the examples, which have proven to be more than 2-30 times in selectivity of CTPS1 over CTPS2, suitably,> 30-60 times, or more suitably ,> 60 times the compound. It is hoped that the selectivity for human CTPS1 is higher than that for human CTPS2.

It is understood that the salts of the compound of formula (I) used in medicine should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of compounds of formula (I) can be used in other applications, such as when preparing compounds of formula (I). Suitable pharmaceutically acceptable salts are understood by those skilled in the art. Pharmaceutically acceptable salts include those described by Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid addition salts can use inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids such as succinic acid, maleic acid, acetic acid, fumaric acid, and lemon. Acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid. Other salts, such as oxalate or formate, can be used, for example, to isolate compounds of formula (I) and are included within the scope of the present invention.

Certain compounds of formula (I) may form acid or base addition salts with one or more equivalents of an acid or base. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

The compound of formula (I) can be made crystalline or amorphous, and if it is crystalline, it can be a solvate, such as a hydrate, if necessary. Within the scope of the present invention are stoichiometric solvates (for example: hydrates) and compounds with varying amounts of solvents (for example: water).

It is understood that the present invention includes pharmaceutically acceptable derivatives of the compound of formula (I), and these are all included within the scope of the present invention.

As used herein, "pharmaceutically acceptable derivatives" includes any pharmaceutically acceptable prodrugs, such as: esters of compounds of formula (I) or salts of these esters, which can be (directly or indirectly) administered to the recipient ) Provides a compound of formula (I) or an active metabolite or residue thereof.

It is understood that the present invention encompasses all isomers of formula (I) and its pharmaceutically acceptable derivatives, including all geometric isomers, tautomers, and optical isomers, and mixtures thereof (eg, racemic Sexual mixture). Where other parameric centers are present in compounds of formula (I), all possible diastereomers, including mixtures thereof, are included within the scope of the invention. Different isomeric forms can be separated or resolved from each other using conventional methods, or any given isomer can be obtained using conventional synthetic methods or stereospecific or asymmetric synthetic methods.

The present invention includes all isotopic forms of the compounds of the present invention provided herein. Regardless of form (i), all atoms of the specified atomic number have the natural major mass (or a mixture of masses) (referred to herein as "natural isotopic forms"). ) Or (ii) where one or more of the atoms are replaced by an atom having the same atomic number but a different mass number than the major atomic mass number in nature (referred to herein as the "non-naturally variable isotopic type"). Xian understands that naturally occurring atoms may have mixed masses. The term "unnatural variant isotope type" as used herein also includes atoms whose mass number is lower than the specified atomic number commonly found in nature (herein referred to as "rare isotopes"), which has increased relative to the natural proportion, for example: An embodiment in which the atomic number of the atomic number is increased by> 20%,> 50%,> 75%,> 90%,> 95%, or> 99% (the latter embodiment is referred to as an "enriched isotope variant"). The term "non-natural variant isotope type" as used herein also includes embodiments in which the proportion of rare isotopes has decreased relative to its natural proportion. Isotopic types can include radioactive types (ie, radioisotopes have been incorporated therein) and non-radioactive types. Radioactive forms are usually isotopically enriched variants.

Therefore, the unnatural variant isotopic form of a compound may contain one or more artificial or rare isotopes in one or more atoms, such as: deuterium ( ² H or D), carbon-11 ( ¹¹ C), carbon-13 ( ¹³ C), carbon -14 ⁽¹⁴ C), nitrogen -13 ⁽¹³ N), nitrogen -15 ⁽¹⁵ N), oxygen -15 ⁽¹⁵ O), oxygen -17 ⁽¹⁷ O), oxygen -18 ⁽¹⁸ O), phosphorus - 32 ( ³² P), sulfur-35 ( ³⁵ S), chlorine-36 ( ³⁶ Cl), chlorine-37 ( ³⁷ Cl), fluorine-18 ( ¹⁸ F), iodine-123 ( ¹²³ I), iodine-125 ( ¹²⁵ I), or the content ratio of this isotope will be higher than the main proportion of one or more atoms in nature.

Non-naturally-mutated isotopes containing radioisotopes can be used, for example, in drug and / or tissue distribution studies. The radioactive isotope plutonium, that is, ³ H, and carbon-14, that is, ¹⁴ C, are particularly suitable for this purpose because they are easily incorporated into the atom and are detected by off-the-shelf instruments. The inclusion of deuterium (i.e., ² H or D) non-natural variant isotopes provides certain medical benefits due to higher metabolic stability, such as prolonging the half-life in vivo or reducing the need for drugs, so it is less effective in some environments. advantageous.

In addition, isotopes that emit positrons, such as: ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N, can be included to prepare unnatural variant isotopes, which are suitable for positron computer tomography (PET) studies to check the receptor occupation.

In one embodiment, the compounds of the invention are provided as natural isotopes.

In one embodiment, the compounds of the present invention are provided as non-naturally variable isotopes. In one specific embodiment, the unnatural variant isotope is a form that incorporates deuterium (ie, ² H or D), in which a specified hydrogen is included in the chemical structural formula of one or more atoms of the compound of the present invention. In one embodiment, the atomic system of the compound of the present invention is a non-radioactive isotope type. In one embodiment, one or more of the atoms of the compound of the present invention is in a radioactive isotope form. Conveniently, the radioactive isotope is a stable isotope. Conveniently, the non-naturally-mutated isotope type is a pharmaceutically acceptable type. In one embodiment, the compound of the present invention is provided so that one atom of the compound is in a non-naturally-mutated isotope type. In another embodiment, the compounds of the present invention are provided such that two or more atoms are in a non-naturally variable isotopic form.

Non-natural isotope variants can usually be prepared using techniques known to those skilled in the art or by the methods described herein, for example, similar to those described in the accompanying examples for the preparation of natural isotopes. Therefore, non-natural isotopic variants can be prepared by replacing the general reagents used in the examples with appropriate isotopic variant (or labeling) reagents. Since the compound of formula (I) is intended for use in pharmaceutical compositions, it is understood that they are provided in substantially pure form, for example: at least 60% purity, more suitably, at least 75% purity, and preferably at least 85%, especially at least 98% purity (% is based on weight / weight ratio). Impure compound preparations can be used to prepare more pure forms for use in pharmaceutical compositions.

In general, compounds of formula (I) can be prepared according to organic synthesis techniques known to those skilled in the relevant art and the representative methods and modifications thereof shown in the examples below.

General approach:

A general description of a general route suitable for preparing the compounds of the present invention is comprehensively described below.

Generally and as shown in the reaction diagram 1a (where R ₄ is H or Et, where R ₁ , R ₃ , Ar1 and Ar 2 are as defined above), or reaction diagram 1 b (where R ₄ is H or OMe, where R ₁ , R ₂ , R ₃ , Ar1 and Ar2 are as defined above). The compound of formula (I) can be prepared from 2,4-dichloropyrimidine derivatives of general formula (VIII) through 4 or 5 steps. The derivative (VIII) can be reacted with an asymmetric malonate derivative to replace the more reactive chloride to form an intermediate compound of formula (VII) . These reactions can be carried out in the presence of a strong base, such as: sodium hydride, and in a polar solvent, such as: DMF. If monoalkylation is required, an inorganic base (such as: sodium hydroxide) is used and the intermediate (VII) is treated in the presence of an alkylating agent (such as: iodoethane (EtI)) to produce the general formula (V ) Compounds. If it is necessary to remove the methyl (R ₄ = H) linking group, the compound of general formula (VII) can directly form the compound of general formula (IV) (see below).

Palladium catalyzed the sulfonation of 2-chloropyrimidine derivatives (VII) and (V) using a catalyst (eg [ t -BuXPhos Pd (allyl)] OTf) and a substituted sulfonamide nucleophile (VI), It is carried out in the presence of an inorganic base (e.g. potassium carbonate) to form an intermediate derivative (IV) . This compound is then decarboxylated by using a strong acid (eg, TFA) to remove the protecting group to produce an intermediate derivative (II) . These reactions are carried out in DCM at a temperature between 0 ° C and room temperature.

The compound of the general formula (I) can be prepared from the intermediate (II) through a one- or two-step process. First, saponification using a reagent such as TMSOK to produce an intermediate carboxylic acid derivative, and then reacting with an activator to produce a reactive electrophilic carboxylic acid derivative, followed by protection with an amine of formula (III) or suitably, Its derivatives react. 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane-2,4,6-trioxide (T3P) is suitable for activating carboxylate Reagent. Another method involves directly using trimethylaluminum (usually a 2.0M toluene or heptane solution) and adding an amine (III) to activate the ester moiety. These reactions are usually heated to 80-100 ° C for several hours in a solvent such as toluene.

If an alkoxy (R ₄ = OMe) linking group is required, the compound can be prepared in 4 steps starting from the 2,4-dichloropyrimidine derivative of general formula (VIII) (Reaction Figure 1b). The derivative (VIII) can be reacted with a symmetric malonate to form a compound in which R ₄ = OMe in the intermediate formula (VII) . For example: The compound of (VII) is then coupled with first-order sulfonamide under the aforementioned conditions. The compound in which both alkyl groups are methyl groups in formula (IV) is then subjected to a decarboxylation reaction initiated with an alkali metal base to remove the protecting group to produce an intermediate derivative (XXVI) . The intermediate carboxylic acid ester derivative (XXVI) can be subjected to amido coupling as described above to give the final compound of formula (I).

Conveniently, R ₂ is H, and (IX) is converted into (X) by using a base and an alkyl halide or X-CH _2- (CH ₂ ) nX (where n = 1, 2, 3). In the process of the steps, a compound of the general formula (I) is obtained.

Generally, and as shown in Reaction Figures 2a and 2b, compounds of general formula (I) can be prepared from 2,4-dichloropyrimidine derivatives of general formula (VIII) through a 5 or 6 step process. First, the derivative ( VIII ) is reacted with an asymmetric malonate as shown in the reaction diagram 1a, 1b, 2a or 2b. In this step, the intermediate compound is further decarboxylated by using a strong acid (eg, TFA) to remove the protective group to produce an intermediate derivative (IX) .

Certain intermediates, such as: (IX) , where R ₃ = H, are available from commercial products. The formula (IX) methyl 2- (2-chloropyrimidin-4-yl) acetate derivative reacts with an inorganic base (such as potassium carbonate) in the presence of an alkylating agent, resulting in α-alkylation of the ester. Those skilled in the art understand that mono- and dialkylation can be achieved by carefully controlling the reaction conditions, but another more reliable synthetic method for the preparation of monoalkylated products can be considered (as shown in Figure 1a) . R ₄ and R ₅ may be bonded to form a C _3-6 cycloalkyl ring as defined above ( (IX) to form (X) ). These compounds can be prepared by double alkylation using dihaloalkanes (such as 1,2-dibromoethane or 1,3-dibromobutane) in the presence of an inorganic base (such as sodium hydroxide). .

The palladium-catalyzed sulfonation reaction of intermediate (X) can use a catalyst (such as: [ t -BuXPhosPd (allyl)] OTf or t -BuXPhos-Pd-G3) and a substituted sulfonamide nucleophile (VI) , Achieved in the presence of an inorganic base (e.g. potassium carbonate) to form the intermediate derivative (II) . Finally, the preparation method for converting the compound of the general formula (I) is to use the trimethylaluminum (usually 2.0M toluene or heptane solution) to activate the ester moiety from the intermediate (II) , and add the amine (III) (from the city Obtain the commercial product or prepare it according to the reaction figure 6a, 6b, 7a or 7b).

Compounds of general formula (VII) in which R ₂ is O-alkyl can be prepared from a commercial 2,4,6-trichloropyrimidine derivative (such as: (VIII) wherein R ₂ is Cl) through two steps. The reaction of asymmetric malonates can produce compounds such as: ( VII ), which can be treated with alkoxide bases (such as sodium methoxide) to replace the more reactive chlorides to produce R in general formula (VII) ₂ = O-alkyl compounds. These compounds continue to follow the steps of the aforementioned reaction schemes 2a or 2b to produce the final compound of formula (I).

In the general formula (I), R ₁ , Ar ₁ and Ar 2 are as defined above, and compounds in which R ₄ and R _{5 together} with the carbon to which they are attached form a C _3-6 heterocycloalkyl group may start from an intermediate of the general formula (VIII) , Prepared in four steps.

First, the alkyl ester of the general formula ( XXVII ) can be treated with a strong base (such as LHMDS) and then reacted with 2,4-dichloropyrimidine (such as a derivative ( VIII )). These compounds can be converted to the final compound using the method illustrated in Reaction Figure 2b. If the protective group remains after the amidine coupling method, treatment with a strong acid (eg, TFA) results in the final compound of formula (I).

For compounds in which R ₅ is a halogen group (such as F) and R ₄ is a C _1-6 alkyl group, a two-step process can be performed to convert the intermediate of formula (IX) to form (X) , see reaction diagram 2b . First, in the α-monoalkylation of an ester, an inorganic base (such as potassium carbonate) can be used for treatment in the presence of an alkylating agent. These products are reacted with a strong base (such as LHMDS) and exposed to a fluorinating agent (such as: N -fluoro- N- (phenylsulfonyl) benzenesulfonamide) to produce a compound of formula (X) .

Generally and as shown in Reaction Figure 3, the compound of general formula (I) in which R ₃ is H can be obtained from the aniline of formula (III) defined in Reaction Figures 4 and 5, through 7 steps (when R ₄ and / or R ₅ = alkyl) or prepared in 5 steps (when R ₄ = R ₅ = H). First, aniline (III) can be protected with a suitable nitrogen protecting group (such as p-methoxybenzyl ether ) , which is a reaction of aniline (III) with 4-methoxybenzaldehyde, and then a reducing agent (such as : Sodium triethoxyalkoxyborohydride), reduced in situ. The protected aniline of formula (XIII) is then reacted with 3- (third butoxy) -3-lanthoxypropionic acid (XIV) in the presence of a coupling agent (such as HATU) to obtain an intermediate ( XV) . These intermediates (XV) can be reacted with 2,4-dichloropyrimidine (VIII) (R ₃ = H) in the presence of a strong base (eg, NaH) in the S _N Ar reaction to produce a pyrimidine of formula (XVI) . Intermediate (XVI) was subjected to two additional conversion reactions.

First, decarboxylation using a strong acid (eg, TFA) to obtain an intermediate of formula (XVIII), followed by alkylation in the presence of a base (eg, K ₂ CO ₃ ) to form a compound of formula (XIX) . Palladium-catalyzed intermediate The sulfonamide amination reaction of the compound (XIX) can be performed using a catalyst system (such as: Pd-174) in the presence of (VI) type sulfonamide to obtain a compound of formula (XX) . Using a strong acid system (such as: TFA / Trifluoromethanesulfonic acid) to remove the protection of aniline nitrogen to obtain the compound of formula (I).

Alternatively, the compound of formula (XVI) can be subjected to sulfonamidation using type (VI) sulfonamide, and then the double protecting group can be removed by using a strong acid system (eg, TFA / trifluoromethanesulfonic acid) to produce a compound of formula (I).

Conveniently, R ₂ is H, R ₃ is H, R ₄ is F, and R ₅ is C _1-6 alkyl.

In general and as shown in reaction diagram 4a, R ₁ , Ar ₁ and Ar ₂ in the general formula (I) are as defined above, P is a nitrogen protecting group (eg, PMB), R ₄ is a halogen group (eg, F), and R ₅ = C _1-6 alkyl compounds can be prepared starting from methyl ester (II) , which can be used, for example: PMB-Cl protection, to produce intermediates (XXI) , and then treated with a suitable base (such as: LHMDS), then used A fluorinating agent (eg, N-fluoro-N- (phenylsulfonyl) benzenesulfonamide) is used for fluorination. Intermediate (XXII) can use an inorganic base (such as: LiOH) to form a salt to produce intermediate (XXIII) , which is then activated by a coupling reagent (such as: T3P) in the presence of a base, and aniline such as: (III) Coupling gives the protected final compound (XXIV) . The final deprotection step is then performed under strong acid conditions (such as: DCM solution of TFA) to produce the desired final compound of general formula (I).

As shown in Reaction Figure 4b, intermediates of formula (XXI) can also be prepared starting from pyrimidine (IV) , which can be protected using, for example: PMB-Cl, to produce (XXVIII) intermediates. When the alkyl ester is tBu, it can be decarboxylated using a strong acid (eg, TFA) to produce a derivative of formula (XXI) . Alternatively, if the alkyl group is a methyl group, under Krapcho conditions, a chloride ion source (such as LiCl) can be used in a polar aprotic solvent (such as DMSO) and heated (such as 140). ° C), decarboxylation was performed to produce a derivative of general formula (XXI) .

For compounds in which R ₄ is C _1-6 alkyl, but in which R ₄ ≠ R ₅ , a derivative of general formula (XXI) and an inorganic base (such as potassium carbonate) can be reacted in the presence of an alkylating agent to produce Compound of formula (XXII) . These compounds can be converted to the final compound using the method of the aforementioned reaction Figure 4a.

For the desired compound in which R ₄ = H, the compound of formula (XXI) can be directly converted into a carboxylic acid salt, such as: (XXIII) , by using a suitable formulation (such as: TMSOK) according to the aforementioned method. Intermediate (XXIII) can be converted into a compound of formula (I) as described above, or after two steps, direct coupling of (XXII) and an amine of formula (III) in the presence of an activator (eg, AlMe ₃ ), as described above Transformation (XXIV) to form a compound of formula (I).

Conveniently, X is N, Y is CH, R ₃ is H, (IX) uses a base with n ₁ = n ₂ = 2 in formula (XXV) , hal is Cl, alkyl is methyl, R ₄ and R ₅ Compounds which together form a tetrahydropiperanyl ring with the attached carbon atoms are converted into (X) , and a compound of formula (II) is converted into a compound of formula (I) using AlMe ₃ and a compound of formula (III) .

In the general formula (I), R ₁ , Ar1 and Ar 2 are as defined above, and compounds in which R ₄ and R _{5 together} with the carbon to which they are attached form a C _3-6 heterocycloalkyl group may start from the intermediate of general formula (IX) A three-step preparation was performed, see reaction scheme 5a. First, the derivative (IX) can be reacted with a symmetric di-bromoether of the general formula (XXV) , as shown in reaction FIG. 5a, to produce an α-cyclic compound of the formula (X) . The resulting intermediate can be further reacted with sulfonamide of general formula (VI) to produce a compound of formula (II) . Finally, the derivative (II) is reacted with AlMe _{3 in} the presence of (III) type aniline to produce a compound of general formula (I).

In the general formula (I), R ₁ , R ₃ , Ar1 and Ar2 are as defined above, X = Y = CH or X = CH, and Y = N, hal = Br or Cl, and R ₄ is a C _1-6 alkyl group, Compounds in which R ₅ is H or C _1-6 alkyl can be prepared in three or four steps starting from the intermediate of formula (IX) . The derivative of general formula (IX) reacts with an inorganic base (such as potassium carbonate) in the presence of an alkylating agent to produce α-alkylation of an ester to produce a compound of formula (X) . Those skilled in the art understand that mono- and dialkylation can be achieved by carefully controlling the reaction conditions. The compound of formula (X) can then be made into the final compound of formula (I) by following the steps illustrated in the above reaction Figure 5b.

In the general formula (I), R ₁ , R ₃ , Ar1 and Ar2 are as defined above, X = Y = CH or X = CH, and Y = N, and R ₄ and R _{5 together} with the carbon to which they are attached form C _{3 The -6} heterocycloalkyl compound can be prepared in the same manner as described above for the compounds when X = N and Y = CH.

In general formula (II) , when R ₁ and R _{3 are} as defined above, compounds of R ₄ = R ₅ = H, and X and Y = CH can also be obtained from amine products of formula (XXIX) and suitable sulfonyl chloride (XXX), in Prepared by reaction in pyridine. Intermediate (II) is then hydrolyzed, and amidine coupling is performed by the method described above.

In the general formula (I), R ₁ , R ₃ , Ar1 and Ar2 are as defined above, X = CH, and Y = N, hal = Br or Cl, R ₄ is C _1-6 alkyl, and R ₅ is F. Compounds can be prepared starting from intermediates of general formula (IX) . First, an inorganic base (such as potassium carbonate) is treated in the presence of an alkylating agent to perform α-monoalkylation of an ester. After these products are reacted with a strong base (such as LHMDS) and exposed to a fluorinating agent (such as: N-fluoro-N- (phenylsulfonyl) benzenesulfonamide), a compound of formula (X) can be produced. The compound of formula (X) is then subjected to the steps illustrated in Figure 5b of the reaction to produce a compound of formula (I).

Of formula (III), Ar1, R _10, R ₁₁ and R ₁₂ are as defined above, and Ar2 is unsubstituted or substituted 3-pyridinyl ring of the intermediates of the synthetic method may be by formula (XII) glyoxylic Borates (where R _{12 is} as defined above, and Z represents a dihydroxyboryl or dialkyloxyboryl group, usually 4,4,5,5-tetramethyl-1,3,3,2-dioxo Heteroborocyclopentane-2-yl), under Suzuki conditions, is coupled with a substituted pyridine in which X represents a halide in formula (XI) . Suzuki coupling methods were based method, for example: in the catalyst (eg: [1,1 '- bis (diphenylphosphino) ferrocene] dichloropalladium in the presence of (II) complexes, the dichloromethane and Inorganic bases (eg potassium carbonate) Heat in a mixed solvent of alkane and water.

Ar1, R ₁₀ , R ₁₁ and R _{12 in} formula (III) are as defined above, and Ar 2 is an unsubstituted or substituted 2,5-pyridine The synthesis method of the intermediate of the basic ring can be based on the aromatic halides of the general formula (XII) and Z representing halides under the conditions of Suzuki, and X in the general formula (XI) represents a dihydroxyboryl or dialkyloxyboryl group It is usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl) dihydroxyborate coupling. Coupling method according to the Suzuki method, for example: catalyst (such as: (triphenylphosphine) palladium (II) or [1,1 ' -bis (diphenylphosphino) ferrocene]] dichloropalladium (II )) In the presence of inorganic bases (such as potassium carbonate), in two Heat in a mixed solvent of alkane and water.

Generally, and as shown in Reaction Figure 8, R ₁ , R ₃ , Ar ₁ and Ar ₂ in formula (I) are as defined above, where X = N and Y = CH, where R ₄ = H, C _1-6 alkyl or Compounds of CH ₂ CH ₂ OMe, and R ₅ = H can be prepared from four or five steps starting from the intermediate of formula (VII) . The intermediate ( VII) can be treated with an inorganic base (such as sodium hydroxide) in the presence of an alkylating agent (such as iodoethane) and alkylated to produce a compound of the general formula (V) . Decarboxylation is initiated using a strong acid (eg, TFA) to obtain an intermediate of formula (X). These intermediates are then saponified and coupled with amidine to produce a compound of formula (XXXI) according to the method illustrated in Reaction Scheme 1. According to the aforementioned reaction scheme 1, the intermediate of formula (XXXI) is coupled with first-order sulfonamide to obtain the final compound of formula (I).

Generally and as shown in Reaction Figure 8, R ₁ , R ₃ , Ar ₁ and Ar ₂ in formula (I) are as defined above, where X = CH and Y = N, where R ₄ = H or CH ₂ CH ₂ OMe, and Compounds in which R ₅ = H or Me can be prepared starting from the intermediates of general formula (VIII) according to a similar method as described in the reaction diagram of FIG. 8 when X = N and Y = CH. If the alkyl group of R ₅ = Me needs to be alkylated, an alkylating agent can be used to alkylate the intermediate of formula (X) in the presence of a base to produce an intermediate such as: (Xa) . The compound of formula (Xa) is then converted into the final compound through a three-step process as illustrated in reaction FIG.

In the general formula (XXXI), the compounds when R ₄ = R ₅ = H, and X = CH, and Y = N can also be obtained from the acid product of formula (XXXII) and the aniline of formula (III) under the coupling conditions of amidine Made by coupling. Compounds of this type are then subjected to the sulfonamidation conditions described above to produce compounds of formula (I).

In general and as shown in Reaction Figure 9, compounds of general formula (I) in which R ₁ , Ar ₁ and Ar 2 are as defined above can be obtained from literature compounds: 2,2-difluoro-2- (2- (methylthio) pyrimidine-4 -Yl) ethyl acetate (XXXIII) was prepared in 3 steps. The thioethers of general formula (XXXIII) can be converted into thallium (XXXIV) by reacting in the presence of an oxidant (such as: Oxone®) in a polar protic solvent (such as MeOH) at room temperature. The primary sulfonamide (VI) is used to replace the fluorenyl group, and then the ester is hydrolyzed to generate an acid of the general formula (XXXV) . This process can be performed in a one-pot process in the presence of a strong base (such as NaH) in polar aprotic Solvent (such as: DMF). The acid derivative (XXXV) is then activated using a coupling reagent (such as HATU) in the presence of a base and coupled with an aniline such as: (III) to obtain the final compound of formula (I).

Generally and as shown in Reaction Figure 10, R ₁ , R ₃ , Ar ₁ and Ar ₂ in the general formula (X) are as defined above, and a compound in which R ₄ = OMe can be selected from the general formula (VIII) 2,4-dichloropyridine Derivatives are prepared by four, five, or six steps. Derivative (VIII) can react with symmetric malonate (when R ₄ = OMe) in the presence of a strong base (such as sodium hydride) in a polar solvent (such as DMF) to form formula (V) Intermediate compound. Then a two-step process is performed to obtain the compound of general formula (X) . First, saponification with an alkali metal hydroxide (eg, NaOH) produces a dicarboxylic acid that can be spontaneously decarboxylated once acidified. The obtained carboxylic acid is then treated with an activator (eg, thionyl chloride) in an alcoholic solvent (eg, methanol) to be converted into an ester of the general formula (X) . The derivative of the formula (X) can be reacted according to the aforementioned reaction FIG. 5 The illustrated method converts to the final compound of formula (I) .

Generally and as shown in Reaction Figure 11, R ₁ in formula (XXVIII) is as defined above, and the compound in which R ₄ = H or Et can start from a 2,4-dichloropyrimidine derivative of general formula (VIII), Preparation in steps.

Derivative (VIII) can be reacted with sulfonamide of type (VI) in the presence of an inorganic base (such as potassium carbonate), displace more reactive chlorides, and form intermediate compounds of formula (XXXVI) . Compounds of formula (XXXVI) can be protected, for example, with PMB-Cl to produce compounds of formula (XXXVII) .

This compound is then treated with an asymmetric malonate in the presence of a base (e.g., cesium carbonate) in a solvent (e.g., dimethoxyethane) to convert it to a compound of formula (XXXVIII) .

If monoalkylation is required, the intermediate (XXXVIII) is treated with an inorganic base (such as potassium carbonate) in the presence of an alkylating agent (such as EtI) to produce a compound of the general formula (XXVIII) . This compound is then converted to the final compound of formula (I) using the method illustrated in the aforementioned reaction Figure 4.

When R ₄ = H, the compound of the general formula (XXXVIII) can directly form the compound of the general formula (I) (for example, as described above).

Benzamidine

The compound of general formula (I) can be prepared through a four-step process according to the reaction shown in FIG. 12. 2-chloropyrimidine-4-carbonitrile (XXXIX) can be converted to the corresponding sulfonamide (XXXX) using the palladium-catalyzed sulfonation conditions of the aforementioned reaction FIG. 1. The use of sodium borohydride from a nitrile group and reduction in the presence of nickel (II) chloride and di-tert-butyl dicarbonate can produce a protected benzylamine derivative of the general formula (XXXXI) . You can use HCl. The alkyl group is subjected to acid hydrolysis to remove the protective group to produce a benzylamine derivative of the general formula (XXXXII) . Then using the amidine coupling conditions, using a coupling reagent and a biarylcarboxylic acid (XXXXIII) (obtained from a commercially available product or prepared according to reaction FIG. 19) to convert the benzylamine derivative (XXXXII) to form the general formula (I): amine.

In the general formula (I), R ₁ , Ar ₁ and Ar _{2 are} as defined above, X = N and Y = CH, R ₃ is H, R ₄ is C _1-6 alkyl, and R ₅ is H or C _{1- 6} alkyl, or compounds in which R ₄ and R ₅ and the carbon to which they are attached form a C _3-6 cycloalkyl group can be processed according to Figure 13 (and some steps shown in Figure 12) through a six-step process be made of. First, the derivative (IX) can be reacted with an alkyl halide to produce a compound in which R ₄ = alkyl and R ₅ = H in the general formula (X) . Alternatively, the derivative (IX) is reacted with an alkyl dihalide to produce a compound in which R ₄ and R ₅ in the general formula (X) can be linked to form a C _3-6 heterocycloalkyl ring as defined above.

Hydrolysis of the methyl ester (X) with an alkali metal base (such as lithium hydroxide) in a mixed solvent such as: THF / MeOH to obtain a carboxylic acid (XXXII) . For example: Curtius rearrangement using diphenylphosphonium azide in the presence of triethylamine and tertiary butanol to produce a carbamate, such as: (XXXXIV ) . Next, using the conditions described in the aforementioned reaction FIG. 1, palladium-catalyzed sulfonation was performed to obtain the corresponding sulfonamide (XXXXI) . From the carbamate of formula (XXXXI) according to Figure 12, the final compound of formula (I) is obtained.

In the general formula (I), R ₁ , Ar ₁ and Ar _{2 are} as defined above. Compounds in which X = CH and Y = N, R ₄ is C _1-6 alkyl, and R ₅ is H can be obtained from commercially available products. The acid of formula (XXXII) starts and is prepared in four steps according to the continuous steps illustrated in Figure 13 of the reaction.

In formula (I) , R ₁ , R ₃ , Ar ₁ and Ar _{2 are} as defined above, and R ₄ = alkyl, and R ₅ = H. The pyrimidin-4-yl (prop-2-yl) benzamide derivatives can be prepared according to The reaction is shown in Figure 14 and prepared via two different routes.

Both of these pathways start with the conversion of 2-bromopyrimidine to the corresponding ketone (XXXXVI) , which is treated with a suitable base (such as: TMPMgCl. LiCl) and exposed to a Weinreb amide derivative. These two pathways then converge on the compound of general formula (L) , where a two-step process is performed to obtain the final analog.

Route A: After treatment with a ketone derivative (XXXXVI) with ammonium trifluoroacetate and reduction with sodium borohydride, benzylamine (L) can be produced.

Route B: A ketone of the general formula (XXXXVI) is treated with Lewis acid (e.g., titanium isopropoxide), and then exposed to sulfenimide (e.g., 2-methylpropane-2-sulfenamide) ), Converted to sulfenimidine (XXXXVII). Reduction with sodium borohydride can produce sulfenimidine (XXXXVIII) . The intermediate of formula (XXXXVIII) can then be removed by using a strong acid (such as HCl) to remove the protecting group, which can also cause halogen exchange to produce an amine with X = Cl in general formula (L) .

The benzamide coupling conditions proposed in reaction FIG. 12 can be used to convert the benzylamine derivative (L) to form the amidine in the general formula (LI) . The palladium-catalyzed sulfonation according to Reaction Scheme 12 can produce compounds of general formula (I) .

Generally, and as shown in Reaction Figure 15, a compound of general formula (XXXXII) can be prepared from a ketone derivative of general formula (XXXXVI) through a three-step process. The sulfonamidation of the (XXXXVI) derivative can be carried out using the conditions illustrated in Reaction Figure 12 to produce a compound of formula (LII) . After the oxime is formed using methoxyamine, it is reduced in a polar protic solvent (such as MeOH) in the presence of a suitable catalyst (such as: Pd / C) in a H ₂ gas atmosphere to produce the general formula ( XXXXII) amine derivative. Such amines can be reacted according to Figure 12 to obtain the final compound.

Alternatively, the compound of general formula (XXXXII) can be prepared by a three-step process according to the reaction shown in FIG. 16.

N- (2- (2-bromopyrimidin-4-yl) butane-2-yl) -2-methylpropane-2-sulfenamidine (XXXXVII) can be synthesized as described above (Reaction Figure 14). The imine is then exposed to a nucleophile, such as: MeMgBr, which produces an intermediate such as: (XXXXVIII) . Then, according to the description of Reaction Figure 1, the sulfonamide is catalyzed by palladium to obtain the corresponding sulfonamide (LIII) . Hydrochloric acid was used for acid hydrolysis to remove the protective group to produce a benzylamine derivative of the general formula (XXXXII) , which was then converted into the final compound according to reaction FIG. 12.

In formula (I) , R ₁ , R ₃ , Ar1 and Ar2 are as defined above, and R ₄ = R ₅ = alkyl benzamidine derivatives can be prepared through 5 steps according to the description of reaction FIG. 17. Aromatic chloride products such as: (LIV) are coupled with first-order sulfonamide using the sulfonamide conditions described in Reaction Figure 1. Then perform a double Grignard addition in an aprotic solvent (such as THF) to form an intermediate of formula (LVI) . A Ritter reaction is then performed using an alkyl nitrile (eg, 2-chloroacetonitrile) in the presence of an acid (eg, H ₂ SO ₄ ). The intermediate of formula (LVII) can be reacted with thiourea in a protic solvent (such as ethanol), in the presence of acetic acid, and heated under reflux to remove the protective group to produce a benzylamine derivative (XXXXII) . Using the amidine coupling conditions proposed in Reaction Figure 12, the final compound of formula (I) was obtained.

Generally, and as shown in Reaction Figure 18, the intermediate (II) can be converted into a compound of the general formula (I) through a three-step process. First, saponification from (II) using a formulation such as TMSOK yields an intermediate carboxylic acid derivative, which is then reacted with an activator (such as T3P) and bromo-aniline of formula (XI) . The intermediate of formula (LVIII) is then coupled with the dihydroxyborate of general formula (XII) under the conditions of Suzuki, and converted into the compound of general formula (I) according to the present invention.

The dihydroxyborate is usually a dihydroxyboryl or dialkyloxyboryl group, and is usually 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolane. -2-yl. Coupling according to the Suzuki method, for example: in the presence of catalysts (eg: [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II)) and inorganic bases (eg potassium carbonate) Next Heat in a solvent mixture of alkane and water. Those who are familiar with this technology know that there are many catalysts and conditions that can be used by these companies.

Ar ₂ in formula (XXXXIII) is unsubstituted or substituted 2-pyridine The intermediate of the ring or 3-pyridyl ring can be synthesized as shown in Figure 19, which is an aromatic halide of general formula (XII) (where R ₁₂ and R _{13 are} as defined above, and Z represents Br or Cl), And R ₁₀ and R ₁₁ in the general formula (XI) are as defined above, and X represents a dihydroxyboryl group or a dialkyloxyboryl group, such as: 4,4,5,5-tetramethyl-1,3,3, 2-Dioxaborane-2-yl dihydroxyborate, coupled under Suzuki conditions. Coupling according to the Suzuki method, for example: catalyst (such as: [1,1 ' -bis (diphenylphosphino) ferrocene] dichloropalladium (II) .CH ₂ Cl ₂ adduct) and inorganic base (Eg: cesium carbonate) in the presence of Heating in a solvent mixture of alkane and water under an inert atmosphere (such as a nitrogen atmosphere) to produce a compound of formula (LVIX) . The third butyl ester can be used as a strong acid (such as TFA), the protective group can be removed in CH ₂ Cl ₂ solvent, the alkali metal hydroxide (such as: NaOH) can be used for hydrolysis in a solvent mixture such as: THF / MeOH, or Hydrolysis from a nitrile using a strong acid (such as concentrated HCl) gives a carboxylic acid of general formula (XXXXIII) .

Intermediate of the present invention

The present invention also relates to a novel intermediate for synthesizing a compound of formula (I), such as: compounds of formula (II) to (LVIX) , such as: compounds of formula (II) to (XXV) , such as: formula (II)-( XX) compounds. The intermediates of particular interest are their compounds of the following general formula, in which the variable groups and related preferences are as defined for the aforementioned compounds of formula (I):-compounds of formula (II) :

Where R is H, C _1-6 alkyl (for example: methyl and ethyl) or benzyl;-compound of formula (III) : A compound of formula (XX) : A compound of formula (XXIV) : Wherein P is a nitrogen protecting group, such as: p-methoxybenzyl.

The following compounds are also of interest, in which the variable groups and related preferences have been defined as the aforementioned compounds of formula (I):-compounds of formula (II) :

Wherein R is H, C _1-6 alkyl (for example: methyl and ethyl) or benzyl;-compound of formula (III) : A compound of formula (XX) : A compound of formula (XXIV) : A compound of formula (XXXI) : A compound of formula (XXXXII) : A compound of formula (XXXXIII) : A compound of formula (LI) : A compound of formula (LVIII) :

Aspects of the invention include all novel intermediates illustrated in the examples, including:-intermediates INTC to INTC47; and-intermediates INTD1 to INTD51.

Intermediates INTC48 to INTC53 are also available.

Intermediates INTC54 to INTC177 are also available.

Intermediates INTD52 to INTD86 are also available.

Aspects of the invention include salts of any of the intermediates disclosed herein (such as any of the compounds of formula (II)-(LVIX) ), such as pharmaceutically acceptable salts.

Medical method

The compound of formula (I) of the present invention has use as a CTPS1 inhibitor.

Therefore, the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof (for example, a salt) and / or a derivative thereof for use in medicine, in particular, for treatment or Prevention of diseases or disorders in which CTPS1 inhibitors can benefit, such as those diseases and disorders mentioned below.

The present invention provides a method for treating or preventing a disease or disorder in which CTPS1 inhibitors can benefit, for example, the following diseases and disorders, which include administering an effective amount of the formula to an individual in need thereof (I) A compound or a pharmaceutically acceptable salt thereof and / or a solvate thereof (for example, a salt) and / or a derivative thereof.

The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof (for example, a salt) and / or a derivative thereof, which is used for manufacturing medicine for treatment or prevention. Diseases or disorders in which CTPS1 inhibitors can benefit, such as those diseases and disorders mentioned below.

More suitably, the disease or disorder in which it may benefit from an inhibitor of CTPS1 is a disease or disorder in which it may benefit from a reduction in T-cell and / or B-cell proliferation.

The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof (for example, a salt) and / or a derivative thereof for inhibiting CTPS1 in an individual.

The present invention provides a method for inhibiting CTPS1 in an individual, which comprises administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof (for example, a salt) and / or derivative.

The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate (e.g., a salt thereof) and / or a derivative thereof, which is used for the manufacture of a medicament for individual inhibition CTPS1.

The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate (e.g., a salt thereof) and / or a derivative thereof for reducing T-cells and / or B- Cell proliferation.

The present invention provides a method for reducing T-cell and / or B-cell proliferation for an individual, which comprises administering to the individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof. (Eg, salt) and / or its derivatives.

The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate (e.g., a salt thereof) and / or a derivative thereof, which is used for the manufacture of medicine for the purpose of reducing T-cell and / or B-cell proliferation.

More suitably, the disease or disorder in which it may benefit from an inhibitor of CTPS1 is a disease or disorder in which it may benefit from a reduction in T-cell and / or B-cell proliferation.

As used herein, the term "treatment" or "treatment" includes controlling, alleviating, alleviating, or regulating a disease state or its symptoms.

As used herein, the term "prevention" or "prevention" means preventing the symptoms of a disease or disorder for an individual or preventing the recurrence of the symptoms of a disease or disorder in an affected individual, and is not limited to completely preventing the disease.

Conveniently, the disease or disorder is selected from the group consisting of rejection of transplanted cells and tissues, graft-related diseases or disorders, allergies, and autoimmune diseases.

In one embodiment, the disease or condition is rejection of transplanted cells and tissues. The individual has received a graft transplant selected from the group consisting of: heart, kidney, lung, liver, pancreas, islets, brain tissue, stomach, large intestine, small intestine, cornea, skin, trachea, bone, bone marrow ( Or any other source of hematopoietic precursor cells and stem cells, including hematopoietic cells or umbilical cord blood cells that move from the bone marrow into the surrounding blood), muscle, or bladder. The compounds of the invention can be used to prevent or suppress an immune response associated with rejection of a donor tissue, cell, transplant, or organ transplant in an individual.

In another embodiment, the disease or disorder is a graft-related disease or disorder. Graft-related diseases or disorders include graft-versus-host disease (GVHD), such as GVHD associated with bone marrow transplantation, and transplantation due to rejection of organs, tissues, or cells (eg, allogeneic or xenogeneic tissues or cells, including For example: skin, muscle, neurons, islets, organs, liver parenchymal cells, etc. grafts) or related immune disorders, and the host fights graft disease (HVGD). The compounds of the invention can be used to prevent or suppress acute rejection of these transplants in recipients and / or for long-term maintenance therapy to prevent recipients from rejecting such transplants (e.g., suppression of rejection in donors suffering from diabetes from donors). Will produce insulin islet cell transplants). Therefore, the compounds of the present invention are useful for preventing host against graft disease (HVGD) and graft versus host disease (GVHD).

CTPS1 inhibitors can be administered to an individual before, after, and / or during transplantation. In some embodiments, a CTPS1 inhibitor may be administered to an individual periodically before and / or after transplantation.

In another embodiment, the disease or condition is an allergy.

In other embodiments, the immune-related disease or disorder is an autoimmune disease. As used herein, "autoimmune disease" refers to a disease or disorder directed at an individual's autologous tissue. Examples of autoimmune diseases include, but are not limited to: Addison's disease, Adult Onset Still's Disease, alopecia areata, Alzheimer's disease, anti-neutrophil cytoplasmic antibodies (ANCA ) -Related vasculitis, ankylosing spondylitis, antiphospholipid syndrome (Hughes Syndrome), aplastic anemia, arthritis, asthma, atherosclerosis, atherosclerotic plaques, atopic Dermatitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune pituitary inflammation (lymphocytic pituitary inflammation), autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune myocarditis, autoimmune Neutropenia, autoimmune ovarian inflammation, autoimmune ketitis, autoimmune diseases that require immunosuppressive therapy, azoospermia, Behcet's disease, Berger's diease Bullous pemphigoid, cardiomyopathy, cardiovascular disease, celiac disease (including refractory celiac disease (types I and II)), chronic fatigue immune dysfunction syndrome (CFIDS), chronic idiopathic Polyneuritis, chronic inflammatory demyelinating polyneuropathy (CIPD), chronic recurrent polyneuropathy (Guillain-Barré syndrome), Churg-Strauss syndrome syndrome (CSS), cicatricial pemphigoid, cold agglutinin disease (CAD), chronic obstructive pulmonary disease (COPD), CREST syndrome, cryoglobulin syndrome, cutaneous lupus, herpes dermatitis, dermatomyositis , Eczema, acquired epidermolytic vesicular disease, congenital mixed cryoglobulinemia, Evan's Syndrome, bulging eyes, fibromyalgia, Goodpasture's Syndrome, Ge Graves disease, hemophagocytic lymphohistiocytosis (HLH) (including type 1 hemophagocytic lymphohistiocytosis), histiocytosis / histiocytosis, Hashimoto's thyroiditis (Hashimoto's Thyroiditis), idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, immunoproliferative disease or disorder, inflammatory bowel disease (IBD), interstitial lung disease, juvenile joints , Juvenile idiopathic arthritis (JIA), Kawasaki Disease, Lambert-Eaton myasthenic syndrom, lichen planus, local scleroderma, lupus nephritis, Menier's Disease (Ménière's Disease), microvascular hemolytic anemia, microscopic polyangiitis, Miller Fisher syndrome / acute diffuse cerebrospinal nerve root disease, mixed connective tissue disease, multiple sclerosis ( MS), rheumatism, myalgia encephalomyelitis (ME), myasthenia gravis, eye inflammation, pemphigoid pemphigus, pemphigus vulgaris, malignant anemia, multiple nodular arteritis, multiple cartilage Inflammation, polycrine syndrome ((Whitaker's syndrome), rheumatic polymyalgia, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis / Autoimmune cholangitis, primary glomerulonephritis, primary sclerosing cholangitis, psoriasis, psoriasis arthritis, pure red blood cell anemia, Raynaud's Phenomenon, Reit's syndrome er's syndrome) / reactive arthritis, relapsing polychondritis, postoperative restenosis, rheumatic fever, rheumatism, rheumatoid arthritis, sarcomatoid disease, Schmidt's syndrome, scleroderma / Systemic sclerosis, Sjörgen's syndrome, Stiff-Man syndrome, Sweet syndrome (fever neutrophilic skin disease), systemic lupus erythematosus (SLE ), Systemic scleroderma, Takayasu arteritis, temporal arteritis / giant cell arteritis, thyroiditis, type 1 diabetes, type 2 diabetes, uveitis, vasculitis, white spot disease, Wegener's Granulomatosis, X-linked lymphoproliferative disease.

Special attention is given to diseases and disorders that are mainly driven by T-cell activation and proliferation, including:-Diseases and disorders that are not related to allogeneic reactivity, including: alopecia areata, atopic dermatitis, eczema, psoriasis, lichen planus, psoriasis Arthritis, white spot disease; ■ uveitis; ■ ankylosing spondylitis, Reiter's syndrome / reactive arthritis; ■ aplastic anemia, autoimmune lymphoproliferative syndrome / disorder, hemophagocytic Lymphocytic hyperplasia; ■ Type 1 diabetes; and ■ Refractory celiac disease;-Acute rejection of transplanted tissues and organs; transplantation of bone marrow cells or any other allogeneic source (including hematopoietic precursor cells and / or stem cells) Acute graft against host disease (GVHD).

Also concerned about diseases and conditions that are driven by the activation and proliferation of both T-cells and B-cells and that mainly involve B-cells, including:-Diseases and conditions that have been fully determined to involve pathogenic autoantibodies, including: ● Allergies; ● Cicatricial pemphigoid, bullous pemphigoid, acquired epidermolytic vesicular disease, deciduous pemphigoid, pemphigus vulgaris, herpes dermatitis; ● ANCA-related vasculitis And microscopic polyangiitis, vasculitis, Wegener's Granulomatosis; Chag-Strauss syndrome (CSS), multiple nodular arteritis, cryoglobulin syndrome Mixed with congenital cryoglobulinemia; ● Systemic lupus erythematosus (SLE), antiphospholipid syndrome (Hughes Syndrome), cutaneous lupus, lupus nephritis, mixed connective tissue disease; ● thyroiditis, Hashimoto's thyroiditis, Graves' disease, bulging eyes; ● Autoimmune hemolytic anemia, autoimmune neutrophilic hypoxia, ITP, malignant anemia, pure red blood cell anemia, microvascular hemolytic anemia; ● Primary glomerulonephritis, Berger's diease, Goodpasture's Syndrome, IgA nephropathy; and ● Chronic idiopathic polyneuritis, chronic inflammatory demyelinating nerve Inflammation (CIPD), chronic recurrent polyneuropathy (Guillain-Barré syndrome), Miller Fisher syndrome, stiff-man syndrome, Lambert-Eton muscle weakness syndrome (Lambert -Eaton myasthenic syndrome), myasthenia gravis.

-B-cells are involved and the characteristics are less clear (although sometimes confirmed by the efficacy of anti-CD20 monoclonal antibodies or intravenous immunoglobulin infusions) and may not correspond to or be limited to the production of pathogenic antibodies (though, sometimes Diseases and disorders that still or even often have non-pathogenic antibodies and are used as diagnostic biomarkers) include: ● Addison's disease, autoimmune ovarian inflammation and azoospermia, polycrine disease syndrome (Whitaker's syndrome), Schmidt's syndrome; ● Autoimmune myocarditis, cardiomyopathy, Kawasaki disease; ● Rheumatoid arthritis, Thurgren's syndrome ( Sjögren's syndrome), mixed connective tissue disease, polymyositis and dermatomyositis; polychondritis; ● primary glomerulonephritis; ● multiple sclerosis; ● autoimmune hepatitis, primary biliary cirrhosis / Autoimmune cholangitis; ■ High acute rejection of transplanted organs; ■ Chronic rejection of transplants or transplants; ■ After transplantation of bone marrow cells or hematopoietic precursor cells Sexual grafts against host response / disease are also concerned with T-cell activation / proliferation and innate immune cells and other subpopulations of inflammatory cells (including bone marrow cells such as macrophages or granulocytes) and resident cells (such as : Fibroblasts and endothelial cells) have common opportunities for diseases / diseases, including: ■ COPD, idiopathic pulmonary fibrosis, interstitial lung disease, sarcomatoid disease; Adult Onset Still's Disease, Juvenile Idiopathic Arthritis, Systemic Sclerosis, CREST Syndrome, in which B-cell and pathogenic antibodies may also play a role; Sweet syndrome; High's arteritis, Temporal arteritis / giant cell arteritis; ulcerative cholangitis, inflammatory bowel disease (IBD), including Crohn's Disease and ulcerative colitis, primary sclerosing cholangitis.

I am also concerned about diseases and disorders whose mechanisms are still unknown but involve T-cell activation and proliferation, including: ■ Alzheimer's disease, cardiovascular syndrome, type 2 diabetes, postoperative restenosis, chronic fatigue immune dysfunction syndrome ( CFIDS).

-Autoimmune lymphoproliferative disorders, including: ■ Autoimmune lymphoproliferative syndromes and X-linked lymphoproliferative diseases.

Conveniently, the disease or disorder is selected from the group consisting of: inflammatory skin diseases such as psoriasis or lichen planus; acute and / or chronic GVHD, such as: steroid-resistant acute GVHD; acute lymphoproliferative syndrome; systemic lupus erythematosus and lupus Nephritis or cutaneous lupus; or transplantation. In addition, the disease or disorder may be selected from the group consisting of myasthenia gravis, multiple sclerosis, and scleroderma / systemic sclerosis.

Compounds of formula (I) are useful for treating cancer.

Therefore, in one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate and / or a derivative thereof is provided for treating cancer.

In addition, a method for treating cancer in an individual is provided, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and / or a solvate and / or a derivative thereof to an individual in need thereof.

In addition, a compound of formula (I), or a pharmaceutically acceptable salt and / or a solvate and / or a derivative thereof, is provided for use in the manufacture of medicine for treating cancer in an individual.

Conveniently, the cancer is a hematological cancer such as: acute myeloid leukemia, vascular immunoblast T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet syndrome, T-cell non-Ho Non-Hodgkins lymphoma (including natural killer / T-cell lymphoma, adult T-cell leukemia / lymphoma, enteric T-cell lymphoma, liver-spleen T-cell lymphoma, and skin T- Cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma (including Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, cuff Cell lymphoma, marginal zone lymphoma), hairy cell leukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphoid plasma cell lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, Myelodysplastic syndromes, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (e.g. chronic myelogenous leukemia, primary myelofibrosis, idiopathic thrombocytosis, true redness blood Disease), or chronic lymphocytic leukemia.

Alternatively, the cancer is a non-blood cancer, such as selected from the group consisting of bladder cancer, breast cancer, melanoma, neuroblastoma, malignant costal mesothelioma, and sarcoma.

In addition, compounds of formula (I) can be used to promote recovery from vascular injury or surgery for individuals, and to reduce morbidity and mortality associated with neointimal and postoperative restenosis. For example, compounds of formula (I) can be used to prevent, reduce, or inhibit neointimal formation. A medical device can be treated with an effective amount of a composition comprising a compound of formula (I) prior to embedding or implantation to prevent, reduce, or inhibit neointimal formation after the device or implant is embedded or implanted in an individual. form. The device can be a device that is temporarily embedded in an individual or a device that is permanently implanted. In some embodiments, the device is a surgical device. Examples of medical devices include, but are not limited to: needles, cannulas, catheters, shunts, balloons, and implants, such as stents and valves.

Conveniently, the individual is a mammal, and in particular, the individual is a human.

Pharmaceutical composition

The compounds of the present invention for medical use are usually administered as a pharmaceutical composition. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof (for example, a salt) and / or a derivative thereof, and a pharmaceutically acceptable substance Agent or excipient.

In one embodiment, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof (for example, a salt) and / or a derivative thereof is provided for use in treatment or prevention. Diseases or disorders described herein.

In another embodiment, a method for preventing or treating a disease or disorder described herein is provided, which comprises administering to an individual in need thereof an effective amount of a compound comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and / Or a solvate (e.g., a salt) and / or a pharmaceutical composition of a derivative thereof.

The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate (e.g., a salt thereof) and / or a derivative thereof for the manufacture of medicine for Treat or prevent a disease or condition described herein. The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate and / or derivative thereof can be administered by any suitable method, such as oral, parenteral, buccal, sublingual, nasal , Rectal or transdermal administration, and the pharmaceutical composition can be administered in accordance with this.

The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate and / or derivative thereof may be administered topically, for example, to the eyes, intestines, or skin. Accordingly, in one embodiment, a pharmaceutical composition is provided comprising a compound of the invention, optionally in combination with one or more diluents or carriers acceptable for topical administration.

The pharmaceutical composition of the present invention can be delivered locally to the skin. Compositions suitable for transdermal administration include ointments, gels, and patches. These pharmaceutical compositions are also conveniently in the form of creams, lotions, foams, powders, pastes or elixirs.

Pharmaceutical compositions suitably include vitamin D3 analogs (e.g., calcipotriol and maxacalcitol), steroids (e.g., fluticasone propionate, betamethasone valerate (e.g. βmethasone valerate) and cloβsol propionate), retinoids (for example: tazarotene), coal tar and dithranol. Topical medicines are often used in combination with each other (for example: vitamin D3 and steroids) or in combination with other agents (for example: salicylic acid).

The pharmaceutical composition of the present invention can be delivered locally to the eyes. These pharmaceutical compositions are conveniently in the form of eye drops or salves.

The pharmaceutical composition of the present invention can be delivered locally to the intestine. These pharmaceutical compositions are conveniently delivered orally, such as in the form of tablets or capsules, or transrectally, such as in the form of suppositories.

Conveniently, the delayed release formulation is in a capsule form.

When the compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate thereof and / or a derivative thereof is active when administered orally, it can be formulated into a liquid or a solid, for example, as a syrup, suspension, Lotion, lozenge, capsule or lozenge.

Liquid formulations usually consist of an active ingredient (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate (e.g., a salt) and / or a derivative thereof) in a suitable liquid carrier (group) , For example: aqueous solvents, such as: water, ethanol, or glycerol, or non-aqueous solvents, such as: suspensions or solutions in polyethylene glycol or oil. The formulation may also contain suspending agents, preservatives, flavoring agents and / or coloring agents.

Compositions in lozenge form can be prepared using any suitable pharmaceutical carrier (group) routinely used to prepare solid formulations, such as: magnesium stearate, starch, lactose, sucrose and cellulose.

Compositions in the form of capsules can be prepared using routine encapsulation processes, for example, containing active ingredients (e.g., compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates (e.g., salts) and (Or its derivatives) pills can be prepared using standard carriers, and then filled into hard gelatin capsules; or, homogeneous solutions or suspensions can be prepared using any suitable pharmaceutical carrier (group), for example: water-based colloids, fibers Vegetables, silicates or oils, then filled into soft gelatin capsules with a homogeneous solution or suspension.

A typical parenteral composition is composed of an active ingredient (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a solvate (e.g., a salt) and / or a derivative thereof) in a sterile aqueous solution. Agent or a solution or suspension in a parenterally acceptable oil (eg, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil). Alternatively, the solution may be lyophilized and reconstituted with a suitable solvent just before administration.

Compositions for nasal administration should be formulated into aerosols, drops, gels and powders. Aerosol formulations usually contain a solution or homogeneous suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent, and are usually contained in a single or multiple doses in a sealed container, which can be in the form of a box or Refill with atomizer. Alternatively, the sealed container may be a disposable dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve. The dosage form includes an aerosol dispenser, which will contain a propellant, which is a compressed gas (for example: air) or an organic propellant (for example: chlorofluorocarbon or hydrofluorocarbon). Aerosol formulations can also be pumped atomizers.

Compositions suitable for buccal or sublingual administration include lozenges, lozenges, and throat sugar. The active ingredients are formulated using carriers, such as sugar and acacia gum, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are preferably in the form of suppositories, which contain conventional suppository bases such as cocoa butter.

Conveniently, the composition is in a unit dosage form, such as a lozenge, capsule or ampoule.

The composition may include, for example, 0.1% to 100% by weight of the active material, for example, 10 to 60% by weight of the active material, depending on the method of administration. The composition may contain 0% to 99% by weight, for example, 40% to 90% by weight of the carrier, depending on the method of administration. The composition may contain 0.05 mg to 2000 mg, for example, 1.0 mg to 500 mg of active material, depending on the method of administration. The composition may contain a carrier of 50 mg to 1000 mg, for example, 100 mg to 400 mg, depending on the method of administration. The dosage of the compound used to treat or prevent the above-mentioned conditions will be determined in a general manner depending on the severity of the disease, the weight of the patient, and other similar factors. However, in general, a suitable unit dose may be from 0.05 mg to 1000 mg, more preferably 1.0 mg to 500 mg, and these unit doses may be administered more than once a day, for example: twice or three times a day. These therapies can last for weeks or months.

The invention provides, in another aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or derivative thereof (e.g., a compound of formula (I) or a pharmaceutically acceptable compound A combination of accepted derivatives) with other pharmaceutically acceptable active ingredients or ingredient groups.

The present invention provides a compound of formula (I) for use in combination with other pharmaceutically acceptable active ingredients or ingredient groups.

When the compounds are used in combination with other medical agents, the compounds may be administered separately, sequentially, or simultaneously using any convenient route.

The optimal combination may depend on the disease or condition. Possible combinations include them with one or more active agents selected from the list consisting of: 5-aminosalicylic acid, or a prodrug thereof (e.g., sulfasalazine, olsalazine) Or bisalazide); corticosteroids (for example: prednisolone, methylprednisolone, or budesonide); immunosuppressants (for example: cyclosporine (cyclosporine), tacrolimus, sirolimus, methotrexate, azathioprine, mycophenolate mofetil, leflunomide (leflunomide), cyclophosphamide, 6-hydrothiopurine or anti-lymphocyte (or thymocyte) globulin); anti-TNF-α antibodies (for example: infliximab, adalimumab Anti (adalimumab), certolizumab pegol or golimumab); anti-IL12 / IL23 antibodies (e.g. ustekinumab); anti-IL6 or anti- IL6R antibody, anti-IL17 antibody or small molecule IL12 / IL23 inhibitor (for example: apilimod); anti-α-4-β-7 antibody ( For example: vedolizumab); MAdCAM-1 blockers (for example: PF-00547659); antibodies against the cell attachment molecule α-4-integrin (for example: natalizumab) Antibodies against the α2 subunit of the IL2 receptor (for example: daclizumab or basiliximab); JAK inhibitors, including JAK1 and JAK3 inhibitors (for example: tofacitinib, Baricitinib (R348); Syk inhibitors and their prodrugs (for example: fostamatinib and R-406); phosphodiesterase-4 inhibitors (for example: tetomilast ( tetomilast)); HMPL-004; probiotics; Dersalazine; semapimod / CPSI-2364; and protein kinase C inhibitors (eg, AEB-071).

Other pharmaceutically acceptable active ingredients for cancer can be selected from: anti-mitotic agents, such as: vinblastine, paclitaxel, and docetaxel; alkylating agents, such as: cisplatin ( cisplatin, carboplatin, dacarbazine, and cyclophosphamide; antimetabolites, such as 5-fluorouracil, cytarabine, and hydroxyurea; injectants, such as adriamycin ) And bleomycin; topoisomerase inhibitors, such as: etoposide, topotecan and irinotecan; thymidine synthase inhibitors , Such as: raltitrexed; PI3 kinase inhibitors such as: idelalisib; mTor inhibitors such as everolimus and temsirolimus; proteasome inhibitors , Such as: bortezomib; histone deacetylase inhibitors, such as: panobinostat or vorinostat; and hedgehog signaling pathway blockers, such as: vilmod Kyrgyzstan (vismodegib).

The other pharmaceutically acceptable active ingredient may be selected from: tyrosine kinase inhibitors, such as, for example, axitinib, dasatinib, erlotinib, imatinib Imatinib, nilotinib, pazopanib and sunitinib.

The combination therapy may include anti-cancer antibodies and may be selected from the group consisting of olaratumab, daratumumab, necitumumab, and dastuximab Anti-Dinutuximab, Traztuzumab emtansine, Pertuzumab, Obinutuzumab, Brentuximab, ofumumab , Panitumumab, catumaxomab, bevacizumab, cetuximab, tositumomab, trastuzumab ( traztuzumab), getozumab-gentozumab ozogamycin, and rituximab.

The compound or pharmaceutical composition of the present invention can also be used in combination with radiation therapy.

Some of the above combinations are suitable for use in the form of pharmaceutical formulations, so pharmaceutical formulations including combinations of the above definitions and pharmaceutically acceptable carriers or excipients have become another aspect of the present invention. The individual components of these combinations may be administered sequentially or simultaneously as separate or combined pharmaceutical formulations. Individual components of the combination can also be administered separately through the same or different routes.

When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second medical agent having activity against the same disease state, the dosage of each compound may be different from that when the compound is used alone. Those skilled in the art can easily understand the proper dosage.

Medical device

In one embodiment, the compound of the present invention or a pharmaceutical composition comprising the compound can be formulated to be incorporated into a medical device, thus providing the compound or composition for direct administration to a site where the condition disclosed herein can be prevented or treated.

In one embodiment, the compounding method of the compound of the present invention or a pharmaceutical composition thereof is included in a coating applied on a medical device. Various coatings can be used, such as, for example, polymer coatings that release the compound over a specified period of time. The compound or its pharmaceutical composition can be directly embedded in a medical device. In some embodiments, the compound is contained in a delivery vehicle (eg, microparticles or microfat particles) that promotes release and delivery, and is coated on or in the device. In some embodiments, the compound or pharmaceutical composition is miscible with the coating.

In some embodiments, the medical device is a vascular implant, such as a stent. Medical use of the human frame to prevent or eliminate vascular constriction. The implant can be inserted into a constricted blood vessel, thereby expanding the constricted blood vessel. Overgrowth of adjacent cells after implantation of a blood vessel causes constriction of the blood vessel especially at the end of the implant, which reduces the effectiveness of the implant. If a vascular implant is inserted into a human artery in order to eliminate, for example, atherosclerotic stenosis, an intimal thickening will occur at the end of the vascular implant within one year, causing stenosis again ("postoperative restenosis").

Therefore, in some embodiments, the stent is coated or carried with a composition comprising the compound of the present invention or a pharmaceutical composition thereof and a targeting signal, a transmission device, or a combination thereof selected as required. Many stents are available from commercial sources or are known in the art.

In some embodiments, the stent is a stent that can dissolve the drug. A variety of stent capable of delivering medical substances to the treatment site at the same time and providing radial support to the blood vessel wall are known in the related art. Intraluminal devices, including stents, are sometimes coated on their surface with substances such as drug release agents, growth factors, or the like. A stent with a hollow tubular structure has also been developed. The side wall has small holes or holes that allow the drug to flow out from the middle lumen. Although the hollow nature of the stent allows the drug solution to be loaded in the central lumen, allowing the drug to be delivered through holes or holes in the side wall of the stent, the hollow tubular structure may not have the proper mechanical strength to provide a proper skeleton for the blood vessel.

In some embodiments, the device can also be coated or impregnated with the compound of the invention or its pharmaceutical composition, and one or more other medical agents, including (but not limited to): antiplatelets, anticoagulants, anti-inflammatory agents, anti- Microbial agents, anti-metabolites, other anti-neoplastic agents, other anti-proliferative agents, immune modulators, anti-proliferative agents, preparations that affect migration and extracellular matrix production, preparations that affect platelet deposition or thrombosis, and promote blood vessels Healing and re-endothelialization agents, such as those described in Sousa et al. (2003) and Salu et al. (2004).

Examples of antithrombin agents include, but are not limited to: heparin (including low molecular weight heparin), R-hirudin (Hirudin), hirudin, argatroban, efegatran , Tick anticoagulant peptide, and Ppack.

Examples of antiproliferative agents include, but are not limited to: paclitaxel (Taxol), QP-2 Vincristine, Methotrexat, Angiopeptin, Mitomycin Mitomycin), BCP 678, antisense c-myc, ABT 578, Actinomycin-D, RestenASE, 1-chlorodeoxyadenosine, PCNA ribozyme (Ribozym), and Celecoxib.

Examples of anti-restenosis agents include, but are not limited to: immunomodulating agents such as: sirolimus (Rapamycin), tacrolimus, Biorest, midazolam Mizoribin, cyclosporine, interferon-γ lb, Leflunomid, Tranilast, Corticosteroide, Mycophenolic acid and Biphosphonate ).

Examples of anti-metastatic agents and extracellular matrix regulators include (but are not limited to): Halofuginone, propyl-hydroxylase-inhibitors, C-protease-inhibitors, MMP-inhibitors, and balamastat ( Batimastat), Probucol.

Examples of antiplatelet agents include, but are not limited to: heparin.

Examples of wound healing agents and endothelial growth promoters include vascular epithelial growth factor ("VEGF"), 17-estradiol, Tkase-inhibitor, BCP 671, statins, nitrogen oxides ("NO" )-Donor, and Endothelial Progenitor Cell ("EPC")-Antibody.

In addition to being applied to coronary arteries, drugs and active agents can also be incorporated into stents or stent coatings for other uses. For example, when used in urology, antibiotics can be incorporated into the stent or the stent coating to prevent infection. When used in gynecology and urology, the active agent can be incorporated into the stent or in the stent coating for local treatment of cancer. It is also beneficial to incorporate a developer, a radiopaque marker, or other additives in the stent or on the stent to allow the stent to be developed in vivo for tracking, positioning, and other purposes. These additives can be added to the absorbent composition used to make the stent or stent coating, or can be absorbed into, dissolve on, or sprayed on some or all of the stent surface. Preferred additives for this purpose include silver, iodine and iodine-labeled compounds, barium sulfate, hafnium oxide, bismuth derivatives, zirconium dioxide, cadmium, tungsten, gold, tantalum, bismuth, platinum, iridium, and rhodium. These additives can be, but are not limited to: micron or nano size particles or nano particles.

Radiation opacity can be analyzed by fluorescence or x-rays.

The compound of the present invention can be incorporated into a stent with one or more other preparations or a pharmaceutical composition thereof, which can be processed and / or used after loading the compound with one or more other preparations or a pharmaceutical composition thereof in an absorbable material. The (etc.) formulation is coated on the surface of the stent. The release rate of a formulation can be controlled in a number of ways, including changes such as the ratio of the absorbable material relative to the compound to one or more other formulations or pharmaceutical compositions, the molecular weight of the absorbable material, the compound and one or more other formulations or pharmaceutical compositions Composition, composition of absorbable polymer, coating thickness, number of coatings and their relative thickness, and / or concentration of the compound with one or more other formulations or pharmaceutical compositions. The surface of the polymer and other materials (including absorbable polymers) can also be coated on the active agent coating to control the release rate. For example, P4HB can be applied as a surface layer on a metal stent. The metal stent coated with P4HB and including an active agent can delay the release of the active agent.

The invention is further illustrated by the following non-limiting examples.

Examples

The definitions of abbreviations used herein are as follows. Any undefined abbreviation is the project's generally accepted definition.

abbreviation

General process

All starting materials and solvents were obtained from commercial sources or prepared from literature. Unless otherwise stated, all reactions were stirred. The organic solution was dehydrated through anhydrous magnesium sulfate as usual. The hydrogenation was carried out in a Thales H-cube flow reactor under specified conditions.

Column chromatography is performed on a box pre-filled with a specified amount of silica (230-400 mesh, 40-63um).

SCX was purchased from Supelco and used after 1M hydrochloric acid treatment. Unless otherwise stated, the reaction mixture purified from the plan was first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded directly onto SCX and washed with MeOH. Then 0.7M NH ₃ in MeOH solution of the material from the desired.

Preparative reversed phase high performance liquid chromatography Preparative HPLC Acid process

Waters X-Select CSH column C18, 5um (19 x 50mm), flow rate 28mL min ^-1 , dissolve in a gradient of H ₂ O-MeCN (containing 0.1% v / v formic acid) for 6.5min. Detection was performed at 254 nm using UV.

Alkaline process

Waters X-Bridge Prep column C18, 5um (19 x 50mm), flow rate 28mL min ^-1 , dissolve with 10mM NH ₄ HCO ₃ -MeCN gradient for 6.5min, and detect using UV at 254nm.

Analytical method Reverse phase HPLC conditions for LCMS analysis HPLC acidity: acidic LCMS 4 minutes (5-95%)

Analytical LCMS uses a Waters X-Select CSH C18, 2.5um, 4.6x30mm column, and gradient dissolution using a MeCN (containing 0.1% formic acid) water (containing 0.1% formic acid) solution. The gradient is 5-95% MeCN (containing 0.1% formic acid) from 0.00 to 3.00 minutes, 2.5 mL / min, and rinsed from 3.01 to 3.5 minutes, 4.5 mL / min. From 3.60 to 4.00 minutes, re-equilibrate the column to 5% MeCN at 2.5 mL / min. The UV spectrum of the eluted peak was measured at 254 nm using an Agilent 1260 Infinity VWD. Mass spectra were measured using an Agilent 6120 MSD with positive / negative conversion.

HPLC alkaline: basic LCMS for 4 minutes (5-95%)

Analytical LCMS was performed using a Waters X-Select BEH C18, 2.5um, 4.6x30mm column, and gradient dissolution using a 10 mM ammonium bicarbonate aqueous solution containing MeCN. The gradient is from 5 to 95% MeCN at 2.5 mL / min from 0.00 to 3.00 minutes, and rinsed from 3.01 to 3.5 minutes at 4.5 mL / min.

From 3.60 to 4.00 minutes, re-equilibrate the column to 5% MeCN at 2.5 mL / min. The UV spectrum of the eluted peak was measured at 254 nm using an Agilent 1260 Infinity VWD. Mass spectra were measured using an Agilent 6120 MSD with positive / negative conversion.

UPLC analysis of reversed-phase HPLC conditions UPLC acidity: Acidic UPLC for 3 minutes

Analytical UPLC / MS was performed using Waters Acquity CSH C18, 1.7um, 2.1x30mm column, and gradient dissolution using a solution containing 0.1% formic acid in MeCN (containing 0.1% formic acid).

The structure of the gradient is from 5% MeCN and is maintained from 0.0 to 0.11 minutes. A gradient of 5 to 95% between 0.11 and 2.15 minutes, rinse from 2.15 to 2.56 minutes. The column was re-equilibrated to 5% MeCN from 2.56 to 2.83 minutes. The UV spectra of the dissolved peaks were measured using an Acquity PDA, and the mass spectra were recorded with an ESI positive / negative conversion using an Acquity QDa detector.

Acid UPLC 2 Acid UPLC 1 minute

Analytical UPLC / MS was performed using Waters Acquity CSH C18, 1.7um, 2.1x30mm column, and gradient dissolution using a solution containing 0.1% formic acid in MeCN (containing 0.1% formic acid).

The structure of the gradient starts from 5% MeCN and is maintained from 0.0 to 0.08 minutes. A gradient of 5 to 95% between 0.08-0.70 minutes, from 0.7 to 0.8 minutes. The column was re-equilibrated to 5% MeCN from 0.8 to 0.9 minutes. The UV spectra of the dissolved peaks were measured using an Acquity PDA, and the mass spectra were recorded with an ESI positive / negative conversion using an Acquity QDa detector.

UPLC alkaline: alkaline UPLC for 3 minutes

Analytical UPLC / MS was performed on a Waters Acquity BEH C18, 1.7um, 2.1x30mm column using a gradient dissolution of a 10 mM ammonium bicarbonate aqueous solution containing MeCN. The structure of the gradient is from 5% MeCN and is maintained from 0.0 to 0.11 minutes. A gradient of 5 to 95% between 0.11-2.15 minutes, rinse from 2.15 to 2.56 minutes. The column was re-equilibrated to 5% MeCN from 2.56 to 2.83 minutes. The UV spectra of the dissolved peaks were measured using an Acquity PDA, and the mass spectra were recorded with an ESI positive / negative conversion using an Acquity QDa detector.

Basic UPLC 2 Basic UPLC 1 minute

Analytical UPLC / MS was performed on a Waters Acquity BEH C18, 1.7um, 2.1x30mm column using a gradient dissolution of a 10 mM ammonium bicarbonate aqueous solution containing MeCN. The structure of the gradient starts from 5% MeCN and is maintained from 0.0 to 0.08 minutes. A gradient from 5 to 95% between 0.08-0.70 minutes and a rinse from 0.7 to 0.8 minutes. The column was re-equilibrated to 5% MeCN from 0.8 to 0.9 minutes. The UV spectrum of the dissolved peak was determined using an Acquity PDA, and the mass spectrum was determined using an Acquity QDa detector under ESI positive / negative conversion.

The column temperature was 40 ° C in all operations. The injection volume was 3 uL and the flow rate was 0.77 mL / min. The PDA scan for all operations is from 210 to 400 nm.

Normal phase HPLC conditions for palm analysis

Parapetal IC3 method: Parapetal HPLC (Diacel Chiralpak IC, 5um, 4.6x250mm, 1.0mL / min, 25-70% EtOH (0.2% TFA) in isohexane (0.2% TFA) solution.

Palmaric IC4 method: Palmaric HPLC (Diacel Chiralpak IC, 5um, 4.6x250mm, 1.0mL / min, 40% EtOH (0.2% TFA) in 4: 1 heptane / chloroform (0.2% TFA) solution.

Method for palmar IC5: Palmar HPLC (Diacel Chiralpak IC, 5um, 4.6x250mm, 1.0mL / min, 20% EtOH (0.2% TFA) in isohexane (0.2% TFA) solution.

Reverse phase HPLC conditions for palmity analysis

Parapetal IC6 method: Parapetal HPLC (Diacel Chiralpak IC, 5um, 4.6x250mm, 1.0mL / min, 50% MeCN (0.1% formic acid) in water (0.1% formic acid) solution.

Parapetal IC7 method: Parapetal HPLC (Diacel Chiralpak IC, 5um, 4.6x250mm, 1.0mL / min, 5-95% MeCN (0.1% formic acid) in water (0.1% formic acid) solution.

¹ H NMR spectrum

¹ H NMR spectra were obtained on a Bruker Avance III photometer at 400 MHz, or on a Bruker Avance III HD photometer at 500 MHz using residual undeuterated solvents as a reference. Data are obtained unless otherwise stated. Operate in DMSO-d6.

Preparation of intermediates

Known synthetic intermediate systems are purchased from commercial sources or made using published literature processes. Other intermediate systems were prepared using the representative synthesis methods described herein.

Any of methods 1-10 (mentioned below) or AN can be used to synthesize a compound of formula (I). For example: Presenting a reaction diagram using compounds where X = N, Y = CR ₂ , and Z = CR ₃ can also be used to synthesize X,

Y and Z are compounds as defined in the scope of the patent application.

Preparation method of diester intermediate

2- (2-chloropyrimidin-4-yl) malonate 1- (third butyl) ester 3-methyl ester INTC1

NaH (60 wt% mineral oil, 5.10 g, 128 mmol) was added portionwise to an ice-cooled stirred solution containing methyl butyl malonate (20.5 mL, 121 mmol) in THF (160 mL). The reaction was stirred at 0 ° C for 20 mins and then at RT for 60 mins until hydrogen evolution ceased. Then, 2,4-dichloropyrimidine (10 g, 67.1 mmol) was added, and the resulting mixture was stirred at 70 ° C for 3 hrs. The reaction was cooled, between ₄ Cl _(sat.aq, 500mL) and EtOAc (500mL) was dissolved points NH, two phases were separated, the organic layer was passed through a phase separator. The crude product was purified by silica gel chromatography (220 g column, 0-30% EtOAc / isohexane) to give 2- (2-chloropyrimidin-4-yl) malonate 1-third butyl ester 3-methyl Ester (13.1 g, 44.3 mmol, 66% yield) as a clear pale yellow oil; Rt 2.09 mins (HPLC, acidic); m / z 230 (M + H- t Bu) ⁺ (ES ⁺ ) and 287 ( M + H) ⁺ (ES ⁺ ); ¹ H NMR (400MHz, DMSO-d6) δ 8.83 (d, J = 5.1Hz, 1H), 7.65 (d, J = 5.1Hz, 1H), 5.21 (s, 1H ), 3.73 (s, 3H), 1.42 (s, 9H).

2- (2-chloro-5-fluoropyrimidin-4-yl) malonate 1- (third butyl) ester 3-methyl ester INTC2

NaH (0.575 g, 14.4 mmol in 60 wt% mineral oil) was added portionwise to a stirred solution of DMF (20 mL) containing the third butyl methyl malonate (2.23 mL, 13.2 mmol). The reaction was stirred at RT and N ₂ for 10 mins until hydrogen evolution ceased. The reaction was cooled to 0 ° C, and 2,4-dichloro-5-fluoropyrimidine (2.0 g, 12.0 mmol) was added. The resulting mixture was stirred slowly at RT for 18 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-50% EtOAc / isohexane) to give 2- (2-chloro-5-fluoropyrimidin-4-yl) malonate 1-third butyl ester 3-methyl ester (1.96 g, 5.47 mmol, 46% yield) as a clear, colorless oil; Rt 1.42 mins (HPLC, acidic); m / z 305 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (400 MHz, DMSO-d6) δ 9.08-8.90 (m, 1H), 5.47-5.38 (m, 1H), 3.75 (s, 3H), 1.43 (s, 9H).

2- (2-chloro-5-methylpyrimidin-4-yl) malonate 1- (third butyl) ester 3-methyl ester INTC3

Take NaH (60wt% mineral oil homogeneous liquid, 0.466g, 11.7mmol) and add it to the THF (10mL) ice-cooled stirred solution containing the third butyl methyl malonate (1.97mL, 11.7mmol) . The reaction was stirred at RT for 10 mins. Then, 2,4-dichloro-5-methylpyrimidine (1.0 g, 6.13 mmol) was added, and the resulting mixture was stirred at 70 ° C for 2 hrs. The reaction was cooled, dissolved in saturated sub-NH, two phases were separated, the organic layer was between EtOAc (10mL) ₄ Cl (aq, 10 mL) through a phase separator. The crude product was purified by silica gel chromatography (12 g column, 0-30% EtOAc / isohexane) to give 2- (2-chloro-5-methylpyrimidin-4-yl) malonate 1-third butyl Ester 3-methyl ester (1.40 g, 4.41 mmol, 72% yield) as a colorless oil; Rt 1.39 mins (HPLC, acidic); m / z 201 (M-Boc + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.66 (d, J = 0.8Hz, 1H), 5.38 (s, 1H), 3.74 (s, 3H), 2.19 (d, J = 0.7Hz, 3H), 1.44 (s, 9H).

2- (2-chloro-6-methylpyrimidin-4-yl) malonate 1-third butyl ester 3-methyl ester INTC54

According to the production method of INTC1 , 2,4-dichloro-6-methylpyrimidine and a third butyl malonate methyl ester are used to produce 2- (2-chloro-6-methylpyrimidin-4-yl). Clear oil as 1-third-butyl malonate 3-methyl ester (61% yield). Rt 1.39 (UPLC, basic); m / z 301 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 7.48 (s, 1H), 5.11 (s, 1H) , 3.70 (s, 3H), 2.52 (s, 3H), 1.40 (s, 9H).

2- (2-chloro-6- (trifluoromethyl) pyrimidin-4-yl) malonate 1-third butyl ester 3-methyl ester INTC55

According to the production method of INTC1 , the product of 2,4-dichloro-6- (trifluoromethyl) pyrimidine and the third methyl ester of malonate is used to produce 2- (2-chloro-6- (trifluoromethyl) Base) Pyrimidin-4-yl) malonic acid 1-Third-butyl ester 3-methyl ester (67% yield) as a clear oil. Rt 1.34 (UPLC, basic); no m / z observed; ¹ H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 5.39 (s, 1H), 3.74 (s, 3H), 1.42 (s , 9H).

2- (2-chloropyrimidin-4-yl) -2-methoxymalonate dimethyl ester INTC56

According to the method of INTC1 , 2,4-dichloropyrimidine and 2-methoxymalonate are used to produce 2- (2-chloropyrimidin-4-yl) -2-methoxymalonate Methyl ester (79% yield) as a clear, colorless oil. Rt 1.55 (HPLC, acidic); m / z 275 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR was not recorded. This material was used directly in the next step without further analysis.

2- (2-chloropyrimidin-4-yl) -2-isopropylmalonate dimethyl ester INTC57

According to the method of INTC1 , 2,4-dichloropyrimidine and 2-isopropylmalonate are used to produce 2- (2-chloropyrimidin-4-yl) -2-isopropylmalonate Methyl ester (98% yield) as a red gum. Rt 0.64 (UPLC acid 2); m / z 286 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR was not recorded. This material was used directly in the next step without further analysis of the characteristics.

Decarboxylation of chloro-pyrimidine

2- (2-chloropyrimidin-4-yl) acetic acid methyl ester INTC4

TFA (55.3 mL, 717 mmol) was added dropwise to DCM containing 2- (2-chloropyrimidin-4-yl) malonate 1-third butyl ester 3-methyl ester INTC1 (12.1 g, 42.2 mmol) ( 50 mL) was stirred under ice-cooling. After the reaction was stirred at 25 ° C for 1 hr, it was concentrated in vacuo. The residue was dissolved in EtOAc (200mL) using NaHCO ₃ (200mL) and basified and the organic layer was separated, passed through a phase separator, the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (220 g box, 0-50% EtOAc / isohexane) to give methyl 2- (2-chloropyrimidin-4-yl) acetate (7.12 g, 37.8 mmol, 90% yield ) Of light yellow oil. Rt 1.16mins (HPLC, acidic); m / z 187 (M + H) ⁺ (ES ⁺ ); 1H NMR (500MHz, DMSO-d6) δ 8.76 (d, J = 5.0Hz, 1H), 7.60 (d, J = 5.0Hz, 1H), 3.96 (s, 2H), 3.66 (s, 3H).

TFA (10eq) was added dropwise to an ice-cooled stirred solution of malonate derivative (1eq) in DCM (15 parts by volume). The reaction flask was stirred at RT for 18 hrs and then concentrated. The crude product was purified by normal phase chromatography.

Alkylation

2- (2-chloropyrimidin-4-yl) -2-methylpropionic acid methyl ester INTC7

Add MeI (0.24mL, 3.89mmol) to acetone containing methyl 2- (2-chloropyrimidin-4-yl) acetate INTC4 (0.29g, 1.55mmol ) and K ₂ CO ₃ (0.644g, 4.66mmol) (5 mL) was stirred in the suspension. The reaction flask was sealed and stirred for 18 hrs at 60 ° C. The reaction mixture was concentrated in vacuo, water (40 mL) was added and extracted with DCM (2 x 40 mL). The organic phase is dehydrated (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-50% EtOAc / isohexane) to give 2- (2-chloropyrimidin-4-yl) -2-methylpropanoic acid methyl ester (0.25 g, 1.11 mmol, 71% yield) as a clear pale yellow liquid; Rt 1.70 mins (HPLC, acidic); m / z 215 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 5.2Hz, 1H), 7.66 (d, J = 5.2Hz, 1H), 3.63 (s, 3H), 1.53 (s, 6H).

2- (2-chloropyrimidin-4-yl) propionic acid methyl ester INTC8

Add MeI (14.1mL, 225mmol) to acetone (150mL) containing methyl 2- (2-chloropyrimidin-4-yl) acetate INTC4 (10.37g, 45.0mmol) and K ₂ CO ₃ (31.1g, 225mmol) ) Stir the suspension. The reaction mixture was stirred at 60 ° C. for 40 hrs under N ₂ . The reaction mixture was concentrated in vacuo and the resulting mixture was diluted in EtOAc and filtered. The inorganic phase was washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (220 g column, 0-30% EtOAc / isohexane) to give methyl 2- (2-chloropyrimidin-4-yl) propanoate (1.27 g, 5.00 mmol, 11% Yield) by-products; Rt 0.89 mins (UPLC, acidic); m / z 201 (M + H) ⁺ (ES ⁺ ). No ¹ H-NMR data were recorded.

Take the base (2.5-5 eq) and add it to a suitable polar aprotic solvent (e.g. DMF or acetone) containing 2- (2-chloropyrimidin-4-yl) acetate (1 eq) (10 parts by volume) The mixture was stirred under ice-cooling. After 20 min, an alkyl halide (1-5 eq) was added. The reaction flask was stirred at 0 ° C for 30 mins and then at RT for 2 hrs. Using NH ₄ Cl (aq), or 1M HCl (aq) quenched. After stirring for 20 mins, it was extracted with EtOAc. The organic phase was dehydrated (phase separator) and concentrated. The crude product was purified by normal phase chromatography.

S on 2,6-dichloropyrimidine _N AR

2- (2-chloro-6-methoxypyrimidin-4-yl) -2-methylpropanoic acid methyl ester INTC65

Add to a stirred solution of 2- (2,6-dichloropyrimidin-4-yl) -2-methylpropanoate INTC64 (0.77 g, 2.78 mmol ) in MeOH (10 mL) at N ₂ and 0 ° C. 5.4M sodium methoxide (MeOH) (0.6 mL, 3.24 mmol). After the mixture was stirred at 0 ° C for 30 min, it was stirred at RT for another 30 min. The reaction was then concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-50% EtOAc / isohexane) to give 2- (2-chloro-6-methoxypyrimidin-4-yl) -2-methylpropanoate Ester (0.54 g, 1.72 mmol, 62% yield) as a white solid. Rt 1.35min (UPLC, acid); m / z 245 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); 1H NMR (400MHz, DMSO-d6) δ 6.99 (s, 1H), 3.96 (s, 3H), 3.61 (s, 3H), 1.48 (s, 6H).

Heterocyclic formation via alkylation

4- (2-chloropyrimidin-4-yl) tetrahydro- 2H - piperan -4-carboxylic acid methyl ester INTC52

To a solution of methyl 2- (2-chloropyrimidin-4-yl) acetate INTC4 (2.0 g, 10.7 mmol) in DMF (10 mL, 10.7 mmol) at 0 ° C was added NaOH (0.986 g, 24.6 mmol). After the reaction mixture was stirred at 0 ° C for 20 mins, 1-bromo-2- (2-bromoethoxy) ethane (1.8 mL, 12.9 mmol) was added. The reaction was stirred at RT for 23 hrs. After the reaction mixture was acidified with 1M HCl (aqueous solution, 53.6 mL, 53.6 mmol), it was extracted with DCM (70 mL). The phases were separated using a phase separator cartridge, and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were concentrated in vacuo. The crude product was purified by silica gel chromatography (80 g column, 0-50% EtOAc / isohexane) to give 4- (2-chloropyrimidin-4-yl) tetrahydro- 2H -piperan-4-carboxylic acid methyl Ester (1.83 g, 5.57 mmol, 52% yield) as a yellow oil. Rt 1.56min (HPLC, acidic); m / z 257 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.80 (d, J = 5.3Hz, 1H), 7.69 (d, J = 5.3Hz, 1H), 3.72-3.67 (m, 2H), 3.66 (s, 3H), 3.55-3.50 (m, 2H), 2.33-2.22 (m, 2H), 2.16-2.06 (m , 2H).

Via enol S _N AR forms heterocycle

4- (2-chloropyrimidin-4-yl) piperidine-1,4-dicarboxylic acid 1-third butyl ester 4-methyl ester INTC66

Take LiHMDS (1.61mL, 1.61mmol) once and add it to piperidine-1,4-dicarboxylic acid 1-third butyl ester 4-methyl ester (340mg, 1.40mmol) and 2,4-dichloropyrimidine ( 200 mg, 1.34 mmol) in THF (10 mL) in an ice-cooled stirred solution. The reaction mixture was allowed to warm to RT and stirred for 2 hrs. Add NaH ₂ PO ₄ (aq, 1M, 3mL) quenched. The product was extracted with DCM (2 x 10 mL). The combined organic extracts were dehydrated through a hydrophobic phase separator and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-50% EtOAc / isohexane) to give 4- (2-chloropyrimidin-4-yl) piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-methyl ester (315 mg, 0.66 mmol, 49% yield) as a colorless oil. Rt 2.29min (HPLC, acidic); m / z 255 ( ³⁵ Cl M-Boc + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.79 (d, J = 5.3Hz, 1H) , 7.68 (d, J = 5.3Hz, 1H), 3.69-3.59 (m, 5H), 3.13 (s, 2H), 2.26-2.22 (m, 2H), 2.06-2.00 (m, 2H), 1.40 (s , 9H).

3- (2-chloropyrimidin-4-yl) azetidine-1,3-dicarboxylic acid 1-third butyl ester 3-methyl ester INTC67

According to INTC66 production method, azetidine-1,3-dicarboxylic acid 1-third butyl ester 3-methyl ester and 2,4-dichloropyrimidine are used in toluene to produce 3- (2-chloropyrimidine 4-yl) Azetane-1,3-dicarboxylic acid 1-third butyl ester 3-methyl ester (7% yield) as a pale yellow oil. Rt 2.12min (HPLC, basic); m / z 272 ( ³⁵ Cl M- t Bu + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.83 (d, J = 5.2Hz, 1H), 7.72 (d, J = 5.2Hz, 1H), 4.39-4.35 (m, 2H), 4.34-4.28 (m, 2H), 3.71 (s, 3H), 1.39 (s, 9H).

Chloro-pyrimidine hydrolysis

Lithium 2- (2-chloropyrimidin-4-yl) -4-methoxybutyrate INTC68

To a solution containing 2- (2-chloropyrimidin-4-yl) -4-methoxybutyric acid methyl ester INTC60 (479 mg, 1.96 mmol) in THF (5 mL) and MeOH (2.5 mL) was added LiOH (56 mg , 2.35 mmol) in water (3 mL). The reaction mixture was stirred at RT for 72 hrs. The reaction mixture was concentrated in vacuo to give lithium 2- (2-chloropyrimidin-4-yl) -4-methoxybutyrate (441 mg, 1.49 mmol, 76% yield) as a colorless solid. Rt 1.34min (HPLC, acidic); m / z 231 ( ³⁵ Cl M + H as free acid) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.64 (d, J = 5.1Hz, 1H ), 7.48 (d, J = 5.1 Hz, 1H), 3.39-3.33 (m, 1H), 3.22 (s, 3H), 2.82-2.75 (m, 2H), 1.96-1.85 (m, 2H).

Coupling (sulfonamide)

2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) malonate 1- (third butyl) ester 3-methyl ester INTC17

In a 20 mL vial, add cyclopropanesulfonamide (0.254 g, 2.09 mmol), Cs ₂ CO ₃ (1.14 g, 3.49 mmol), 2- (2-chloropyrimidin-4-yl) malonate, 1-tert-butyl 3-methyl ester INTC1 (0.50 g, 1.74 mmol) Alkane (2 mL). The mixture was degassed (N _2, 5mins). In another 20 mL vial, take [Pd (allyl) Cl] ₂ (16 mg, 0.044 mmol), tBuXPhos (74 mg, 0.174 mmol) and two After the alkane (1 mL) was stirred under N ₂ for 5 mins, it was added to the first vial. The resulting reaction mixture was heated under N ₂ and 60 ° C. for 2.5 hrs. The mixture was allowed to cool to RT, diluted with H ₂ O (2 mL), and carefully acidified to pH 4 using 1 M HCl (aqueous solution, 5 mL). The residue was extracted with EtOAc (2 x 20 mL), the organic phase was filtered through a phase separator and the solvent was removed in vacuo. The yellow residue was triturated with TBME (10 mL), filtered, and washed with TBME (10 mL) to give 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) malonate 1-third butyl Ester 3-methyl ester (0.394 g, 1.05 mmol, 60% yield) as a white solid. Rt 1.87mins (HPLC, acidic); m / z 372 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (400MHz, DMSO-d6) δ 12.57 (s, 1H), 11.61 (s, 1H), 7.28 -7.21 (m, 1H), 6.10 (s, 1H), 3.67 (s, 3H), 2.75-2.65 (m, 1H), 1.44 (s, 9H), 1.18-0.83 (m, 4H). 8: 2 mixture of tautomers.

Take 2-chloropyrimidine intermediate (1eq), sulfamethoxamine (1.2eq) and base (2eq) in two Alkane (40 parts by volume). After the mixture was degassed (N ₂ , 5 mins), a catalyst (5 mol%) was added. The resulting mixture was heated under nitrogen at 90 ° C for 2 hrs. The mixture was filtered, washed with EtOAc or DCM, and the resulting filtrate was concentrated. The crude product is purified by normal phase chromatography or triturated with a suitable solvent.

Decarboxylation

2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) acetic acid methyl ester 2,2,2-trifluoroacetate INTC33

TFA (1mL, 13.0mmol) was added dropwise to a solution containing 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) malonate 1-third-butyl ester 3-methyl ester INTC17 (0.27g , 0.73 mmol) of DCM (2 mL) in a stirred ice-cooled solution. The reaction flask was stirred at RT for 2 hrs and concentrated in vacuo to yield methyl 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) acetate 2,2,2-trifluoroacetate (0.29 g, 0.68 mmol, 93% yield) as a yellow solid; Rt 0.79 mins (HPLC, basic); m / z 272 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H), 11.39-10.93 (m, 2H), 8.57 (d, J = 5.1Hz, 1H), 7.13 (d, J = 5.1Hz, 1H), 7.00 (dd, J = 7.6, 5.1Hz, 1H), 5.95-5.87 (m, 1H), 4.92 (s, 1H), 3.84 (s, 2H), 3.65 (s, 3H), 3.61 (s, 3H), 3.29-3.10 (m, 1H), 2.72 -2.60 (m, 1H), 1.17-0.85 (m, 8H). 1: 1 mixture of tautomers.

TFA (10 eq) was added dropwise to an ice-cooled stirred solution containing malonate derivative (1 eq) in DCM (15 parts by volume). The reaction flask was stirred at RT for 18 hrs and then concentrated. The crude product was purified by normal phase chromatography.

hydrolysis

Potassium 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butyrate INTC37

A solution of methyl 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butyrate INTC35 (2.4 g, 7.22 mmol) in THF (80 mL) was treated with TMSOK (2.26 g, 15.9 mmol). The reaction mixture was stirred at RT for 18 hrs. The resulting suspension was concentrated in vacuo to give a pale yellow solid of potassium 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butyrate (3 g, 6.49 mmol, 90% yield); Rt 0.19 mins (UPLC , Basic); m / z 286 (M + H) ⁺ (ES ⁺ ), ionized to free acid; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 7.97 (d, J = 5.0Hz, 1H), 6.35 (d, J = 5.0Hz, 1H), 3.01 (tt, J = 8.2, 5.0Hz, 1H), 2.88 (dd, J = 8.0, 6.9Hz, 1H), 1.88-1.79 (m, 1H), 1.61- 1.50 (m, 1H), 0.84-0.74 (m, 5H), 0.65-0.55 (m, 2H), no NH protons were observed.

Potassium 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -4-methoxybutyrate INTC38

A solution of 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -4-methoxybutyric acid methyl ester INTC36 (0.23g, 0.69mmol ) in THF (5mL) was taken using TMSOK (0.22 g, 1.54 mmol). The reaction mixture was stirred at RT for 18 hrs. After the resulting suspension was quenched with MeOH (2 mL), it was concentrated in vacuo to give potassium 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -4-methoxybutyrate (0.33 g, 0.65 mmol , 94% yield) light red solid; Rt 0.14mins (UPLC, basic); m / z 316 (M + H) ⁺ (ES ⁺ ), ionized to free acid; ¹ H NMR (500MHz, DMSO- d ₆ ) δ 8.03 (dd, J = 5.0, 2.9Hz, 1H, minor), 7.97 (d, J = 5.0Hz, 1H, major), 6.59 (d, J = 5.1Hz, 1H, minor), 6.33 (d, J = 5.0Hz, 1H, main), 3.28-3.13 (m, 7H), 3.12-2.96 (m, 1H), 2.22-1.99 (m, 1H), 1.83-1.77 (m, 1H), 0.84 -0.75 (m, 2H), 0.63-0.57 (m, 2H). A mixture of tautomers.

Potassium 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) acetate INTC39

A solution of methyl 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) acetate (600 mg, 2.212 mmol) INTC33 in THF (12 mL) was treated with TMSOK (624 mg, 4.87 mmol). The reaction mixture was stirred at RT for 18 hrs. The resulting suspension was concentrated in vacuo to give potassium 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) acetate (1.069 g, 2.208 mmol, full yield) as a pale yellow solid. Rt 0.14 min (UPLC, acidic); m / z 258 (M + H) ⁺ (ES ⁺ ) ionizes to free acid. ¹ H NMR (500MHz, DMSO-d6) δ 7.97 (d, J = 4.9Hz, 1H), 6.33 (d, J = 4.9Hz, 1H), 2.99-2.92 (m, 1H), 0.82-0.76 (m, 2H), 0.66-0.57 (m, 2H). No CH ₂ and NH signals were observed.

2- (2- (cyclopropanesulfonamido) -5-fluoropyrimidin-4-yl) acetic acid INTC40

LiOH (0.105 g, 4.37 mmol) was added to MeOH containing 2- (2- (cyclopropanesulfonamido) -5-fluoropyrimidin-4-yl) acetate (0.49 g, 1.457 mmol) INTC34 ( 5 mL) and water (2 mL) and stirred at RT for 18 hrs. The reaction mixture was concentrated in vacuo. The crude product was purified by RP Flash C18 chromatography (40 g column, 0-50% MeCN / water 0.1% formic acid) to give 2- (2- (cyclopropanesulfonamido) -5-fluoro Pyrimidin-4-yl) acetic acid (0.44 g, 0.991 mmol, 68% yield) as a yellow solid. Rt 0.65mins (UPLC, acidic); m / z 276 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (400MHz, DMSO-d6) δ 8.49 (s, 1H), 4.15 (s, 1H), 2.97 -2.85 (m, 1H), 2.22-2.15 (m, 2H), 0.86-0.69 (m, 2H), 0.69-0.52 (m, 2H), no CO ₂ H was observed.

4- (6-ethoxypyridine 2-yl) -N- (4-methoxybenzyl) aniline INTC41

Take sodium triethoxylate borohydride (0.148 g, 0.697 mmol) and add 4- (6-ethoxypyridine) 2-yl) aniline INTD18 (0.1 g, 0.465 mmol) and 4-methoxybenzaldehyde (0.085 mL, 0.697 mmol) in DCM (3 mL). The reaction was stirred at RT for 16 hrs. Saturated NaHCO ₃ (aq) in the reaction (20 mL), using DCM (3 x 20mL) and extracted aqueous phase, combined organic layers were concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g box, 0-50% EtOAc / isohexane) to yield 4- (6-ethoxypyridine 2-yl) -N- (4-methoxybenzyl) aniline (0.174 g, 0.467 mmol, full yield) as a white solid. Rt 1.68 min (UPLC, basic); m / z 336 (M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 8.59 (s, 1H), 8.00 (s, 1H), 7.88-7.83 (m, 2H), 7.32-7.26 (m, 2H), 6.93-6.86 (m, 2H ), 6.71 (t, J = 6.0Hz, 1H), 6.70-6.65 (m, 2H), 4.43 (q, J = 7.0Hz, 2H), 4.27 (d, J = 5.8Hz, 2H), 3.73 (s , 3H), 1.37 (t, J = 7.0Hz, 3H).

3-((4- (6-ethoxypyridine 2-yl) phenyl) (4-methoxybenzyl) amino) -3-butoxypropionic acid third butyl ester INTC42

Take HATU (0.289g, 0.760mmol) and add 4- (6-ethoxypyridine) 2-yl) -N- (4-methoxybenzyl) aniline INTC41 (0.17 g, 0.507 mmol), 3- (third butoxy) -3- pendant propionic acid (0.1 mL, 0.649 mmol) and TEA (0.21 mL, 1.507 mmol) in a stirred solution of DCM (5 mL). The resulting reaction was stirred at RT for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were dehydrated (phase separator) and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to give 3-((4- (6-ethoxypyridine) 2-yl) phenyl) (4-methoxybenzyl) amino) -3-butyloxypropionic acid third butyl ester (0.2g, 0.377mmol, 74% yield) clear colorless gum Thing. Rt 1.74min (UPLC, basic); m / z 478 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.81 (s, 1H), 8.25 (s, 1H), 8.15-8.09 (m, 2H), 7.34-7.27 (m, 2H), 7.18-7.11 (m, 2H), 6.88-6.82 (m, 2H), 4.87 (s, 2H), 4.47 (q, J = 7.0 Hz, 2H), 3.72 (s, 3H), 3.20 (s, 2H), 1.39 (t, J = 7.1Hz, 3H), 1.35 (s, 9H).

2- (2-chloropyrimidin-4-yl) -3-((4- (6-ethoxypyridine 2-yl) phenyl) (4-methoxybenzyl) amino) -3-butoxypropionic acid third butyl ester INTC43

Take NaH (60% mineral oil homogeneous liquid) (0.034g, 0.838mmol) and add it to the solution containing 3-((4- (6-ethoxypyridine) 2-yl) phenyl) (4-methoxybenzyl) amino) -3-butyloxypropionic acid third butyl ester INTC42 (0.2g, 0.419mmol ) in THF (4mL, 0.419mmol) Stir the solution. After the reaction was stirred at RT for 10 min, 2,4-dichloropyrimidine (0.087 g, 0.586 mmol) was added. The resulting mixture was stirred at 70 ° C. for ₂ hrs under N ₂ . The reaction mixture was quenched with brine (20 mL). The aqueous phase was extracted with DCM (3 x 50 mL), dehydrated (phase separator), and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to give 2- (2-chloropyrimidin-4-yl) -3-((4- (6-ethoxypyridine 2-yl) phenyl) (4-methoxybenzyl) amino) -3-butyloxypropionic acid third butyl ester (0.13g, 0.189mmol, 45% yield) clear colorless gum物 (gum). Rt 1.86min (UPLC, basic); m / z 591 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.81 (s, 1H), 8.77 (d, J = 5.1 Hz, 1H), 8.26 (s, 1H), 8.15-8.12 (m, 2H), 7.66-7.63 (m, 1H), 7.22-7.16 (m, 4H), 6.90-6.85 (m, 2H), 5.02 ( d, J = 14.7Hz, 1H), 4.84 (s, 1H), 4.74 (d, J = 14.6Hz, 1H), 4.47 (q, J = 7.0Hz, 2H), 3.73 (s, 3H), 1.39 ( t, J = 7.1Hz, 3H), 1.37 (s, 9H).

2- (2-chloropyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) - N - (4- methoxybenzyl) as acetamide INTC44

TFA (0.234mL, 3.03mmol) was added dropwise to the solution containing 2- (2-chloropyrimidin-4-yl) -3-((4- (6-ethoxypyridine) 2-yl) phenyl) (4-methoxybenzyl) amino) -3-butoxypropionic acid third butyl ester INTC43 (0.13 g, 0.189 mmol) in DCM (20 mL) and stirred under ice cooling In solution. After the reaction flask was stirred at 25 ° C. for 7 hrs, it was carefully basified with NaHCO ₃ (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL), dehydrated (phase separator) and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to give 2- (2-chloropyrimidin-4-yl) -N- (4- (6-ethoxypyridine) 2-yl) phenyl) -N- (4-methoxybenzyl) acetamidamine (0.05 g, 0.092 mmol, 49% yield) was a clear, colorless gum. Rt 1.62min (UPLC, acid); m / z 490 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.81 (s, 1H), 8.66 (d, J = 5.0Hz , 1H), 8.25 (s, 1H), 8.14-8.10 (m, 2H), 7.45 (d, J = 5.1Hz, 1H), 7.39-7.34 (m, 2H), 7.17 (d, J = 8.2Hz, 2H), 6.89-6.82 (m, 2H), 4.89 (s, 2H), 4.46 (q, J = 7.1Hz, 2H), 3.76 (s, 2H), 3.72 (s, 3H), 1.39 (t, J = 7.0Hz, 3H).

2- (2-chloropyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) -N- (4-methoxybenzyl) butanamine INTC45

Take iodoethane (0.410mL, 5.10mmol) and add 2- (2-chloropyrimidin-4-yl) -N- (4- (6-ethoxypyridine) 2-yl) phenyl) -N- (4-methoxybenzyl) acetamide INTC44 (0.5 g, 1.021 mmol) and potassium carbonate (0.705 g, 5.10 mmol) in a stirred mixture of acetone (5 mL) . The reaction flask was heated to 60 ° C and stirred under N ₂ for 18 hrs. The reaction mixture was concentrated, diluted in water (40 mL), and extracted with DCM (3 x 40 mL). The organic phases were combined, dehydrated (phase separator), and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-100% EtOAc / isohexane) to give 2- (2-chloropyrimidin-4-yl) -N- (4- (6-ethoxypyridine) 2-yl) phenyl) -N- (4-methoxybenzyl) butanamide (0.31 g, 0.539 mmol, 53% yield) was a clear pale yellow gum. Rt 2.73min (HPLC, acidic); m / z 519 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.80 (s, 1H), 8.63 (d, J = 5.1Hz , 1H), 8.25 (s, 1H), 8.07 (d, J = 8.3Hz, 2H), 7.32 (d, J = 5.2Hz, 1H), 7.17-7.08 (m, 4H), 6.88-6.81 (m, 2H), 4.92 (d, J = 14.7Hz, 1H), 4.82 (d, J = 14.6Hz, 1H), 4.50-4.43 (m, 2H), 3.73-3.69 (m, 4H), 2.09-2.00 (m , 1H), 1.83-1.74 (m, 1H), 1.39 (t, J = 7.0Hz, 3H), 0.82 (t, J = 7.3Hz, 3H).

2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6-ethoxypyridine 2-yl) phenyl) -N- (4-methoxybenzyl) butanamine INTC46

In a 20 mL vial, add cyclopropanesulfonamide (0.078 g, 0.646 mmol), Cs ₂ CO ₃ (0.351 g, 1.08 mmol), 2- (2-chloropyrimidin-4-yl) -N- (4- (6 -Ethoxypyridine 2-yl) phenyl) -N- (4-methoxybenzyl) butanamine INTC45 ( 0.31g, 0.539mmol ) (10 mL). The mixture was purged with N _{2 for} 5 min. Pd-174 (0.012 g, 0.016 mmol) was added, and the mixture was subsequently heated at 80 ° C for 1 hr and then at 100 ° C for 7 hrs. Cyclopropanesulfonamide (0.078 g, 0.646 mmol) and Pd-174 (0.012 g, 0.016 mmol) were further added, and the mixture was heated at 100 ° C. for 3 h. The reaction mixture with saturated NH ₄ Cl (aq, 40 mL) quenched using DCM (3 x 40mL) and extracted, dried (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (40g cartridge, 0-100% EtOAc / isohexane) to give 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4 -(6-ethoxypyridine 2-yl) phenyl) -N- (4-methoxybenzyl) butanamine (0.18 g, 0.269 mmol, 50% yield) was a thick yellow gum. Rt 1.65min (UPLC, acidic); 603.6 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.22 (s, 1H), 8.80 (s, 1H), 8.49-8.42 ( m, 1H), 8.25 (s, 1H), 8.08 (d, J = 8.1Hz, 2H), 7.22 (d, J = 8.1Hz, 2H), 7.14-7.08 (m, 2H), 6.96-6.89 (m , 1H), 6.87-6.81 (m, 2H), 4.99 (d, J = 14.6Hz, 1H), 4.76 (d, J = 14.7Hz, 1H), 4.47 (q, J = 7.0Hz, 2H), 3.71 (s, 3H), 3.65 (t, J = 7.3Hz, 1H), 3.22-3.13 (m, 1H), 2.10.-1.96 (m, 1H), 1.83-1.72 (m, 1H), 1.39 (t, J = 7.0Hz, 3H), 1.12-1.06 (m, 2H), 0.93-0.87 (m, 2H), 0.83 (t, J = 7.3Hz, 3H).

2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -3-((4- (6-ethoxypyridine 2-yl) phenyl) (4-methoxybenzyl) amino) -3-butoxypropionic acid third butyl ester INTC47

In a 20 mL vial, add cyclopropanesulfonamide (0.074 g, 0.610 mmol), Cs ₂ CO ₃ (0.331 g, 1.017 mmol), 2- (2-chloropyrimidin-4-yl) -3-((4- ( 6-ethoxypyridine 2-yl) phenyl) (4-methoxybenzyl) amino) -3-butoxypropionic acid third butyl ester INTC43 (0.3g, 0.508mmol) (10 mL). The mixture was purged with N _{2 for} 5 min. In another 20 mL vial, add [Pd (allyl) Cl] ₂ (4.68 mg, 0.013 mmol), tBuXPhos (0.022 g, 0.051 mmol) and two Alkane (2 mL). After the mixture was stirred under N ₂ for 5 min, it was added to the first mixture. The resulting mixture was heated under N ₂ and 60 ° C. for 4 hrs. Cyclopropanesulfonamide (0.074 g, 0.610 mmol) and Pd-174 (11.00 mg, 0.015 mmol) were added sequentially. The mixture was heated at 80 ° C for 1 hr. The reaction mixture with saturated NH ₄ Cl (aq, 40 mL) quenched, extracted with DCM (3 x 20mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-100% EtOAc / isohexane) to give 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -3-((4- (6-ethoxypyridine 2-yl) phenyl) (4-methoxybenzyl) amino) -3-pentoxypropanoic acid third butyl ester (0.1 g, 0.130 mmol, 26% yield) as a white solid. Rt 2.51 min (HPLC, basic); m / z 675 (M + H) ⁺ (ES ⁺ ).

PMB protection

2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) butyric acid methyl ester INTC48

Add 1- (bromomethyl) -4-methoxybenzene (0.470 mL, 3.34 mmol) to methyl 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butanoate ( 1 g, 3.34 mmol) INTC35 and K ₂ CO ₃ (0.46 g, 3.34 mmol) in a DMF (20 mL) heterogeneous stirred mixture. The resulting reaction mixture was stirred at RT for 18 hrs, poured into water (200 mL), and extracted with EtOAc (3 x 50 mL). The organic extracts were washed with water (100 mL) and brine (100 mL), dried MgSO ₄ dried, filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-50% EtOAc / isohexane) to give 2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidine -4-yl) butyric acid methyl ester (844 mg, 1.95 mmol, 58% yield) as a colorless oil. Rt 2.43min (HPLC, acidic); m / z 420 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.64 (d, J = 5.1Hz, 1H), 7.25 (d , J = 8.3Hz, 2H), 7.19 (d, J = 5.1Hz, 1H), 6.86 (d, J = 8.3Hz, 2H), 5.17-5.02 (m, 2H), 3.71 (s, 3H), 3.64 -3.55 (m, 4H), 2.05-1.93 (m, 2H), 1.89-1.76 (m, 1H), 1.10-0.96 (m, 4H), 0.82 (t, J = 7.3Hz, 3H).

2- (2- ( N- (4-methoxybenzyl) methylsulfonamido) pyrimidin-4-yl) -2- (2-methoxyethyl) malonate Butyl ester 3-methyl ester INTC79

According to the method of INTC48 , 2- (2-methoxyethyl) -2- (2- (methylsulfonamido) pyrimidin-4-yl) malonate 1-third butyl ester 3-methyl Ester INTC73 with 1- (chloromethyl) -4-methoxybenzene to give 2- (2- ( N- (4-methoxybenzyl) methylsulfonamido) pyrimidin-4-yl ) -2- (2-methoxyethyl) malonic acid 1-third butyl ester 3-methyl ester (65% yield) as a colorless oil. Rt 2.55min (HPLC, acidic); m / z 524 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.72 (d, J = 5.3Hz, 1H), 7.47 (d , J = 5.3Hz, 1H), 7.27-7.21 (m, 2H), 6.92-6.82 (m, 2H), 5.17-5.10 (m, 2H), 3.71 (s, 3H), 3.67 (s, 3H), 3.44 (s, 3H), 3.29-3.22 (m, 1H), 3.22-3.15 (m, 1H), 3.09 (s, 3H), 2.48-2.29 (m, 2H), 1.37 (s, 9H).

2-isopropyl-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) malonate dimethyl ester INTC80

According to the preparation method of INTC48 , 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-isopropylmalonate dimethyl ester INTC78 and 1- (chloromethyl) -4- Methoxybenzene to give 2-isopropyl-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) malonate (28% yield) as a colorless oil. Rt 0.72 min (UPLC, acid 2); m / z 492 (M + H) + (ES +); ¹ H NMR was not recorded.

Decarboxylation of sulfamethoxamine protected by PMB

4-methoxy-2- (2- ( N- (4-methoxybenzyl) methylsulfonamido) pyrimidin-4-yl) butyric acid methyl ester INTC81

Take HCl (4M Hexane solution) (0.44 mL, 14.51 mmol) was added to the solution containing 2- (2- ( N- (4-methoxybenzyl) methylsulfonamido) pyrimidin-4-yl) -2- (2- In a stirred solution of methoxyethyl) -malonate 1-third-butyl ester 3-methyl ester INTC79 (8.0 g, 14.5 mmol) in DCM (100 mL), the resulting reaction mixture was stirred at 50 ° C. for 4 hrs. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography (220 g column, 0-100% EtOAc / isohexane) to give 4-methoxy-2- (2- ( N- (4-methoxybenzene Methyl) methylsulfonamido) pyrimidin-4-yl) butyrate methyl ester (2.47 g, 5.54 mmol, 38% yield) as a colorless oil. Rt 2.13min (HPLC, acidic); m / z 424 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.64 (d, J = 5.1Hz, 1H), 7.32-7.25 (m, 2H), 7.19 (d, J = 5.1Hz, 1H), 6.90-6.84 (m, 2H), 5.20-5.07 (m, 2H), 3.97 (t, J = 7.4Hz, 1H), 3.72 ( s, 3H), 3.59 (s, 3H), 3.50 (s, 3H), 3.37-3.26 (m, 2H), 3.16 (s, 3H), 2.29-2.19 (m, 1H), 2.09-2.00 (m, 1H).

2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) -3-methylbutyrate methyl ester INTC82

In 2-isopropyl-2- (2- (N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) malonate dimethyl ester INTC80 ( 2.79g , 5.68 mmol) in a solution of water (0.11 mL, 6.11 mmol) in DMSO (7 mL) was added lithium chloride (0.29 g, 6.81 mmol). The reaction mixture was heated at 140 ° C for 1 hr. The reaction mixture was cooled to RT and diluted with EtOAc (100 mL) and water (100 mL). The phases were separated and the organic phase was washed with water (100 mL), water / brine (1: 1, 50 mL) and saturated brine (50 mL). The organic phase was anhydrified on MgSO _4, filtered, and concentrated Silica (10g) on. The crude product was purified by silica gel chromatography (40 g box, 0-30% EtOAc / isohexane) to give 2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidine- 4-methyl) -3-methylbutanoic acid methyl ester (2.00 g, 3.69 mmol, 65% yield) as a colorless gum. Rt 0.70 min (UPLC, acid 2); m / z 434 (M + H) ⁺ (ES ⁺ ); ¹ H NMR was not recorded.

Alkylation of PMB-Protected Sulfonamide

4-methoxy-2- (2- ( N- (4-methoxybenzyl) methylsulfonamido) pyrimidin-4-yl) -2-methylbutanoic acid methyl ester INTC83

Using Method B using 4-methoxy-2- (2- (N- (4-methoxybenzyl) methylsulfonamido) pyrimidin-4-yl) butyric acid methyl ester INTC81 and NaH And MeI in DMF solution to produce 4-methoxy-2- (2- (N- (4-methoxybenzyl) methylsulfonamido) pyrimidin-4-yl) -2-methyl Methyl butyrate (89% yield) as a colorless oil. Rt 2.20min (HPLC, acidic); m / z 438 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.66 (d, J = 5.2Hz, 1H), 7.29-7.19 (m, 3H), 6.91-6.81 (m, 2H), 5.13 (s, 2H), 3.72 (s, 3H), 3.57 (s, 3H), 3.47 (s, 3H), 3.33-3.25 (m, 2H ), 3.12 (s, 3H), 2.29-2.13 (m, 2H), 1.48 (s, 3H).

2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) -2-methylbutyrate methyl ester INTC84

Using method B , using 2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) butyric acid methyl ester INTC48 with K ₂ CO ₃ and MeI Preparation of DMF solution to produce 2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) -2-methylbutanoic acid methyl ester (39% produced Rate) of colorless colloid. Rt 2.57min (HPLC, acidic); m / z 434 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.66 (d, J = 5.3Hz, 1H), 7.26-7.17 (m, 3H), 6.90-6.82 (m, 2H), 5.10 (s, 2H), 3.71 (s, 3H), 3.64 (s, 3H), 2.05-1.88 (m, 2H), 1.44 (s, 3H ), 1.04-0.97 (m, 4H), 0.76 (t, J = 7.4Hz, 3H). (1H is obscured by DMSO).

Fluorination

2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) butyric acid methyl ester INTC49

Containing at -78 deg.] C of 2- (2- (N - (4- methoxybenzyl) amino cyclopropane sulfonylurea) pyrimidin-4-yl) butyric acid methyl ester INTC48 (400mg, 0.95mmol) of To a solution of THF (10 mL), LHMDS (1.19 mL, 1.19 mmol, 1M THF solution) was added dropwise over 5 minutes. The resulting mixture was warmed to RT and stirred for 1 hr. The solution was cooled again to -78 ° C, and a solution of N -fluoro- N- (phenylsulfonyl) benzenesulfonamide (376 mg, 1.19 mmol) in THF (3 mL) was added dropwise over 5 minutes. The resulting mixture was warmed to RT and stirred for 1 hr. Sat.NaHCO ₃ solution using dilute (aqueous solution, 100mL) and EtOAc (100mL), and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 50 mL). Combined organic layers were dehydrated over Na ₂ SO _4, filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-50% EtOAc / isohexane) to give 2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonium) Amino) pyrimidin-4-yl) butyric acid methyl ester (390 mg, 0.865 mmol, 91% yield) as a clear oil. Rt 2.48min (HPLC, acidic); m / z 438 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.81 (d, J = 5.1Hz, 1H), 7.37 (dd , J = 5.1, 1.5Hz, 1H), 7.29-7.19 (m, 2H), 6.90-6.83 (m, 2H), 5.17-5.03 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H ) 3.65-3.57 (m, 1H), 2.40-2.14 (m, 2H), 1.11-0.97 (m, 4H), 0.84 (t, J = 7.4Hz, 3H).

Enantiomerically enriched INTC49 was prepared using the following method : 2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidine) at -40 ° C in 5 mins time To a solution of methyl-4-yl) butyrate INTC48 (0.066 g, 0.157 mmol) in THF (2.5 mL) was added LHMDS (0.189 mL, 0.189 mmol) dropwise. The resulting mixture was warmed to RT and stirred for 1 hr. A second solution of (-)-cinchonidine (0.069 g, 0.236 mmol) and Selectfluor (0.072 g, 0.205 mmol) in MeCN (2.5 mL) was prepared and stirred at RT for 30 mins. The fluorinating agent solution was then cooled to -40 ° C, and the deprotonated ester solution was added dropwise over a period of 5 minutes. The reaction mixture was stirred at -40 ° C for 1 h, left the cooling tank and returned to RT in 2 h. The reaction mixture was stirred at RT for 20 h. The reaction mixture _(aq, 10mL) and diluted with EtOAc (20mL) using sat.NaHCO. The phases were separated, and the organic phase was washed with sat. NaHCO ₃ (aqueous solution, 10 mL) and 1M HCl (aqueous solution, 10 mL) in this order. The combined organic phases were dehydrated (MgSO _4), filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (4 g box, 0-50% EtOAc / isohexane) to give 2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamide) Methyl) pyrimidin-4-yl) butyrate (0.024 g, 0.052 mmol, 33% yield) as a colorless oil. Rt 0.70min (UPLC 2, acid); m / z 438 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.81 (d, J = 5.1Hz, 1H), 7.37 ( dd, J = 5.1, 1.5Hz, 1H), 7.29-7.19 (m, 2H), 6.90-6.83 (m, 2H), 5.17-5.03 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H) 3.65-3.57 (m, 1H), 2.40-2.14 (m, 2H), 1.11-0.97 (m, 4H), 0.84 (t, J = 7.4Hz, 3H).

2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-fluorobutyric acid methyl ester INTC177

In 2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropane-sulfoamido) pyrimidin-4-yl) butyric acid methyl ester INTC49 (24mg, 0.055mmol) To a solution of DCM (5 mL) was added TFA (0.5 mL, 6.49 mmol). The reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo and the resulting brown residue was purified by silica gel chromatography (4 g box, 0-50% EtOAc / isohexane) to give 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl)- 2-fluorobutyric acid methyl ester (18 mg, 0.053 mmol, 97% yield) as a colorless oil. Rt 0.55min (UPLC 2, acid); m / z 318 (M + H) ^{+ .1} H NMR (500MHz, DMSO-d6) δ 11.50 (s, 1H), 8.73 (d, J = 5.2Hz, 1H) , 7.31 (d, J = 5.2Hz, 1H), 3.73 (s, 3H), 3.25-3.16 (m, 1H), 2.45-2.18 (m, 2H), 1.22-1.01 (m, 4H), 0.89 (t , J = 7.4Hz, 3H).

The product of the enantiomeric mixture was analyzed by HPLC using the chiral IC7 method; Rt = 29.08 mins (10%) and 29.75 mins (90%).

Formation of lithium salt

2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) butyrate lithium INTC50

In methyl 2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) butyrate methyl ester INTC49 (1.45 g, 3.31 mmol) To a solution of THF (15 mL) and MeOH (7.5 mL) was added a solution of LiOH (0.091 g, 3.81 mmol) in water (5 mL). The reaction mixture was stirred at RT for 3 hrs. The reaction mixture was concentrated in vacuo and the resulting yellow oil was dissolved in MeCN (10 mL) and concentrated in vacuo to give 2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) ) Pyrimidin-4-yl) lithium butyrate (1.46 g, 3.30 mmol, full yield) as a pale yellow foam, used without further purification. Rt 0.95min (UPLC, basic); m / z 424 (ionization to COOH, M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.57-8.52 (m, 1H), 7.34 -7.28 (m, 2H), 7.20-7.14 (m, 1H), 6.90-6.83 (m, 2H), 5.19-5.04 (m, 2H), 4.14-4.10 (m, 1H), 3.71 (s, 3H) , 2.33-2.20 (m, 1H), 2.17-2.08 (m, 1H), 1.15-1.04 (m, 1H), 1.06-0.97 (m, 1H), 0.93-0.80 (m, 2H), 0.80-0.73 ( m, 3H).

A solution of heteroaromatic ester (1eq) in THF (10 parts by volume) was cooled to -78 ° C, and LiHMDS (1.25eq 1M THF solution) was added thereto. The reaction mixture was then warmed to RT for 1 hr. The solution was cooled to -78 ° C, and a solution of NSFI (1.25 eq) (THF solution) or solid was added dropwise, and the temperature was raised to RT for 2 hrs. The solution was diluted with sat. NaHCO ₃ (aq) and the product was extracted with EtOAc. The crude product was purified by normal phase chromatography.

2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) -3-methylbutanoic acid methyl ester INTC86

2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) -3-methylbutyrate methyl ester at -78 ° C INTC82 (1.50 g, 3.46 mmol) of anhydrous THF (30 mL) was added dropwise to LiHMDS (1M THF solution) (4.15 mL, 4.15 mmol). The reaction mixture was stirred at -78 ° C for 5mins, and after heating to RT for 1hr, it was cooled to -78 ° C again. Then a solution of SelectCN (1.90 g, 5.10 mmol) in MeCN (30 mL) was added dropwise to the reaction mixture over 5 mins. The reaction mixture was warmed to RT, and after stirring for 1 hr, sat. NaHCO ₃ (aqueous solution, 5 mL) was added. After the reaction mixture was partially concentrated in vacuo (about 10 mL) and then adding EtOAc (100mL) and sat.NaHCO ₃ (aq, 100 mL). The phases were separated and the organic phase was washed with sat. Brine (50 mL). The organic layer was dried over MgSO ₄ dried, filtered, and concentrated on Silica (15g). The crude product was purified by silica gel chromatography (40 g box, 0-60% EtOAc / isohexane) to give 2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropane-sulfohydrazone). Amino) pyrimidin-4-yl) -3-methylbutanoic acid methyl ester (680 mg, 1.48 mmol, 43% yield) as a yellow gum. Rt 0.72min (UPLC, acid 2); m / z 452 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.79 (d, J = 5.1Hz, 1H), 7.33 ( dd, J = 5.1, 2.2Hz, 1H), 7.29-7.22 (m, 2H), 6.91-6.84 (m, 2H), 5.19-5.07 (m, 2H), 3.74-3.66 (m, 7H), 2.93- 2.77 (m, 1H), 1.17-1.05 (m, 2H), 1.06-0.97 (m, 5H), 0.67 (d, J = 6.8Hz, 3H).

Potassium salt formation

2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) -3-methylbutyric acid potassium INTC87

According to INTC37 production method, 2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) -3-methylbutyrate methyl ester INTC82 and trimethyl Preparation of potassium silanolate to produce potassium 2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) -3-methylbutanoate (99% yield Rate) of a pale yellow solid. Rt 1.59 min (HPLC, basic); m / z 420 (M + H) ⁺ (ES +); ¹ H NMR was not recorded.

Difluoro derivative via thioether

Ethyl 2,2-difluoro-2- (2- (methylsulfonyl) pyrimidin-4-yl) acetate INTC100

A suspension of MeOH (8 mL) and water (5 mL) containing ethyl 2,2-difluoro-2- (2- (methylthio) pyrimidin-4-yl) acetate (240 mg, 0.97 mmol) and water (5 mL) was used. Treated with potassium hydrogen sulfate complex salt (Oxone) (1.19 g, 1.93 mmol) and stirred vigorously for 3 hrs. DCM (10 mL) was added, the phases were separated using a phase separator, and extracted with DCM (2 x 5 mL). The combined organic phases were concentrated on silica (1 g), and the crude product was purified by silica gel chromatography (12 g column, 0-50% EtOAc / isohexane) to give 2,2-difluoro-2- (2- ( Methylsulfonyl) pyrimidin-4-yl) acetate (80 mg, 0.28 mmol, 29% yield) is a colorless gum that solidifies when left standing. Rt 0.52 (UPLC, acidic); m / z 281 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 9.42 (d, J = 5.1Hz, 1H), 8.34 (d, J = 5.1Hz, 1H), 4.39 (q, J = 7.1Hz, 2H), 3.46 (s, 3H), 1.25 (t, J = 7.1Hz, 3H).

2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2,2-difluoroacetic acid INTC101

Cyclopropanesulfonamide (40 mg, 0.33 mmol) with ethyl 2,2-difluoro-2- (2- (methylsulfonyl) pyrimidin-4-yl) acetate INTC100 (80 mg, 0.29 mmol) A solution of DMF (1 mL) was treated with NaH (60% by weight in mineral oil) (14 mg, 0.35 mmol), stirred at RT for 5 mins, and then heated to 60 ° C for 6 hrs. 1M HCl (10 mL) was added and the reaction mixture was extracted with EtOAc (4 x 10 mL). The organic phases were combined, dried over Na ₂ SO ₄ dried, filtered, and concentrated on a Silica (500mg). The crude product was purified by silica gel chromatography (4 g column, 0-5% MeOH / DCM) to give 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2,2-difluoroacetic acid. (80 mg, 0.136 mmol, 48% yield) as a brown solid. Rt 0.49 (UPLC, acidic); m / z 294 (M + H) ⁺ (ES ⁺ ); NMR data were not collected.

Selected amines

Formation of lithium salt

(4- (Carboxyl (methoxy) methyl) pyrimidin-2-yl) (cyclopropylsulfonyl) lithium lithium INTC99

Take 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methoxymalonate dimethyl ester (0.50g, 1.25mmol ) INTC75 in MeOH (15mL) and stir the mixture for use LiOH (0.10 g, 4.18 mmol) in water (5 mL) was treated. The reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated in vacuo to yield lithium (4- (carboxylate (methoxy) methyl) pyrimidin-2-yl) (cyclopropylsulfonyl) amide (0.4 g, 1.19 mmol, 95% yield). Brown solid. Rt 0.18 mins (UPLC, basic); m / z 288 was free acid (M + H) ⁺ (ES ⁺ ); ¹ H NMR was not collected.

Pyridine core Sulfonate

2- (6- (Cyclopropanesulfonamido) pyridin-2-yl) ethyl acetate INTC102

A pyridine (9.0 mL) solution containing ethyl 2- (6-aminopyridin-2-yl) acetate (2 g, 11.10 mmol) and DMAP (0.136 g, 1.11 mmol) was cooled to 0 ° C. Cyclopropanesulfenyl chloride (1.12 mL, 11.10 mmol) was then added dropwise. The solution was allowed to slowly warm to RT and stirred for 18 hrs. The reaction mixture was quenched with MeOH (10 mL) and concentrated in vacuo. The crude product was purified by C18-RP silica gel chromatography (80g column, 0-50% MeCN / water 0.1% formic acid) to give ethyl 2- (6- (cyclopropanesulfonamido) pyridin-2-yl) acetate ethyl Ester (1.35 g, 4.70 mmol, 42% yield) as a light brown oil; Rt 0.95 mins (UPLC, acidic); m / z 285 (M + H) ⁺ (ES ⁺ ). No NMR data was collected.

Alkylation

2- (6- Bromopyridin -2-yl) -2-methylpropionic acid ethyl ester INTC103

T- BuOK (0.115 g, 1.02 mmol) was added to a stirred ice-cooled solution containing 2- (6-bromopyridin-2-yl) acetate (0.100 g, 0.41 mmol) in THF (1.5 mL). After 30 min, MeI (2M TBME solution, 0.82 mL, 1.64 mmol) was added dropwise. The reaction flask was warmed to RT and stirred for 18 hrs. The reaction mixture was quenched with MeOH (1 mL) and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-50% EtOAc / isohexane) to give ethyl 2- (6-bromopyridin-2-yl) -2-methylpropanoate (0.06 g, 0.21 mmol, 51% yield) of clear colorless liquid; Rt 1.54mins (UPLC, acidic); m / z 273 ( ⁷⁹ Br M + H) ⁺ (ES ⁺ ); ¹ H NMR (400MHz, DMSO-d6) δ 7.79-7.71 (m, 1H), 7.56-7.51 (m, 1H), 7.49-7.43 (m, 1H), 4.15-3.99 (m, 2H), 1.50 (s, 6H), 1.19-1.05 (m, 3H ).

2- (6- Bromopyridin -2-yl) butyric acid ethyl ester INTC104

Take LiHMDS (1M THF solution) (2.25mL, 2.25mmol) and add it to -78 ° C, 2- (6-bromopyridin-2-yl) ethyl acetate (0.5g, 2.05mmol) in THF (10mL) and stir In solution. After 1 hr, EtI (0.182 mL, 2.25 mmol) was added dropwise at the same temperature, the reaction was warmed to RT, and stirred for 18 hrs. The reaction was partitioned between EtOAc (20 mL) and sat. NH ₄ Cl (aq., 20 mL). The organic phase was passed through a phase separator and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (40 g box, 0-50% EtOAc / isohexane) to give ethyl 2- (6-bromopyridin-2-yl) butanoate (0.35 g, 1.27 mmol, 62% yield Rate) of light yellow liquid. Rt 2.30mins (HPLC, acidic); m / z 272 ( ⁷⁹ Br M + H) ⁺ (ES ⁺ ); ¹ H NMR (400MHz, DMSO-d6) δ 7.76-7.72 (m, 1H), 7.55 (dd, J = 7.9, 0.9Hz, 1H), 7.42 (dd, J = 7.6, 0.9Hz, 1H), 4.12-4.05 (m, 2H), 3.74 (t, J = 7.5Hz, 1H), 2.05-1.94 (m , 1H), 1.89-1.76 (m, 1H), 1.13 (t, J = 7.1Hz, 3H), 0.83 (t, J = 7.4Hz, 3H).

Heterocyclic formation via alkylation

4- (6- Bromopyridin -2-yl) tetrahydro- 2H - piperan -4-carboxylic acid ethyl ester INTC105

According to the production method of INTC52 , using the commercial ethyl 2- (6-bromopyridin-2-yl) acetate (2.51g, 10.28mmol) and 1-bromo-2- (2-bromoethoxy) ethane, 4 -(6-Bromopyridin-2-yl) tetrahydro-2H-piperan-4-carboxylic acid ethyl ester (52% yield) as a clear oil. Rt 1.42mins (UPLC, basic); m / z 314 ( ⁷⁹ Br M + H) ⁺ (ES ⁺ ); ¹ H NMR (400MHz, DMSO-d6) δ 7.80-7.76 (m, 1H), 7.57 (d , J = 7.9Hz, 1H), 7.49 (d, J = 7.7Hz, 1H), 4.12 (q, J = 7.1Hz, 2H), 3.77-3.70 (m, 2H), 3.52-3.45 (m, 2H) , 2.30-2.23 (m, 2H), 2.07-2.01 (m, 2H), 1.12 (t, J = 7.1Hz, 3H).

Take 2-bromopyridine intermediate (1eq), sulfonamide (1.2eq) and base (2eq) in two Alkane (40 parts by volume). After the mixture was degassed (N ₂ , 5 mins), a catalyst (5 mol%) was added. The resulting mixture was heated under nitrogen at 90 ° C for 2 hrs. The mixture was filtered, washed with EtOAc or DCM, and the resulting filtrate was concentrated. The crude product was purified by normal phase chromatography.

2M LiOH (aqueous solution, 2eq) was added to a solution of an ester (1eq) in MeOH (3 parts by volume) and THF (3 parts by volume). The resulting reaction mixture was stirred at 50 ° C for 2 hrs. After the solvent was removed under reduced pressure, it was acidified to pH 3 using 1M HCl (aq). The solution was extracted with EtOAc and the organic phase was passed through a phase separator and the solvent was removed. The compound was used as a crude product or purified by reverse phase chromatography.

Pyridine Core part Ester formation

2- (6-chloropyridine -2-yl) methyl acetate INTC112

Add thionyl chloride (1.15mL, 15.65mmol) dropwise to 0 ° C containing 2- (6-chloropyridine) 2-yl) acetic acid (2.70 g, 15.65 mmol) in MeOH (50 mL) was stirred in a cold solution. After the addition, the reaction mixture was stirred at RT for 1 hr. The reaction mixture was concentrated in vacuo, the crude residue was diluted with DCM (100mL), washed sequentially with sat.NaHCO ₃ (aq, 2 x 100mL) and washed with brine (100mL). The organic extracts was dried (MgSO _4), filtered, and the solvents were removed in vacuo to produce 2- (6-chloro-pyridine 2-yl) methyl acetate (2.63 g, 13.67 mmol, 87% yield) as a brown oil. Rt 1.25min (HPLC, acidic); m / z 187 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.74 (s, 1H), 8.68 (s, 1H) , 4.00 (s, 2H), 3.66 (s, 3H).

2- (6-chloropyridine -2-yl) -2-methoxyacetic acid methyl ester INTC121

Use 2- (6-chloropyridine) according to the method of INTC112 2-yl) -2-methoxyacetic acid INTC120 , yielding 2- (6-chloropyridine 2-methyl) -2-methoxyacetic acid methyl ester (3.35 g, 15.31 mmol, 96% yield) as a clear yellow oil. Rt 1.33 min (HPLC, basic); m / z 217 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ), no NMR data recorded.

Preparation method of diester intermediate

2- (6-chloropyridine 2-yl) malonate 1-third butyl ester 3-methyl ester INTC113

Use 2,6-dichloropyridine according to the method of INTC1 Commodity, producing 2- (6-chloropyridine 2-yl) 3-methyl butyl malonate 3-methyl ester (78% yield) as a clear, colorless oil. Rt 2.18 min (HPLC, acidic); m / z 286 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.72 (s, 1H) , 5.28 (s, 1H), 3.73 (s, 3H), 1.44-1.37 (m, 9H).

2- (6-chloropyridine -2-yl) -2-methoxymalonate dimethyl ester INTC114

According to INTC1 method, use dimethyl 2-methoxymalonate and 2,6-dichloropyridine To produce 2- (6-chloropyridine 2-Clyl) -2-methoxymalonate (33% yield) as a clear, colorless oil. Rt 1.65min (HPLC, acidic); m / z 275 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.89 (d, J = 0.6Hz, 1H), 8.86 (d, J = 0.6Hz, 1H), 3.79 (s, 6H), 3.46 (s, 3H).

Pyridine Alkylation

TFA decarboxylation

2- (6-chloropyridine 2-yl) -4-methoxybutyric acid ethyl ester INTC118

Using method A , using 2- (6-chloropyridine 2-yl) -2- (2-methoxyethyl) malonate 1-third butyl ester 3-ethyl ester INTC115 preparation, yielding 2- (6-chloropyridine 2-yl) -4-methoxybutyric acid ethyl ester (2.49 g, 8.65 mmol, 71% yield) as a pale purple oil. Rt 0.59min (UPLC, basic 2); m / z 259 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.73 (s, 1H), 8.69 (s, 1H), 4.16-4.05 (m, 3H), 3.37-3.29 (m, 1H), 3.28-3.20 (m, 1H), 3.16 (s, 3H), 2.35-2.24 (m, 1H), 2.16-2.07 ( m, 1H), 1.13 (t, J = 7.1Hz, 3H).

hydrolysis

2- (6-chloropyridine 2-yl) -2-methoxyacetic acid INTC120

Take 2- (6-chloropyridine) 2-Methyl) -2-methoxymalonate dimethyl ester INTC114 (4.54 g, 16.53 mmol) in THF (40 mL) and water (10 mL). A stirred mixture was treated with 2M NaOH (aqueous solution, 4 mL, 8.00 mmol). . The reaction mixture was allowed to stir at RT for 66 hrs. Additional 2M NaOH (aq., 5eq) was added and the mixture was stirred for 2hrs. The reaction mixture was concentrated in vacuo, and the crude product was purified by RP Flash C18 chromatography (80g column, 5-50% MeCN / 10mM ammonium bicarbonate) to give 2- (6-chloropyridine 2-yl) -2-methoxyacetic acid (3.67 g, 16.30 mmol, 99% yield) as a white solid. Rt 1.06min (HPLC, acidic); m / z 203 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.63 (s, 2H), 4.45 (s, 1H) , 3.26 (s, 3H). An exchangeable proton was not observed.

2- (6-chloropyridine -2-yl) -4-methoxy-2-methylbutanoic acid INTC131

In containing 2- (6-chloropyridine 2-yl) -4-methoxy-2-methylbutanoic acid ethyl ester INTC119 (1.93 g, 7.08 mmol) in EtOH (2 mL) and THF (15 mL) was added with LiOH (0.203 g, 8.49 mmol) Water (5 mL) solution. The reaction was stirred at RT for 18 hrs. A solution of LiOH (0.068 g, 2.83 mmol) in water (5 mL) was added, and the reaction mixture was stirred at RT for 4 hrs. The reaction mixture was concentrated in vacuo and the resulting residue was acidified with 1M HCl (50 mL). Using EtOAc (3 x 50mL) product was extracted, the combined organic phases were dehydrated (MgSO ₄₎ and concentrated in vacuo to produce 2- (6-chloro-pyridine 2-yl) -4-methoxy-2-methylbutanoic acid (1.92 g, 5.98 mmol, 84% yield) as a dark brown oil, which was used without further purification. Rt 0.95min (UPLC, acid); m / z 245 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 12.59 (s, 1H), 8.74 (s, 1H) , 8.70 (s, 1H), 3.36-3.27 (m, 2H), 3.11 (s, 3H), 2.34-2.18 (m, 2H), 1.56 (s, 3H).

2- (6- (cyclopropanesulfonamido) pyridine 2-yl) INTC132 butanoic acid

Use 2- (6- (cyclopropanesulfonamido) pyridine) according to the method of INTC131 2-yl) butyric acid methyl ester INTC126 , resulting in 2- (6- (cyclopropanesulfonamido) pyridine) 2-yl) butyric acid (59% yield) as a colorless gum. Rt 1.35min (HPLC, acidic); m / z 286 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 12.54 (s, 1H), 11.00 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 3.70-3.65 (m, 1H), 3.10-3.03 (m, 1H), 2.09-1.98 (m, 1H), 1.91-1.79 (m, 1H), 1.21 -0.98 (m, 4H), 0.84 (t, J = 7.4Hz, 3H).

2- (6- (cyclopropanesulfonamido) pyridine -2-yl) -2-fluorobutyric acid INTC133

Use 2- (6- (cyclopropanesulfonamido) pyridine) according to the method of INTC131 2-yl) -2-fluorobutyric acid methyl ester INTC130, resulting in 2- (6- (cyclopropanesulfonamido) pyridine) 2-yl) -2-fluorobutanoic acid (95% yield) as a thick red paste. Rt 0.89min (UPLC, acidic); m / z 304 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 13.74 (s, 1H), 11.23 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 3.153.09 (m, 1H), 2.45-2.21 (m, 2H), 1.21-1.15 (m, 1H), 1.15-0.97 (m, 3H), 0.92 (t, J = 7.4Hz, 3H).

2- (6- (cyclopropanesulfonamido) pyridine 2-yl) -2-methoxyacetic acid INTC134

Use 2- (6- (cyclopropanesulfonamido) pyridine) according to the method of INTC131 2-methyl) -2-methoxyacetic acid methyl ester INTC128 , yielding 2- (6- (cyclopropanesulfonamido) pyridine) 2-yl) -2-methoxyacetic acid (24% yield) as a tan solid. Rt 1.06min (HPLC, acidic); m / z 288 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.13 (s, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 6.78 (s, 1H), 4.94 (s, 1H), 3.40 (s, 3H), 3.12-3.02 (m, 1H), 1.16-1.10 (m, 2H), 1.07-0.98 (m , 2H).

Heterocyclic formation via alkylation

4- (6-chloropyridine 2-yl) tetrahydro- 2H - piperan -4-carboxylic acid methyl ester INTC123

Use 2- (6-chloropyridine) according to the method of INTC52 2-yl) methyl acetate INTC112 , producing 4- (6-chloropyridine 2-yl) tetrahydro- 2H -piperan-4-carboxylic acid methyl ester (12% yield) as a yellow oil. Rt 1.05min (UPLC, acid); m / z 257 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.81 (s, 1H), 8.76 (s, 1H) , 3.77-3.62 (m, 5H), 3.58-3.49 (m, 2H), 2.38-2.26 (m, 2H), 2.21-2.10 (m, 2H).

Pyridine Intermediate fluorination

Formamide from selected building elements

2,6-pyrimidine core

N- (2-chloropyrimidin-4-yl) cyclopropanesulfonamide INTC138

To a suspension of 2,4-dichloropyrimidine (15 g, 101 mmol) in acetonitrile (250 mL) was added cyclopropanesulfonamide (14.64 g, 121 mmol) and K ₂ CO ₃ (27.8 g, 201 mmol). The resulting mixture was stirred at reflux for 18 hrs. The mixture was slowly poured into ice-cold 6M HCl (aq., 100 mL) with vigorous stirring, and then diluted with EtOAc (100 mL). The biphasic mixture was filtered, the phases were separated, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated on silica, and purified by silica gel chromatography (330 g column, 50-100% EtOAc / isohexane) to give a white solid. The solid was triturated in water (50 mL) and azeotroped with MeCN (30 mL) in vacuo to yield N- (2-chloropyrimidin-4-yl) cyclopropanesulfonamide (11.68 g, 49.5 mmol, 49% yield ) Of a white solid. Rt 0.79min (UPLC, acid); m / z 234 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.68 (s, 1H), 8.60 (d, J = 5.3Hz, 1H), 7.32 (d, J = 5.3Hz, 1H), 3.11-3.06 (m, 1H), 1.30-0.94 (m, 4H).

N - (2- chloro-pyrimidin-4-yl) - N - (4- methoxybenzyl) cyclopropane sulfonamide Amides INTC139

Under a RT, containing N - (2- chloro-pyrimidin-4-yl) cyclopropane sulfonamide Amides INTC138 (11.68g, 50.0mmol) of DMF (50mL) was stirred solution was added sequentially K ₂ CO ₃ (13.82g, 100 mmol) and 1- (chloromethyl) -4-methoxybenzene (8.13 mL, 60.0 mmol). After the reaction mixture was stirred at RT for 3 hrs, it was heated at 40 ° C for 18 hrs. 1- (chloromethyl) -4-methoxybenzene (2.03 mL, 15.0 mmol) was further added, and the resulting mixture was stirred at 40 ° C for 18 hrs. The mixture was cooled to RT, poured into water (200 mL), and diluted with EtOAc (100 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). Combined organic layers were dehydrated over Na ₂ SO _4, filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (330 g column, 0-50% EtOAc / isohexane) to give a white solid. The solid in MeCN (20mL) grinding, to produce N - (2- chloro-pyrimidin-4-yl) - N - (4- methoxybenzyl) Amides cyclopropane sulfonamide (8.4g, 23.50mmol, 47% Yield) of white powder. Rt 1.41min (UPLC, basic); m / z 354 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.54 (d, J = 5.9Hz, 1H), 7.42 (d, J = 5.9Hz, 1H), 7.28 (d, J = 8.7Hz, 2H), 6.91 (d, J = 8.7Hz, 2H), 5.11 (s, 2H), 3.73 (s, 3H), 3.32-3.26 (m, 1H), 1.23-1.08 (m, 4H).

2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-2-yl) malonate 1-third butyl ester 3-ethyl ester INTC140

Cs ₂ CO ₃ (4.86 g, 14.92 mmol) and N- (2-chloropyrimidine-) were sequentially added to a DME (25 mL) solution containing ethyl malonate (1.41 mL, 7.46 mmol). 4- yl) - N - (4- methoxybenzyl) cyclopropane sulfonamide Amides INTC139 (2.4g, 6.78mmol), the resulting mixture was heated 24hrs at 90 ℃. The reaction mixture was cooled to RT, poured into sat. NH ₄ Cl (aq., 100 mL), and diluted with EtOAc (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). Combined organic layers were dehydrated over Na ₂ SO _4, filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (220 g column, 0-70% EtOAc / isohexane) to give 2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidine 2-yl) malonate 1-third butyl 3-ethyl ester (1.67 g, 3.14 mmol, 46% yield) as a yellow oil. Rt 1.67min (UPLC, acidic); m / z 507 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.59 (d, J = 6.0Hz, 1H), 7.33 (d , J = 6.0Hz, 1H), 7.29-7.22m, 2H), 6.89-6.84 (m, 2H), 5.17-5.07 (m, 2H), 4.99 (s, 1H), 4.14 (q, J = 7.2Hz , 2H), 3.71 (s, 3H), 3.31-3.26 (m, 1H), 1.39 (s, 9H), 1.19-1.14 (m, 3H), 1.14-0.98 (m, 4H).

2-ethyl-2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-2-yl) malonate Ester INTC141

In 2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-2-yl) malonate 1-third butyl ester 3-ethyl ester INTC140 ( To a solution of 2.96 g, 5.85 mmol) in DMF (40 mL), K ₂ CO ₃ (1.780 g, 12.88 mmol) and EtI (0.52 mL, 6.44 mmol) were sequentially added. The resulting mixture was stirred vigorously at 60 ° C for 2 hrs. The reaction mixture was cooled to RT and poured into sat. NH ₄ Cl (aq., 150 mL) and diluted with EtOAc (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). Combined organic layers were washed with a half-saturated brine (50 mL), dehydrated over Na ₂ SO _4, filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (120 g column, 0-50% EtOAc / isohexane) to give 2-ethyl-2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonate Amido) pyrimidin-2-yl) malonate 1-third butyl ester 3-ethyl ester (2.63 g, 4.39 mmol, 75% yield) as a pale yellow oil. Rt 1.82min (UPLC, acidic); m / z 534 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.59 (d, J = 5.9Hz, 1H), 7.30 (d , J = 5.9Hz, 1H), 7.25-7.00 (m, 2H), 6.89-6.84 (m, 2H), 5.16-5.07 (m, 2H), 4.18-4.11 (m, 1H), 4.11-4.01 (m , 1H), 3.71 (s, 3H), 3.30-3.25 (m, 1H), 2.27-2.13 (m, 2H), 1.35 (s, 9H), 1.13 (t, J = 7.1Hz, 3H), 1.10- 0.97 (m, 4H), 0.92 (t, J = 7.3Hz, 3H).

2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-2-yl) butyric acid ethyl ester INTC142

In 2-ethyl-2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-2-yl) malonate 1-third butyl ester 3- To a solution of ethyl ester INTC141 (3.0 g, 5.06 mmol) in DCM (40 mL) was added TFA (15.59 mL, 202 mmol). The resulting solution was stirred at RT for 18 hrs. Solution was poured into sat.NaHCO ₃ (aq, 200 mL) using DCM (50mL) was diluted. The phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL). Adjust to pH 4 with 12M HCl and extract the aqueous layer with DCM (3 x 50 mL). Combined organic layers were dehydrated over Na ₂ SO _4, filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (120 g column, 0-100% EtOAc / isohexane) to give 2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidine 2-yl) ethyl butyrate (1.74 g, 3.85 mmol, 76% yield) as a colorless oil. Rt 1.56min (UPLC, acidic); m / z 434 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.55 (d, J = 5.9Hz, 1H), 7.34-7.21 (m, 3H), 6.90-6.86 (m, 2H), 5.15-5.06 (m, 2H), 4.05-4.00 (m, 2H), 3.78 (t, J = 7.4Hz, 1H), 3.71 (s, 3H ), 1.98-1.87 (m, 2H), 1.13-1.01 (m, 7H), 0.82 (t, J = 7.4Hz, 3H). One CH proton is blocked by the DMSO peak.

N- (5- (6-ethoxypyridine -2-yl) pyridin-2-yl) -2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-2-yl) butanamide INTC143

Using Method 2 using 5- (6-ethoxypyridine 2-yl) pyridin-2-amine INTD33 (449 mg, 2.08 mmol) and 2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-2-yl) butan Acid ethyl ester INTC142 is prepared to produce N- (5- (6-ethoxypyridine) 2-yl) pyridin-2-yl) -2- (4- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-2-yl) butanamide (11% produced Rate) of colorless oil. Rt 1.70min (UPLC, acidic); m / z 604 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 10.99 (s, 1H), 9.07 (d, J = 2.5Hz , 1H), 8.85 (s, 1H), 8.58 (d, J = 5.9Hz, 1H), 8.49 (dd, J = 8.8, 2.5Hz, 1H), 8.25 (s, 1H), 8.24 (d, J = 8.8Hz, 1H), 7.26-7.21 (m, 3H), 6.79-6.74 (m, 2H), 5.12 (d, J = 16.3Hz, 1H), 5.08 (d, J = 16.3Hz, 1H), 4.49 ( q, J = 7.0Hz, 2H), 4.24-4.15 (m, 1H), 3.64 (s, 3H), 3.42-3.37 (m, 1H), 2.15-2.02 (m, 2H), 1.41 (t, J = 7.0Hz, 3H), 1.10-1.05 (m, 2H), 1.00-0.96 (m, 2H), 0.94 (t, J = 7.4Hz, 3H).

Benzamidine intermediates Sulfonylation

N- (4-cyanopyrimidin-2-yl) cyclopropanesulfonamide INTC144

According to method C, 2-chloropyrimidine-4-carbonitrile, cyclopropanesulfonamide and Cs ₂ CO ₃ , tBuXPhos and [Pd (allyl) Cl] ₂ were used. Preparation in alkanes to give N- (4-cyanopyrimidin-2-yl) cyclopropanesulfonamide (88% yield) as a pale orange solid. Rt 0.70mins (UPLC, acidic); m / z 225 (M) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.87 (s, 1H), 8.95 (d, J = 4.9Hz, 1H ), 7.75 (d, J = 4.9Hz, 1H), 3.23-3.14 (m, 1H), 1.19-1.04 (m, 4H).

Nitrile reduction

((2- (Cyclopropanesulfonylamino) pyrimidin-4-yl) methyl) carbamic acid third butyl ester INTC145

To a suspension of N- (4-cyanopyrimidin-2-yl) cyclopropanesulfonamide INTC144 (0.5 g, 2.23 mmol) in MeOH (20 mL) at 0 ° C, di-tert -butyl dicarbonate was sequentially added. Ester (0.973 g, 4.46 mmol) and nickel (II) chloride hexahydrate (0.029 g, 0.223 mmol). Then NaBH ₄ (0.675 g, 17.8 mmol) was added in portions over 30 mins, and the next portion was added only when the previous portion stopped foaming. The reaction mixture was stirred at RT for 18 hrs. The reaction was stopped by adding N- (2-aminoethyl) -1,2-ethylenediamine (0.5 mL, 4.50 mmol), and stirred at RT for 1.5 hrs. The reaction mixture was concentrated to dryness and the resulting orange residue was dissolved in EtOAc (50 mL) and water (50 mL). The phases were separated, the aqueous phase (pH 8) was neutralized with sat. NH ₄ Cl (aqueous solution, 50 mL), and the product was extracted with EtOAc (50 mL). The aqueous phase was acidified to pH 4 by addition of 1 M HCl (aq) in portions. The product was extracted with EtOAc (50 mL). The combined organic phases were dehydrated (phase separator) and concentrated in vacuo. The crude product was concentrated on silica and purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to give ((2- (cyclopropanesulfonamido) pyrimidin-4-yl) methyl ) Clear colorless glass of third butyl carbamate (85 mg, 0.207 mmol, 9% yield); Rt 0.98 mins (UPLC, acidic); m / z 350 (M + Na) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.62 (d, J = 4.9Hz, 1H), 8.55 (d, J = 5.2Hz, 1H), 7.52-7.48 (m, 1H), 6.96 (d, J = 5.2Hz, 1H), 4.14 (d, J = 6.1Hz, 2H), 3.30-3.19 (m, 1H), 1.41 (s, 9H), 1.15-1.05 (m, 2H), 1.08-1.00 (m, 2H ).

Alkylation

1- (2-chloropyrimidin-4-yl) cyclopropanecarboxylic acid methyl ester INTC146

To a solution of methyl 2- (2-chloropyrimidin-4-yl) acetate (3 g, 16.08 mmol) in DMF (40 mL) was added NaOH (1.93 g, 48.2 mmol). After the resulting mixture was stirred at RT for 15 min, 1,2-dibromoethane (2.77 mL, 32.2 mmol) was added dropwise and stirred at RT for 3 hrs. The mixture was poured into sat. NH ₄ Cl (aq., 100 mL) and diluted with EtOAc (40 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 40 mL). Combined organic layers were dehydrated (Na ₂ SO _4), filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (120 g column, 0-50% EtOAc / isohexane) to give methyl 1- (2-chloropyrimidin-4-yl) cyclopropanecarboxylate (1.78 g, 8.12 mmol, 51 % Yield) as a colorless oil. Rt 1.05min (UPLC, basic); m / z 213 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.70 (d, J = 5.2Hz, 1H), 7.88 ( d, J = 5.2Hz, 1H), 3.67 (s, 3H), 1.68-1.63 (m, 2H), 1.59 (dt, J = 5.1, 2.9Hz, 2H).

hydrolysis

1- (2-chloropyrimidin-4-yl) cyclopropanecarboxylic acid INTC147

Prepared by Method J using 1- (2-chloropyrimidin-4-yl) cyclopropanecarboxylic acid methyl ester INTC146 to give 1- (2-chloropyrimidin-4-yl) cyclopropanecarboxylic acid (full yield) as a colorless solid . Rt 0.83 min (UPLC, acidic); m / z 199 (M + H) ⁺ (ES ⁺ ). No NMR data were recorded.

Curtius reaction

(1- (2-chloropyrimidin-4-yl) cyclopropyl) carbamic acid third butyl ester INTC148

To a solution containing 1- (2-chloropyrimidin-4-yl) cyclopropanecarboxylic acid INTC147 (1.85 g, 9.31 mmol) in a third butanol (15 mL) and toluene (15 mL) was sequentially added Et ₃ N (1.49 mL, 10.3 mmol) and DPPA (2.23 mL, 9.78 mmol). The resulting mixture was stirred at 90 ° C for 4 hrs. The mixture was cooled to RT, using sat.NaHCO ₃ (aq, 50mL) and diluted with EtOAc (30mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). Combined organic layers were dehydrated (Na ₂ SO _4), filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (120 g column, 0-50% EtOAc / isohexane) to give (1- (2-chloropyrimidin-4-yl) cyclopropyl) carbamic acid third butyl ester (1.02 g, 3.33 mmol, 36% yield) as a colorless solid. Rt 1.26 min (UPLC, acidic); m / z 270 (M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 8.63 (d, J = 5.3Hz, 1H), 7.91 (s, 1H), 7.38 (d, J = 5.3Hz, 1H), 1.42 (s, 9H), 1.35 -1.21 (m, 4H).

1- (2-bromopyrimidin-4-yl) propan-1-one INTC149

An anhydrous THF (150 mL) solution containing 2-bromopyrimidine (17.91 g, 113 mmol) was cooled to -60 ° C. 1 M lithium 2,2,6,6-tetramethylpiperidine-1-oxide lithium dichloride (THF / toluene solution) (180 mL, 169 mmol) was added dropwise over 1 hr. After the resulting solution was stirred at -55 ° C for 3 hrs, a solution of N -methoxy- N -methylpropanamide (11 g, 94 mmol) in anhydrous THF (20 mL) was added dropwise to the obtained suspension. The reaction mixture was warmed to -40 ° C. After 30 min, the temperature was gradually raised from -40 ° C to RT over 18 hrs. After the reaction mixture was cooled in an ice bath, 5% citric acid (aqueous solution, 80 mL) was carefully added dropwise to stop the reaction. The mixture was diluted with brine (150 mL) and the organic phase was separated. The aqueous phase was re-using DCM (3 x 100mL) was extracted, the combined organic phase was dried (MgSO _4), filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (330 g column, 0-10% EtOAc / isohexane) to give 1- (2-bromopyrimidin-4-yl) propan-1-one (11.39 g, 50.8 mmol, 54% Yield) as a yellow solid. Rt 1.74 min (HPLC, basic); m / z 215 ( ⁷⁹ Br M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 8.97 (d, J = 4.9Hz, 1H), 7.95 (d, J = 4.9Hz, 1H), 3.12 (q, J = 7.1Hz, 2H), 1.09 (t , J = 7.1Hz, 3H).

N- (1- (2- Bromopyrimidin -4-yl) propylene) -2-methylpropane-2-sulfenamidine INTC150

Take Ti (O- i- Pr) ₄ (30.1ml, 103mmol) and add (R) -2-methylpropane-2-sulfinamide (7.3g, 60.2mmol), (S) -2-formaldehyde Propane-2-sulfenamidine (5.9 g, 48.7 mmol) and 1- (2-bromopyrimidin-4-yl) propan-1-one INTC149 (11.5 g, 51.3 mmol). The reaction mixture was heated to 70 ° C for 10 hrs. The reaction mixture was cooled in an ice bath, diluted in THF (200 mL), and treated with brine (50 mL) dropwise. After the mixture was stirred for 15 min, it was filtered through yin's salt (80 g) and dissolved with THF (1 L). The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (330 g column, 0-100% EtOAc / isohexane) to give N- (1- (2-bromopyrimidin-4-yl) propylene) -2-methylpropane- 2-sulfenamidine (12.87 g, 39.6 mmol, 77% yield) (mixture of E and Z isomers) as a pale yellow solid. Rt 1.79 and 2.12 min (HPLC, basic); m / z 318 ( ⁷⁹ Br M + H) ⁺ (ES ⁺ ). No NMR data was collected.

Reduction of sulfenimine

N- (1- (2-bromopyrimidin-4-yl) propyl) -2-methylpropane-2-sulfenamidine INTC151

Take THF (200mL) and water (2mL) containing N- (1- (2-bromopyrimidin-4-yl) propylidene) -2-methylpropane-2- sulfenimidine INTC150 (10g, 30.8mmol ) ) After the solution was cooled to -50 ° C (external bath temperature), it was treated with sodium borohydride (1.2 g, 31.7 mmol). After the reaction mixture was stirred for 10 min, it was returned to RT. After 1h, added sat.NaHCO ₃ (aq, 20mL), the reaction mixture was stirred for 20min. After the mixture was acidified to pH 5 with 1N HCl (aq), it was concentrated in vacuo. The aqueous phase was extracted with DCM (3 x 80 mL), and the combined organic phases were dehydrated (phase separator) and concentrated in vacuo to yield N- (1- (2-bromopyrimidin-4-yl) propyl) -2-methylpropane The orange gum of 2-sulfenamidine (7.2 g, 20.9 mmol, 68% yield) was a 1: 3 mixture of diastereomers. Rt 1.63 and 1.77 mins (HPLC, basic); m / z 320 (M + H) ⁺ (ES ⁺ ). No NMR data was collected.

Add a second R ₄ / R ₅ Grignard reaction of groups

N- (2- (2-bromopyrimidin-4-yl) butane-2-yl) -2-methylpropane-2-sulfenamidine INTC152

N- (1- (2-bromopyrimidin-4-yl) propylidene) -2-methylpropane-2-sulfenamidine INTC150 (100mg, 0.314mmol ) at -78 ° C (100mL) To the solution, MeMgBr (0.13 mL, 0.38 mmol) was added dropwise over 5 min. The resulting mixture was allowed to warm to room temperature, and after stirring for 1 h, sat. NH ₄ Cl (aqueous solution, 50 mL) was added to stop the reaction. Using EtOAc (2 x 100mL) and the product extracted, dehydrated (MgSO _4), filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-100% EtOAc / isohexane) to give N- (2- (2-bromopyrimidin-4-yl) butane-2-yl) -2-methyl Propylpropane-2-sulfenamidine (0.107 g, 0.321 mmol, full yield) was a clear, colorless gum with a single diastereomer. Rt 1.95 min (HPLC, acidic); m / z 332 ( ⁷⁹ Br M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 8.70 (d, J = 5.2Hz, 1H), 7.85 (d, J = 5.2Hz, 1H), 5.63 (s, 1H), 1.97-1.82 (m, 2H) 1.54 (s, 3H), 1.17 (s, 9H), 0.75 (t, J = 7.4Hz, 3H).

Sulfonamide from aromatic halides

Removal protection: Boc

N- (4- (1-aminocyclopropyl) pyrimidin-2-yl) cyclopropanesulfonamide hydrochloride INTC156

In the presence of (1- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) cyclopropyl) carbamic acid third butyl ester INTC153 (200mg, 0.564mmol) HCl solution (2mL) was added HCl (4M Alkane solution) (1.41 mL, 5.64 mmol), and the resulting solution was stirred at RT for 18 hrs. The solvent was removed in vacuo to give N- (4- (1-aminocyclopropyl) pyrimidin-2-yl) cyclopropanesulfonamide hydrochloride (164 mg, 0.564 mmol, full yield) as a slightly yellow solid, which was not Used without any further purification. Rt 0.39 min (UPLC, acidic); m / z 255 (M + H) ⁺ (ES ⁺ ). No NMR data was collected.

N- (4- (Aminomethyl) pyrimidin-2-yl) cyclopropanesulfonamide hydrochloride INTC157

Prepared according to the method of INTC156 using ((2- (cyclopropanesulfonamido) pyrimidin-4-yl) methyl) carbamic acid third butyl ester INTC145 to produce N- (4- (aminomethyl) pyrimidine 2-yl) cyclopropanesulfonamide HCl (70 mg, 0.225 mmol, 88% yield) as a pale yellow solid; Rt 0.13 mins (UPLC, acidic); m / z 229 (M + H) ⁺ (ES ⁺ ) . No NMR data was collected.

Sulfaimide removal protection

1- (2-chloropyrimidin-4-yl) propan-1-amine INTC158

Take a solution of N- (1- (2-bromopyrimidin-4-yl) propyl) -2-methylpropane-2-sulfinamide INTC151 (7.2g, 22.48mmol) in THF (30mL), using 4N HCl bis After the alkane solution (2.9 mL, 95 mmol) was treated with MeOH (1.0 mL), it was stirred at RT for 3 hrs. After the reaction mixture was concentrated in vacuo, it was basified using sat. NaHCO ₃ (aqueous solution, 100 mL). The product was extracted with DCM (3 x 80 mL) and the combined organic phases were dehydrated (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (80 g column, 0-10% (0.7 M ammonia / MeOH) / DCM) to give 1- (2-chloropyrimidin-4-yl) propan-1-amine (1.34 g, 6.01 mmol, 27% yield) as a clear brown oil. Rt 0.75 mins (UPLC, basic); m / z 172 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 8.71 (d, J = 5.1Hz, 1H), 7.64 (d, J = 5.1Hz, 1H), 3.77-3.64 (m, 1H), 2.03 (s, 2H) , 1.74-1.63 (m, 1H), 1.62-1.49 (m, 1H), 0.84 (t, J = 7.4Hz, 3H). Br-Cl exchange was observed in the reaction.

N- (4- (2- Aminobutane -2-yl) pyrimidin-2-yl) cyclopropanesulfonamide hydrochloride INTC159

Prepared according to the method of INTC158 using N- (4- (2- (1,1-dimethylethylsulfinamido) butane-2-yl) pyrimidin-2-yl) cyclopropanesulfonamide INTC154 , generating N - (4- (2- amino-2-yl) pyrimidin-2-yl) sulfonylurea cyclopropane hydrochloride (92% yield) of a yellow solid. Rt 0.41 min (UPLC, basic); m / z 271 (M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 11.39 (s, 1H), 8.79-8.51 (m, 4H), 7.37 (d, J = 5.0Hz, 1H), 3.38 (s, 1H), 2.05-1.85 ( m, 2H), 1.61 (s, 3H), 1.19-0.99 (m, 4H), 0.84-0.68 (m, 3H).

Reductive amination

1- (2-bromopyrimidin-4-yl) propan-1-amine INTC160

Take THF (20mL, containing 2,2,2-trifluoroacetic acid ammonium salt (6.09g, 46.5mmol) and 1- (2-bromopyrimidin-4-yl) propan-1-one INTC149 (500mg, 2.32mmol) 244 mmol) suspension was stirred at 45 ° C. for 15 min, resulting in a clear yellow solution, which was cooled to RT. An additional 2,2,2-trifluoroacetic acid ammonium salt (1.8 g, 13.7 mmol) was added. NaHB (OAc) ₃ (985 mg, 4.65 mmol) was added and the reaction mixture was stirred at RT for 3 hrs. The reaction mixture was concentrated in vacuo to about 10mL, diluted with EtOAc (50mL), washed with 2M Na ₂ CO ₃ (aq, 2 x 50mL). The organic layer was then stirred with Si-Tosic acid (10 g), filtered, washed with EtOAc (2 x 50 mL) and MeOH (2 x 50 mL), and dissolved with a 0.7 M solution of NH ₃ in MeOH to give 1- (2-bromopyrimidine- 4-yl) propan-1-amine (227 mg, 0.99 mmol, 43% yield) as an orange oil. Rt 0.69 mins (UPLC, basic); m / z 216 ( ⁷⁹ Br M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 8.64 (d, J = 5.1Hz, 1H), 7.67 (d, J = 5.1Hz, 1H), 3.72 (t, J = 6.6Hz, 1H), 1.73-1.62 (m, 1H), 1.62-1.51 (m, 1H), 0.84 (t, J = 7.4Hz, 3H), NH _{2 was} not observed.

Oxime formation

N- (4- (1- (methoxyimino) propyl) pyrimidin-2-yl) cyclopropanesulfonamide INTC161

Take O -methylhydroxylamine hydrochloride (170mg, 2.04mmol), N- (4-propanylpyrimidin-2-yl) cyclopropanesulfonamide INTC155 (500mg, 1.96mmol ) and pyridine (0.35mL, 4.33 mmol) of EtOH (4 mL) was heated to reflux for 18 hrs. The reaction mixture was concentrated, dissolved in EtOAc (20 mL), and washed with 1M HCl (15 mL) and brine (15 mL). The organic phase was dried (Na ₂ SO _4), filtered, and concentrated on Silica (3g). The crude product was purified by silica gel chromatography (12 g column, 0-100% EtOAc / isohexane) to give the N- (4- (1- (methoxyimino) propyl) pyrimidin-2-yl) ring Propanesulfonamide (428 mg, 1.43 mmol, 70% yield) as a yellow gum. Rt 0.60 mins (UPLC, basic 2); m / z 285 (M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 11.35 (s, 1H), 8.60 (d, J = 5.2Hz, 1H), 7.45 (d, J = 5.2Hz, 1H), 4.02 (s, 3H), 3.25 -3.15 (m, 1H), 2.76 (q, J = 7.5Hz, 2H), 1.15-1.01 (m, 7H).

N- (4- (1-aminopropyl) pyrimidin-2-yl) cyclopropanesulfonamide INTC162

Take a solution of N- (4- (1- (methoxyimino) propyl) pyrimidin-2-yl) cyclopropanesulfonamide ( 428mg , 1.51 mmol) INTC161 in 7M NH ₃ in MeOH (4mL) Treatment with Pd-C on carbon 10% (10 mg), hydrogenation at 5 bar for 1 hr. The reaction mixture was filtered through yin's salt, dissolved with DCM (30 mL), and concentrated in vacuo to give N- (4- (1-aminopropyl) pyrimidin-2-yl) cyclopropanesulfonamide (380mg, 1.19mmol, 79% yield) as an off-white solid. Rt 0.44 mins (HPLC, basic); m / z 257 (M + H) ⁺ (ES ⁺ ). No NMR data was collected.

HATU amide coupling

Benzamidine Curtius reaction

(1- (6-chloropyridine -2-yl) propyl) carbamic acid third butyl ester INTC169

Use 2- (6-chloropyridine) according to the method of INTC148 Commercial preparation of 2--2-) butanoic acid yields (1- (6-chloropyridine) 2-yl) propyl) carbamic acid tert-butyl ester (6% yield) as a colorless solid. Rt 2.15 min (HPLC, acidic); m / z 272 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ). ¹ H NMR (4: 1 mixture of rotamers) (500MHz, DMSO-d6) δ 8.68 (s, 1H), 8.61 (s, 1H), 7.52 (d, J = 7.9Hz, 1H), 4.55- 4.44 (m, 1H), 1.85-1.57 (m, 2H), 1.37 (s, 9H, major), 1.22 (s, 9H, minor), 0.87 (t, J = 7.3Hz, 3H).

Grignard reaction

N- (6- (2-hydroxyprop-2-yl) pyridine -2-yl) cyclopropanesulfonamide INTC172

6- (cyclopropanesulfonamido) pyridine A solution of methyl-2-formate INTC170 (3.00 g, 11.7 mmol) in THF (30 mL) was cooled to 0 ° C, and MeMgBr (3.0 M Et ₂ O solution) (18 mL, 54.0 mmol) was added dropwise over a period of 15 mins. The reaction The mixture was warmed to RT. The reaction mixture was stirred at RT for 18 hrs. The reaction mixture was reheated to 40 ° C for 24hrs. The reaction mixture was cooled using an ice bath, and 1M HCl (aq., 60 mL) was carefully added. The aqueous phase was extracted with EtOAc (4 x 500 mL). The organic phases were combined, dehydrated (Na ₂ SO _4), filtered, and concentrated Silica (10g) on. The crude product was purified by silica gel chromatography (40 g column, 0-100% EtOAc / isohexane) to give N- (6- (2-hydroxyprop-2-yl) pyridine 2-yl) cyclopropanesulfonamide (340 mg, 1.30 mmol, 11% yield) as a brown gum. Rt 0.24 min (UPLC, acid 2); m / z 258 (M + H) ⁺ (ES ⁺ ). 1H NMR (500MHz, DMSO-d6) δ 10.92 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H), 5.40 (s, 1H), 3.11-3.01 (m, 1H), 1.45 (s , 6H), 1.14-1.02 (m, 4H).

Ritter reaction

2-chloro- N- (2- (6- (cyclopropanesulfonamido) pyridine) pyridine -2-yl) propan-2-yl) acetamide INTC173

N- (6- (2-hydroxyprop-2-yl) pyridine After a mixture of 2--2 -yl) cyclopropanesulfonamide INTC172 (330 mg, 1.28 mmol) and 2-chloroacetonitrile (0.65 mL, 10.3 mmol) in AcOH (0.75 mL, 13.1 mmol) was cooled in an ice bath, H _{2 was} added dropwise. SO ₄ (0.82 mL, 15.4 mmol). The reaction was then warmed to 50 ° C and stirred for 18 hrs. Solution was poured onto ice-water (30 mL), and extracted with EtOAc (3 x 30mL), the organic phases were combined, dehydrated (Na ₂ SO _4), filtered, and concentrated on Silica (2g). The crude product was purified by silica gel chromatography (12 g column, 0-100% EtOAc / isohexane) to give 2-chloro- N- (2- (6- (cyclopropanesulfonamido) pyridine) pyridine 2-yl) propan-2-yl) acetamidamine (100 mg, 0.294 mmol, 19% yield) as a yellow gum. Rt 0.98 min (HPLC, acidic); m / z 333 ( ³⁵ Cl M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 10.94 (s, 1H), 8.63 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 4.08 (s, 2H), 3.16-3.08 ( m, 1H), 1.58 (s, 6H), 1.14-1.03 (m, 4H).

Remove Boc

N- (6- (1-aminopropyl) pyridine -2-yl) cyclopropanesulfonamide.HCl INTC174

INTC156 prepared by the method using (1- (6- (cyclopropanesulfonamide acyl group) pyrazole Preparation of 2-butyl) propyl) carbamic acid third butyl ester INTC171 to produce N- (6- (1-aminopropyl) pyridine 2-yl) cyclopropanesulfonamide HCl (85 mg, 0.276 mmol, 42% yield) as a colorless solid. Rt 0.58 min (HPLC, basic); m / z 257 (M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 11.25 (s, 1H), 8.77-8.66 (m, 3H), 8.45 (s, 1H), 8.31 (s, 1H), 4.37-4.23 (m, 1H) , 3.53-3.45 (m, 1H), 2.09-1.83 (m, 2H), 1.20-0.99 (m, 4H), 0.83 (t, J = 7.4Hz, 3H).

Thiourea removal protection

N- (6- (2-aminopropyl-2-yl) pyridine -2-yl) cyclopropanesulfonamide INTC175

Take 2-chloro- N- (2- (6- (cyclopropanesulfonamido) pyridine) pyridine 2-yl) propan-2-yl) acetamidamine (100 mg, 0.30 mmol) INTC173 in EtOH (1.3 mL) suspension, treated sequentially with thiourea (23 mg, 0.302 mmol), and AcOH (0.35 mL, 6.11 mmol), heated to reflux for 1 hr. After the reaction mixture was cooled to RT, it was concentrated in vacuo. Then carefully use of 0.7M NH ₃ in MeOH (5mL) process, and concentrated. The crude product was purified by RP Flash C18 chromatography (12g column, 0-25% MeCN / 10mM ammonium bicarbonate) to give N- (6- (2-aminopropyl-2-yl) pyridine 2-yl) cyclopropanesulfonamide (63 mg, 0.23 mmol, 78% yield) as a colorless solid. Rt 0.37 min (HPLC, basic); m / z 257 (M + H) ⁺ (ES ⁺ ). ¹ H NMR (500MHz, DMSO-d6) δ 8.03 (s, 1H), 7.82 (s, 1H), 2.77-2.64 (m, 1H), 1.53 (s, 6H), 0.91-0.77 (m, 2H), 0.77-0.66 (m, 2H), 3 x exchangeable H was not observed.

Preparation of amine intermediates

Take a solution containing Ar1-X (1eq) and Ar2-Z (1eq) in a solvent (3 parts by volume) and a base (2.5eq), degas (N ₂ , 5min), and heat to 40 ° C. At this time, add Pd catalyst (3mol%), the reaction mixture was further degassed (N _2, 5min), followed by heating to 90 ℃ 90mins. The reaction mixture was allowed to cool to RT. Usually, the desired compound is purified by column chromatography.

Pd catalyst (5mol%) was added to a degassing (N ₂ , 5mins) solution containing Ar1-X (1eq), Ar2-Z (1eq), and a base (3eq, 6.85mmol) in a solvent (3 volumes) . The solution was then further degassed (N ₂ , 5 mins), then heated to 90 ° C. for 2 hrs, and then cooled to RT. Usually, the desired compound is purified by column chromatography.

Add Bispin (1.1eq) and KOAc (4eq) to the second one containing Ar1-Hal (1eq) (5 parts by volume) solution. The reaction was heated to 60 ℃, and degassed (N _2, 5mins). PdCl ₂ (dppf) (5 mol%) was added to the reaction mixture, and the temperature was raised to 90 ° C. for 1 hr. The reaction mixture was then cooled to RT, followed by the addition of Ar2-Hal (1eq) bis. Alkane (3 parts by volume) solution and K ₂ CO ₃ (4eq) in water (2 parts by volume) solution. The temperature was then raised to 90 ° C for 18hrs. The reaction was cooled to RT, the aqueous phase was operated, and the crude compound was purified by normal phase chromatography.

aniline

2-chloro-6- (prop-1-en-2-yl) pyridine INTD60

Take 2,6-dichloropyridine (1.0g, 6.71mmol) and 4,4,5,5-tetramethyl-2- (prop-1-en-2-yl) -1,3,2-dioxaborolane (1.13 g, 6.72 mmol) (60 mL) solution, treated with 2M K ₂ CO ₃ (aqueous solution, 8.4 mL, 16.8 mmol), degassed (N ₂ , 5 mins), and heated to 40 ° C. PdCl ₂ (dppf) -DCM adduct (274 mg, 0.336 mmol) was added, and after the mixture was further degassed (N ₂ , 5 mins), the reaction was heated to 70 ° C. for 1 hr. After allowing the reaction to cool to RT, it was treated with 1M HCl (aq., 40 mL) and EtOAc (40 mL). The phases were separated by celite, and the aqueous phase was extracted with EtOAc (2 x 20 mL). The organic phases were combined, dehydrated (MgSO _4), filtered, and concentrated on Silica (4g). The crude product was purified by silica gel chromatography (24 g column, 0-15% EtOAc / isohexane) to give 2-chloro-6- (prop-1-en-2-yl) pyridine (1.0 g, 3.75 mmol, 56% yield) of a brown gum; Rt 1.96 mins (HPLC, acidic); no m / z was observed. ¹ H NMR (500MHz, DMSO-d6) δ 8.94 (s, 1H), 8.69 (s, 1H), 6.11-6.08 (m, 1H), 5.55-5.52 (m, 1H), 2.16-2.14 (m, 3H ).

5- (6- (prop-1-en-2-yl) pyridine 2-yl) pyridine-2-amine INTD61

Take 2-chloro-6- (prop-1-en-2-yl) pyridine INTD60 (1g, 3.75mmol ) and 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine (1.65g , 7.50 mmol) bis After the alkane (60 mL) solution was treated with 2M K ₂ CO ₃ (aqueous solution, 7.5 mL, 15.00 mmol), it was degassed (N ₂ , 5 mins) and heated to 40 ° C. PdCl ₂ (dppf) -DCM adduct (0.306 g, 0.375 mmol) was added, and the mixture was degassed (N ₂ , 5 mins), and the reaction was heated to 70 ° C. for 1 hr. After allowing the reaction to cool to RT, it was concentrated (to about 10 mL). It was then treated with 1M HCl (aq., 37.5 mL) and EtOAc (40 mL), filtered over yin's salt, and dissolved with EtOAc (50 mL). Do not separate the organic phase. Phase was added Na ₂ CO ₃ in water was adjusted to a solid after pH 10, extracted with EtOAc (3 x 50mL). The organic phases were combined, dried (MgSO ₄ ), filtered, and concentrated on silica (5 g). The crude product was purified by silica gel chromatography (24 g column, 30-100% EtOAc / isohexane) to give 5- (6 -(Prop-1-en-2-yl) pyridine 2-yl) pyridin-2-amine (320 mg, 1.43 mmol, 38% yield) as an off-white solid; Rt 0.98 mins (HPLC, acidic); m / z 213 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 9.00 (s, 1H), 8.78-8.75 (m, 1H), 8.74 (s, 1H), 8.16 (dd, J = 8.7, 2.5Hz, 1H), 6.57 (dd , J = 8.7, 0.7Hz, 1H), 6.43 (s, 2H), 6.12-6.09 (m, 1H), 5.48-5.45 (m, 1H), 2.23 (s, 3H).

4- (6-isopropylpyridine -2-yl) aniline INTD62

Take 4- (6- (prop-1-en-2-yl) pyridine A solution of 2--2 -yl) aniline INTD52 (380 mg, 1.44 mmol) in MeOH (10 mL) was hydrogenated using a H-Cube flow hydrogenation apparatus (10% Pd / C, 30 x 4 mm, full hydrogen, 25 ° C, 1 mL / min). The reaction mixture was concentrated to give 4- (6-isopropylpyridine 2-yl) aniline (296 mg, 1.37 mmol, 95% yield) as an orange oil; Rt 1.74 mins (HPLC, basic); m / z 214 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 8.85 (s, 1H), 8.31 (s, 1H), 7.89-7.82 (m, 2H), 6.68-6.63 (m, 2H), 5.56 (s, 2H), 3.08 ( hept, J = 6.9Hz, 1H), 1.29 (d, J = 6.9Hz, 6H).

2-methoxy-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine INTD63

2-bromo-6-methoxypyridine (500mg, 2.65mmol) 1,4-bis To the alkane (15 mL) solution, bispin (739 mg, 2.91 mmol) and KOAc (1.04 g, 10.58 mmol) were sequentially added. The resulting mixture was degassed (N ₂ ), and PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (108 mg, 0.132 mmol) was added. The resulting mixture was heated at 110 ° C for 2.5 hrs. The mixture was cooled to RT, filtered through Yin's salt, and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (24 g box, 0-50% EtOAc / isohexane). The residue was dissolved in EtOAc (20 mL) and washed with water (3 x 10 mL). The organic layer was dehydrated over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 2-methoxy-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane. -2-yl) pyridine (281 mg, 0.845 mmol, 32% yield) as a light yellow-brown solid. ¹ H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.34 (s, 1H), 3.93 (s, 3H), 1.33 (s, 12H).

Take the second one containing dihydroxyboric acid (1eq), aryl halide (1.05eq.) And Cs ₂ CO ₃ (3eq.) The mixture was degassed dioxane (40 parts by volume) and water (6 parts by volume) (N _2, 5mins). PdCl ₂ (dppt) .CH ₂ Cl ₂ (5 mol%) was added, the reaction was degassed (N ₂ ), and then heated to 90 ° C. for 18 hrs. After the reaction mixture was filtered through Yin's salt, the aqueous phase was operated and then purified by normal phase chromatography.

A DCM (20 vol) solution containing an ester (1 eq) was treated with TFA (10 eq.) And stirred at RT for 3 hrs. The reaction mixture was then concentrated and azeotroped with MeOH and MeCN. No further purification was performed.

A solution of the THF / MeOH (4/1 part by volume) mixture containing the ester (1 eq) was treated with LiOH (2.2-6 eq.) And stirred between RT and 50 ° C for 3 hrs to 18 hrs. After the organic solvent was removed in vacuo, it was acidified with 1M HCl and extracted with EtOAc. The organic phases were combined, dehydrated (Na ₂ SO _4), filtered, and concentrated. The product was used directly in the next step without further purification.

A THF (4 vol.) Solution containing an ester (1 eq.) Was taken and treated with TMSOK (1 eq.). After stirring at RT for 2 hrs, the reaction mixture was filtered and washed with isohexane. The product was used directly in the next step without further purification.

(5- (6-ethoxypyridine 2-yl) pyridin-2-yl) methanol INTD84

Take two of (5-bromopyridin-2-yl) methanol (1.00g, 5.32mmol), Bispin (1.5g, 5.91mmol) and KOAc (1.6g, 16.0mmol) After dioxane (20mL) was heated to 30 ℃, degassed (N _2). PdCl ₂ (dppf) -CH ₂ Cl ₂ (0.217 g, 0.266 mmol) was added and the reaction mixture was heated to 90 ° C. for 2 hrs. The reaction mixture was cooled to 40 ° C, at which time 2-chloro-6-ethoxypyridine was added. (900 mg, 5.68 mmol), Cs ₂ CO ₃ (3.47 g, 10.6 mmol) and water (5 mL). After the mixture was degassed (N ₂ ), PdCl ₂ (dppf) -CH ₂ Cl ₂ (0.217 g, 0.266 mmol) was added, and the mixture was degassed again (N ₂ ). The reaction mixture was heated to 90 ° C for 18 hrs. After the reaction mixture was partially concentrated (to about 5 mL), it was dissolved in water (20 mL) and EtOAc (50 mL), and dissolved in EtOAc (20 mL) using yin's salt. It was diluted with water (20 mL) and the phases were separated. The organic phase with brine (30mL) was washed, dehydrated (Na ₂ SO _4), filtered, and concentrated on Silica (5g). The crude product was purified by silica chromatography (40 g box, 0-100% EtOAc / isohexane) to give (5- (6-ethoxypyridine 2-yl) pyridin-2-yl) methanol (675 mg, 2.86 mmol, 54% yield) as a brown solid. Rt 1.24min (HPLC, acidic); m / z 232 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 9.27-9.09 (m, 1H), 8.87 (s, 1H) , 8.49 (dd, J = 8.2, 2.3Hz, 1H), 8.29 (s, 1H), 7.62 (d, J = 8.2Hz, 1H), 5.53 (t, J = 5.9Hz, 1H), 4.64 (d, J = 5.9Hz, 2H), 4.50 (q, J = 7.1Hz, 2H), 1.41 (t, J = 7.1Hz, 3H).

5- (6-ethoxypyridine -2-yl) pyridinaldehyde INTD85

Take (5- (6-ethoxypyridine) A solution of 2-yl) pyridin-2-yl) methanol INTD84 (375 mg, 3.18 mmol) in CH ₂ Cl ₂ (15 mL) was treated with manganese dioxide (3 g, 34.5 mmol). After the reaction was stirred at RT for 4 hr, it was filtered through yin's salt and concentrated on silica (4 g). The crude product was purified by silica chromatography (24 g box, 0-100% EtOAc / isohexane) to give 5- (6-ethoxypyridine 2-yl) pyridinaldehyde (309 mg, 1.32 mmol, 42% yield) as a colorless solid. Rt 1.85min (HPLC, acidic); m / z 230 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.07 (d, J = 0.8Hz, 1H), 9.55 ( dd, J = 2.2,0.9Hz, 1H), 9.03 (s, 1H), 8.73 (ddd, J = 8.1,2.2,0.8Hz, 1H), 8.39 (s, 1H), 8.08 (dd, J = 8.1, 0.9Hz, 1H), 4.53 (q, J = 7.0Hz, 2H), 1.42 (t, J = 7.0Hz, 3H).

5- (6-ethoxypyridine 2-yl) picolinic acid INTD86

5- (6-ethoxypyridine) A solution of 2-yl) pyridinaldehyde INTD85 (302 mg, 1.32 mmol) in DMF (5 mL) was treated with oxone monosulphate (1.02 g, 1.66 mmol). The reaction mixture was stirred at RT for 4 days. The reaction mixture was diluted with water (10 mL) and filtered. The filtrate was dissolved in EtOAc (10 mL) and heated to 40 ° C to produce a free-flowing suspension. Isohexane (10 mL) was then added dropwise, cooled to RT, and filtered to produce 5- (6-ethoxypyridine). 2-yl) picolinic acid (240 mg, 0.93 mmol, 71% yield) as a colorless solid. Rt 1.45min (HPLC, acidic); m / z 246 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d ₆ ) δ 13.31 (s, 1H), 9.46-9.38 (m, 1H ), 8.98 (s, 1H), 8.64 (dd, J = 8.1, 2.3Hz, 1H), 8.36 (s, 1H), 8.17 (dd, J = 8.1, 0.8Hz, 1H), 4.51 (q, J = 7.0Hz, 2H), 1.42 (t, J = 7.0Hz, 3H).

Case method Formamide

To a stirred suspension of DMF (15vol) containing acid or potassium salt (1eq, X = H or K) and DIPEA (6eq) was added aniline (1eq) and HATU (1.5eq). After the reaction was stirred at RT for 18 hrs, it was concentrated in vacuo. MeOH and 2M NaOH (aq) were added. After the mixture was stirred for 30 min, it was concentrated in vacuo. The aqueous phase was acidified to pH 6 with 1M HCl (aq) and the product was extracted with DCM. The organic phases were combined, dehydrated (phase separator) and concentrated in vacuo.

The crude product was purified by reverse or normal phase chromatography or a combination of both.

N- (4- (5-chloropyridin-3-yl) phenyl) -2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butanamide P1

Add 4- (5-chloropyridin-3-yl) aniline INTD8 (0.117g, 0.573mmol) and HATU (0.327g, 0.859mmol) to 2- (2- (cyclopropanesulfonamido) pyrimidine-4) -Yl ) Potassium butyrate INTC37 (0.265 g, 0.573 mmol) and DIPEA (0.60 mL, 3.44 mmol) in a stirred suspension of DMF (6 mL). After stirring the reaction at RT for 18 hrs, it was concentrated in vacuo. The crude product was dissolved in MeOH (20 mL) and 2M NaOH (aq) (20 mL) was added. After the mixture was stirred for 30 min, it was concentrated in vacuo. The aqueous phase was acidified to pH 6 with 1M HCl (aq) (40 mL) and the product was extracted with DCM (3 x 20 mL). The organic phases were combined, dehydrated (phase separator), and concentrated in vacuo. The crude product was purified by silica gel chromatography (12g column, 0-100% EtOAc / isohexane), and then purified by RP Flash C18 chromatography (5-75% MeCN / water (0.1% formic acid)) to produce N- ( 4- (5-chloropyridin-3-yl) phenyl) -2- (2 (cyclopropanesulfonamido) pyrimidin-4-yl) butanamide (0.158 g, 0.318 mmol, 56% yield) White solid. Rt 1.36min; m / z 472 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.28 (s, 1H), 10.39 (s, 1H), 8.86 (d, J = 2.0Hz, 1H), 8.63-8.48 (m, 2H), 8.22 (t, J = 2.2Hz, 1H), 7.81-7.71 (m, 4H), 7.19 (d, J = 5.2Hz, 1H), 3.80- 3.71 (m, 1H), 3.31-3.24 (m, 1H), 2.14-2.01 (m, 1H), 2.00-1.88 (m, 1H), 1.16-1.04 (m, 2H), 1.03-0.84 (m, 5H ).

To an ice-cooled solution of toluene (40 parts by volume) containing aniline (2eq) was added AlMe ₃ (2.0M heptane solution, 2eq). After stirring the mixture for 5 mins at this temperature, 10 mins at RT. To this solution was added the entire amount of ester (1eq) in one portion, and the resulting mixture was heated and stirred at 80 ° C for 2hrs. The reaction mixture was cooled in an ice bath, and the reaction was stopped carefully using MeOH (10 vol). After stirring for 20 mins, the mixture was diluted in a DCM / MeOH mixture (10 parts by volume), filtered through Yin's salt, and the filtrate was concentrated. The crude product was purified by reverse or normal phase chromatography.

1- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (4- (6- ethoxy-pyrazol -2-yl) phenyl) cyclopentaneformamide P2

4- (6-ethoxypyridine) To an ice-cooled solution of 2-methyl) aniline INTD18 (0.099 g, 0.461 mmol) in toluene (4 mL) was added AlMe ₃ (2.0 M toluene solution) (0.307 mL, 0.615 mmol). After stirring the mixture for 5 mins at this temperature, it was 20 mins at RT. In this total amount was added 1- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) cyclopentanecarboxylic acid methyl ester a INTC29 (0.1g, 0.307mmol), and the resulting mixture was N ₂ at 100 ℃ Heat and stir for 3h. The reaction mixture was carefully quenched with MeOH (2 mL). After stirring for 20 mins, the mixture was diluted with MeOH (50 mL), filtered through Yin's salt (5 g), and the filtrate was concentrated in vacuo. The crude product was purified by RP Flash C18 chromatography (25-75% MeCN / water (0.1% formic acid)), produced by 1- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (4 -(6-ethoxypyridine 2-yl) phenyl) cyclopentanemidine (0.053 g, 0.099 mmol, 32% yield) as a white solid. Rt 1.59min (UPLC, acid); m / z 509 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.33 (s, 1H), 9.58 (s, 1H), 8.76 (s, 1H), 8.62-8.46 (m, 1H), 8.18 (s, 1H), 8.11-8.00 (m, 2H), 7.83-7.70 (m, 2H), 7.17-6.96 (m, 1H), 4.56 -4.37 (m, 2H), 3.28-3.16 (m, 1H), 2.51-2.40 (m, 2H), 2.25-2.09 (m, 2H), 1.82-1.60 (m, 4H), 1.46-1.34 (m, 3H), 1.12-0.99 (m, 2H), 0.95-0.80 (m, 2H).

2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (4- (6- methoxypyridin- -2-yl) phenyl) -2-methylpropanamide P3

Take 4- (6-methoxypyridine 2-yl) aniline INTD1 (101 mg, 0.501 mmol) was added to an ice-cooled solution of toluene (4 mL) containing AlMe ₃ (2M heptane solution) (0.33 mL, 0.668 mmol). After stirring the mixture for 5 mins at this temperature, 10 mins at RT. The entire amount of 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methylpropanoate INTC21 (100 mg, 0.334 mmol) was added in one portion, and the resulting mixture was heated at 100 ° C for 2 hrs. The reaction mixture was cooled in an ice bath, and the reaction was stopped carefully using MeOH (10 mL). After stirring for 20 mins, the mixture was diluted with a DCM / MeOH mixture (10 mL, 1: 1), filtered through Yin's salt, the solvent was eliminated, and an orange oil was produced. The crude product was purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to give 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- ( 6-methoxypyridine 2-yl) phenyl) -2-methylpropanamide (37 mg, 0.077 mmol, 23% yield) as a light beige solid. Rt 2.03min (HPLC, acidic); m / z 469 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (400MHz, DMSO-d6) δ 11.27 (s, 1H), 9.51 (s, 1H), 8.78 (s, 1H), 8.61 (d, J = 5.3Hz, 1H), 8.21 (s, 1H), 8.14-8.04 (m, 2H), 7.84-7.74 (m, 2H), 7.20 (d, J = 5.3 Hz, 1H), 4.02 (s, 3H), 3.25-3.18 (m, 1H), 1.60 (s, 6H), 1.08-0.99 (m, 2H), 0.85-0.74 (m, 2H).

2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl- N- (4- (5- (trifluoromethyl) pyridin-3-yl) phenyl) propanyl Amine P4

To an ice-cooled solution of 4- (5- (trifluoromethyl) pyridin-3-yl) aniline INTD7 (0.119 g, 0.501 mmol) in toluene (4 mL) and THF (2 mL) was added AlMe ₃ (2.0M heptane Solution) (0.334 mL, 0.668 mmol). After stirring the mixture at this temperature for 5 mins, it was at RT for 10 min. To this solution was added 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methylpropanoic acid methyl ester INTC21 (0.1g, 0.334mmol) in one portion at a time, and the resulting mixture was sealed in a bottle. The mixture was stirred and heated at 80 ° C for 2 hrs. The reaction mixture was cooled in an ice bath, and the reaction was carefully stopped using MeOH. After stirring for 20 min, the mixture was diluted with a DCM / MeOH mixture, filtered through Yin's salt, and the filtrate was concentrated in vacuo. The crude product was purified by RP Flash C18 chromatography (5-75% MeCN / water 0.1% formic acid) to give 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl-N -(4- (5- (trifluoromethyl) -pyridin-3-yl) phenyl) propanamide (0.109 g, 0.205 mmol, 61% yield) as a white solid. Rt 2.17 (HPLC, acidic); m / z 506 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.49 (s, 1H), 9.28- 9.11 (m, 1H), 8.98-8.84 (m, 1H), 8.68-8.54 (m, 1H), 8.50-8.37 (m, 1H), 7.95-7.71 (m, 4H), 7.28-7.12 (m, 1H ), 3.27-3.13 (m, 1H), 1.60 (s, 6H), 1.13-0.95 (m, 2H), 0.91-0.69 (m, 2H).

2-methyl-N- (2-methyl-4- (6-methylpyridine) -2-yl) phenyl) -2- (2- (methylsulfonamido) pyrimidin-4-yl) propanilamine P5

In containing 4- (6-chloropyridine To an ice-cooled solution of 2-methyl) -2-methylaniline INTD26 (0.549 mmol, 121 mg) in toluene (2 mL) was added AlMe ₃ (0.55 mL, 1.098 mmol, 2.0 M heptane solution). After stirring the mixture at this temperature for 5 min, it was at RT for 10 min. To this solution was added 2-methyl-2- (2- (methylsulfonamido) pyrimidin-4-yl) propionic acid methyl ester INTC19 (100 mg, 0.366 mmol) in one portion at a time, and the resulting mixture was at 90 ° C. Stir and heat for 2hrs. The reaction was cooled to 0 ° C, 1M HCl (5 mL) was added, and the residue was extracted with EtOAc (2 x 20 mL). The combined organic extracts were passed through a phase separator and the solvent was removed under reduced pressure. The crude product was purified by RP Flash C18 chromatography (0-100% MeCN / water 0.1% formic acid) to give 2-methyl-N- (2-methyl-4- (6-methylpyridine) 2-yl) phenyl) -2- (2- (methylsulfonamido) pyrimidin-4-yl) propanamide (78.9 mg, 0.170 mmol, 47% yield) as an off-white solid. Rt 1.74 (HPLC, acidic); m / z 441 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.07-8.99 (m, 2H), 8.62 (d, J = 5.3Hz, 1H), 8.48 (s, 1H), 7.99 (d, J = 2.1Hz, 1H), 7.93 (dd, J = 8.3,2.2Hz, 1H), 7.42 (d, J = 8.3Hz, 1H), 7.23 (d, J = 5.3Hz, 1H), 3.39 (s, 3H), 2.56 (s, 3H), 2.19 (s, 3H), 1.62 (s, 6H).

4- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (5- (6- ethoxy-pyrazol -2-yl) pyridin-2-yl) tetrahydro- 2H -piperan-4-carboxamide P115

5- (6-ethoxypyridine) at 0 ° C To a solution of 2-yl) pyridine-2-amine INTD33 (0.14 g, 0.66 mmol) in toluene (3.0 mL, 28.2 mmol) was added AlMe ₃ (0.66 mL, 1.32 mmol, 2.0 M heptane solution). The reaction mixture was stirred at 0 ° C for 5 mins and then at RT for 10 mins. The entire amount of 4- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) tetrahydro- 2H - piperan -4-carboxylic acid methyl ester INTC53 (0.15 g, 0.44 mmol) was added in one portion, and the reaction mixture was heated to After 1 hour at 95 ° C, cool to 0 ° C. The reaction mixture was quenched with 1M HCl (5 mL) and diluted with EtOAc (10 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic phase was anhydrified on MgSO _4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (12g column, 0-100% EtOAc / iso-hexane) to give 4- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (5- ( 6-ethoxypyridine 2-yl) pyridin-2-yl) tetrahydro- 2H -piperan-4-carboxamide (0.022 g, 0.040 mmol, 9% yield) as a white solid. Rt 1.31min (UPLC, acid); m / z 526 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.31 (s, 1H), 10.13 (s, 1H), 9.03 (d, J = 2.5Hz, 1H), 8.84 (s, 1H), 8.63 (d, J = 5.3Hz, 1H), 8.50 (dd, J = 8.8, 2.5Hz, 1H), 8.26 (s, 1H) , 8.20 (d, J = 8.8Hz, 1H), 7.26 (d, J = 5.3Hz, 1H), 4.48 (q, J = 7.0Hz, 2H), 3.81-3.69 (m, 2H), 3.67-3.56 ( m, 2H), 3.31-3.20 (m, 1H), 2.49-2.41 (m, 2H), 2.25-2.17 (m, 2H), 1.40 (t, J = 7.0Hz, 3H), 1.09-1.03 (m, 2H), 0.95-0.84 (m, 2H).

DABAL-Me ₃ (1.5 eq) was added to a toluene (30 parts by volume) solution containing an ester (1 eq) and aniline (1.5 eq), and the resulting mixture was heated at 100 ° C. for 4 h. The reaction mixture was cooled to 0 ° C, and the reaction was stopped by careful addition of 1M HCl (aqueous solution, 20 parts by volume). The aqueous phase was extracted with EtOAc (3 x 20 parts by volume). The combined organic phases 1M HCl (aq, 2 x 10 vol), dried over Na ₂ SO ₄ dried, filtered, and concentrated in vacuo. The crude product was purified by reverse or normal phase chromatography.

Sequentially added pyridine (10eq) and T3P (50wt% DMF solution, 2eq) to amine (1.1eq) and potassium 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butyrate (1eq ) (16 parts by volume) in a stirred solution. The resulting reaction was stirred at RT for 24 hrs. The crude reaction mixture was concentrated in vacuo, diluted with NH ₄ Cl (sat. Aq), and extracted with DCM. The combined organic extracts were dehydrated (phase separator) and the solvent was removed. The crude product was purified by reverse or normal phase chromatography.

2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (2- fluoro-4- (pyrazol -2-yl) phenyl) butanamine P6

Take T3P (50wt% DMF solution) (1.120mL, 1.546mmol) and add 2-yl) aniline INTD23 (154mg, 0.773mmol), potassium 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butyrate INTC37 (250mg, 0.773mmol) and pyridine (0.313mL, 3.87 mmol) of DMF (1 mL) in a stirred suspension. The resulting reaction was stirred at RT for 18 hrs. Water (5 mL) was added and the newly formed precipitate was filtered. Dissolved in DCM (10 mL) and concentrated in vacuo to recover the product. The crude product was purified by preparative HPLC (20-50% MeCN / water 0.1% formic acid) to give 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (2-fluoro-4- (Pyridine 2-yl) phenyl) butanamide (32 mg, 0.069 mmol, 9% yield) as a colorless powder. Rt 1.15min (UPLC, acid); m / z 457 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.26 (s, 1H), 10.25 (s, 1H), 9.29 (d, J = 1.6Hz, 1H), 8.72 (dd, J = 2.5, 1.5Hz, 1H), 8.62 (d, J = 2.5Hz, 1H), 8.57 (d, J = 5.2Hz, 1H), 8.12 -8.03 (m, 2H), 8.03-7.97 (m, 1H), 7.20 (d, J = 5.2Hz, 1H), 4.00 (dd, J = 7.5Hz, 1H), 3.31-3.28 (m, 1H), 2.12-2.02 (m, 1H), 2.00-1.92 (m, 1H), 1.16-1.07 (m, 2H), 1.03-0.93 (m, 5H).

2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (5- (trifluoromethyl) pyridin-3-yl) phenyl) butanamide P7

Take T3P (50% by weight DMF solution) (0.78mL, 1.082mmol) and add it to potassium 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) butyrate, INTC37 (250mg, 0.541mmol) and 4- (5- (Trifluoromethyl) pyridin-3-yl) aniline INTD7 (129 mg, 0.541 mmol) in pyridine (0.13 mL, 1.623 mmol) and DMF (3 mL) were stirred in a suspension. The resulting reaction was stirred at RT for 18 hrs. The crude reaction mixture (aq) was diluted with saturated NH ₄ Cl (10mL), extracted with DCM (3 x 10mL). The combined organic extracts were dehydrated (phase separator) and the solvent was removed under reduced pressure. The crude product was sequentially purified by silica gel chromatography (0-10% MeOH in DCM) and RP Flash C18 chromatography (15-75% MeCN / water 0.1% formic acid) to produce 2- (2- (cyclopropanesulfonic acid). Amidino) pyrimidin-4-yl) -N- (4- (5- (trifluoromethyl) pyridin-3-yl) phenyl) butamidamine (19 mg; 0.036 mmol; 7% yield). Rt 1.44 (UPLC, acidic); m / z 506 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.41 (s, 1H), 9.20 ( d, J = 2.2Hz, 1H), 8.94-8.92 (m, 1H), 8.57 (d, J = 5.2Hz, 1H), 8.45-8.42 (m, 1H), 7.87-7.83 (m, 2H), 7.79 -7.75 (m, 2H), 7.21 (d, J = 5.2Hz, 1H), 3.77 (dd, J = 8.7, 6.3Hz, 1H), 3.31-3.26 (m, 1H), 2.13-2.03 (m, 1H ), 1.98-1.89 (m, 1H), 1.13-1.06 (m, 2H), 1.01-0.89 (m, 5H).

2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N- (4- (6- (trifluoromethyl) pyridine -2-yl) phenyl) acetamidamine P8

Take T3P (50wt% DMF solution) (0.343mL, 0.474mmol) and add it to INTC39 (100mg, 0.237mmol ), 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) acetate, 4- ( 6- (trifluoromethyl) pyridine 2-yl) aniline INTD19 (56.7 mg, 0.237 mmol) and pyridine (0.096 mL, 1.185 mmol) in a stirred suspension of DMF (1 mL). The resulting reaction was stirred at RT for 18 hrs. Water (5 mL) was added and the newly formed precipitate was filtered to give a crude product. The crude product was sequentially purified by silica gel chromatography (0-10% MeOH in DCM) and preparative HPLC (5-95% MeCN / water 0.1% formic acid) to yield 2- (2- (cyclopropanesulfonamido) ) Pyrimidin-4-yl) -N- (4- (6- (trifluoromethyl) pyridine 2-yl) phenyl) acetamidamine (10 mg, 0.021 mmol, 9% yield) as a yellow powder. Rt 1.31min (UPLC, acidic); m / z 479 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6), a mixture of tautomers was observed δ 12.81 (s, 1H, Minor), 11.24 (s, 1H, major), 10.95 (s, 1H, minor), 10.58 (s, 1H, major), 10.09 (s, 1H, minor), 9.58 (s, 1H, major) , 9.57 (s, 1H, minor), 9.09 (s, 1H, major), 9.06 (s, 1H, minor), 8.57 (d, J = 5.1Hz, 1H, major), 8.24-8.13 (m, 2 x 2H, major and minor), 7.85-7.79 (m, 2 x 2H, major and minor), 7.18 (d, J = 5.0Hz, 1H, major), 6.95 (d, J = 7.5Hz, 1H , Minor), 5.89 (d, J = 7.5Hz, 1H, Minor), 5.06 (s, 1H, Minor), 3.89 (s, 2H, Major), 3.28-3.22 (m, 1H, Major), 2.73-2.65 (m, 1H, minor), 1.13-0.90 (m, 2 x 4H, major and minor).

Method 4: T3P amidine coupling from lithium salt

N- (5- (6-ethoxypyridine -2-yl) pyridin-2-yl) -2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) butanamide INTC51

0 ℃ containing the 2-fluoro -2- (2- (N - (4- methoxybenzyl) cyclopropane - Sulfonic amino) pyrimidin-4-yl) butanoic acid Lithium INTC50 (0.50g, 1.17 mmol) in DMF (5 mL) 2-yl) pyridine-2-amine INTD33 (0.30 g, 1.40 mmol) and pyridine (0.57 mL, 7.01 mmol) and T3P (50 wt% DMF solution) (1.69 mL, 2.34 mmol). The reaction mixture was stirred at 0 C for 2 hrs and then warmed to RT for 20 hrs. The reaction mixture was cooled to 0 ° C, and T3P (50 wt% DMF solution) (0.5 mL, 0.69 mmol) was added. After the reaction mixture was stirred at 0 ° C for 1 hr, it was 3 hrs at RT. The reaction mixture was diluted with sat. NH ₄ Cl (aqueous solution, 45 mL), and the resulting precipitate was isolated by filtration and washed with water (2 x 20 mL). The resulting yellow precipitate was dissolved in DCM (30 mL) and MeOH (30 mL) and concentrated on silica. The crude product was purified by silica gel chromatography (24 g column, 0-60% EtOAc / isohexane) to give N- (5- (6-ethoxypyridine) -2-yl) pyridin-2-yl) -2-fluoro-2- (2- ( N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) butanamide (0.274 g, 0.433 mmol, 37% yield) as a colorless oil. Rt 1.84min (UPLC, acid); m / z 622 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 10.69 (s, 1H), 9.10 (d, J = 2.5Hz , 1H), 8.88-8.81 (m, 2H), 8.52 (dd, J = 8.7, 2.5Hz, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.7Hz, 1H), 7.52 (dd, J = 5.2, 1.3Hz, 1H), 7.30-7.23 (m, 2H), 6.81-6.74 (m, 2H), 5.20-5.08 (m, 2H), 4.48 (q, J = 7.0Hz, 2H), 3.76 -3.70 (m, 1H), 3.65 (s, 3H), 2.50-2.39 (m, 1H), 2.38-2.24 (m, 1H), 1.40 (t, J = 7.0Hz, 3H), 1.14-1.06 (m , 1H), 1.10-0.97 (m, 2H), 0.96-0.92 (m, 1H), 0.89 (t, J = 7.3Hz, 3H).

In a DCM solution containing protected amidine, a mixture of TFA (88eq) and trifluoromethanesulfonic acid (1-6eq) was added. The mixture was stirred at RT for 18-36hrs and concentrated in vacuo. The crude product was purified by silica gel column chromatography or RP chromatography.

2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (4- (6- ethoxy-pyrazol -2-yl) phenyl) butyramine P105

A mixture of 2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (4- (6- ethoxy-pyrazol 2-yl) phenyl) - N - (4- methoxybenzyl) butan Amides INTC46 (0.18g, 0.299mmol) of TFA (2mL, 26.0mmol) and DCM (2mL) mixture solution at 25 deg.] C Stir for 18hrs. The reaction was heated at 50 ° C for 2 hrs. Trifluoromethanesulfonic acid (0.027 mL, 0.299 mmol) was added to the reaction, and the mixture was stirred at 25 ° C for 2 hrs. After the reaction mixture was concentrated, it was diluted in 1N HCl (aq) (20 mL). The aqueous phase was extracted with DCM (3 x 20 mL), dehydrated (phase separator), and the solvent was removed under reduced pressure. The crude product was purified by RP Flash C18 chromatography (24g column, 5-75% MeCN / water with 0.1% formic acid) to give 2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (4- (6-ethoxypyridine 2-yl) phenyl) butanamide (0.02 g, 0.041 mmol, 14% yield) as a white solid. Rt 2.23 min (HPLC, acidic); 483 (M + H) ⁺ (ES ⁺ ).

2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (4- (6- ethoxy-pyrazol -2-yl) phenyl) acetamidamine P18

In containing 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -3-((4- (6-ethoxypyridine 2-yl) phenyl) (4-methoxybenzyl) amino) -3-butoxypropionic acid third butyl ester INTC47 (0.1g, 0.148mmol) TFA (1mL, 12.98mmol) To the solution with DCM (20 mL) was added trifluoromethanesulfonic acid (0.039 mL, 0.445 mmol). The mixture was stirred at 25 ° C for 18 hrs. Trifluoromethanesulfonic acid (0.039 mL, 0.445 mmol) was further added, and the mixture was stirred at 25 ° C. for 18 hrs. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12g column, 0-10% MeOH / DCM) yielded the 2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (4- (6 -Ethoxypyridine 2-yl) phenyl) acetamidamine (0.03 g, 0.063 mmol, 42% yield) as a pale yellow solid. Rt 1.98 min (HPLC, acidic); m / z 455 (M + H) ⁺ (ES ⁺ ).

2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (5- (6- ethoxy-pyrazol 2-yl) pyridin-2-yl) -2-fluorobutanamine P112

Add TFA (0.28mL, 3.70mmol) to N- (5- (6-ethoxypyridine) 2-yl) pyridin-2-yl) -2-fluoro-2- (2- (N- (4-methoxybenzyl) cyclopropanesulfonamido) pyrimidin-4-yl) butanamide In a stirred solution of INTC51 (115 mg, 0.185 mmol) in DCM (10 mL), the resulting reaction mixture was stirred at RT for 4 hrs. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography (12 g column, 0-100% EtOAc / isohexane) to give 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -N -(5- (6-ethoxypyridine 2-yl) pyridin-2-yl) -2-fluorobutanamine (77 mg, 0.15 mmol, 81% yield) as a white solid. Rt 2.28min (HPLC, acidic); m / z 502 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.50 (s, 1H), 10.60 (d, J = 2.3Hz , 1H), 9.10 (d, J = 2.5Hz, 1H), 8.87 (s, 1H), 8.76 (d, J = 5.1Hz, 1H), 8.53 (dd, J = 8.8, 2.5Hz, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.8Hz, 1H), 7.48 (d, J = 5.1Hz, 1H), 4.49 (q, J = 7.0Hz, 2H), 3.38-3.27 (m, 1H) , 2.44-2.29 (m, 2H), 1.40 (t, J = 7.0Hz, 3H), 1.20-0.92 (m, 7H).

Racemate P112 was separated by palm preparative HPLC using a Diacel Chiralpak IC column (20% EtOH in [4: 1 heptane: chloroform (0.2% TFA)]) to produce:

Stereochemistry of P112 Enantiomer 1 Unidentified Product (P113)

2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (5- (6- ethoxy-pyrazol 2-yl) pyridin-2-yl) -2-fluorobutanidine; Rt 2.28 mins (HPLC, acidic); m / z 502 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500 MHz, DMSO -d6) δ 11.50 (s, 1H), 10.60 (d, J = 2.2Hz, 1H), 9.11 (d, J = 2.5Hz, 1H), 8.87 (s, 1H), 8.76 (d, J = 5.1Hz , 1H), 8.53 (dd, J = 8.8, 2.5Hz, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.8Hz, 1H), 7.48 (d, J = 5.1Hz, 1H), 4.49 (q, J = 7.0Hz, 2H), 3.39-3.26 (m, 1H), 2.54-2.43 (m, 1H), 2.41-2.28 (m, 1H), 1.40 (t, J = 7.0Hz, 3H), 1.22-0.89 (m, 7H).

The product was analyzed by HPLC using the counter IC3 method; Rt = 10.47mins, 100% ee at 254nm.

Stereochemistry of P112 Enantiomer 2 Unidentified Product (P114)

2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (5- (6- ethoxy-pyrazol 2-yl) pyridin-2-yl) -2-fluorobutanamine; Rt 2.28min (HPLC, acidic); m / z 502 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO -d6) δ 11.50 (s, 1H), 10.60 (d, J = 2.3Hz, 1H), 9.11 (d, J = 2.5Hz, 1H), 8.87 (s, 1H), 8.76 (d, J = 5.1Hz , 1H), 8.53 (dd, J = 8.7, 2.5Hz, 1H), 8.27 (s, 1H), 8.10 (d, J = 8.7Hz, 1H), 7.48 (d, J = 5.1Hz, 1H), 4.49 (q, J = 7.0Hz, 2H), 3.39- 3.25 (m, 1H), 2.55-2.42 (m, 1H), 2.42-2.27 (m, 1H), 1.40 (t, J = 7.0Hz, 3H), 1.25-0.88 (m, 7H).

The product Rt = 14.24mins was analyzed by HPLC using the counter IC3 method, and it was 100% ee at 254nm.

Take 2-chloro-heteroaromatic intermediates (1eq), sulfonamide (1.2eq) and base (2eq) in two Alkane (40 parts by volume). After the mixture was degassed (evacuated and refilled with N ₂ x 3), a catalyst (10 mol%) was added. The resulting mixture was heated under nitrogen at 90 ° C for 2 hrs. The mixture was cooled to RT and diluted with sat. NH ₄ Cl (aq., 80 parts by volume) and DCM (80 parts by volume). The phases were separated and the aqueous phase was extracted with DCM (2 x 80 parts by volume). The combined organic phases were dehydrated (MgSO _4), filtered, and concentrated in vacuo. The crude product is purified by normal phase chromatography or triturated with a suitable solvent.

1-Chloro- N, N , 2-trimethylprop-1-en-1-amine (2eq) was added to a DCM (20 vol) solution containing a carboxylic acid (1eq). The reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated in vacuo, the residue was redissolved in DCM (20 vol), and pyridine (2 mL) and the appropriate amine (1.1 eq) were added sequentially. The reaction mixture was stirred at RT for 2 hrs. The water phase operation is performed, and the crude product is purified by normal phase chromatography, reverse phase chromatography, or triturated with a suitable solvent.

Ar1-Br (1eq) To the alkane (10 vol) suspension was added a solution of aryl dihydroxyboronic acid or ester (1 eq) and K ₂ CO ₃ (2 eq) in water (5 vol). The resulting suspension was degassed (N ₂ , 5 mins). PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct or other appropriate catalyst (10 mol%) was added, and the reaction mixture was stirred at 80 ° C. for 2 hrs. The reaction mixture was then cooled to RT. The water phase operation is performed, and the crude product is purified by normal phase chromatography, reverse phase chromatography, or triturated with a suitable solvent.

Pyridine (10 eq) and T3P (50 wt% DMF solution, 2 eq) were sequentially added to a stirred solution of DMF (16 parts by volume) containing an amine (1.1 eq) and a carboxylic acid (1 eq). The resulting reaction was stirred at RT for 24 hrs. The crude reaction mixture was concentrated in vacuo, diluted with NH ₄ Cl (sat.aq), and extracted with DCM. The combined organic extracts were dehydrated (phase separator) and the solvent was removed. The crude product was purified by reverse or normal phase chromatography.

2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (5- (6- isopropyl-pyrazole -2-yl) pyridin-2-yl) -2-methylpropanamine P116

Take 2- (2- (cyclopropanesulfonamido) pyrimidin-4-yl) -2-methyl- N- (5- (6- (prop-1-en-2-yl) pyridine A solution of 2--2-yl) pyridin-2-yl) propanilamine P122 (77 mg, 0.161 mmol) in MeOH / DCM (4: 1,10 mL) was hydrogenated using a H-Cube flow hydrogenation device (10% Pd / C, 30x4mm , Full hydrogen, 25 ° C, 1mL / min). The crude product was purified by silica gel chromatography (12g column, 50-100% EtOAc / isohexane) yielded the 2- (2- (cyclopropane Sulfonic group) pyrimidin-4-yl) - N - (5- ( 6-isopropylpyridine 2-yl) pyridin-2-yl) -2-methylpropanamide (21 mg, 0.043 mmol, 27% yield) as a white solid. Rt 2.22 mins (HPLC, acidic); m / z 482 (M + H) ⁺ (ES ⁺ ); ¹ H NMR (500MHz, DMSO-d6) δ 11.23 (s, 1H), 10.15 (s, 1H), 9.10 (s, 1H), 9.03 (dd, J = 2.4,0.8Hz, 1H), 8.59 (d, J = 5.3Hz, 1H), 8.56 (s, 1H), 8.52 (dd, J = 8.8,2.5Hz, 1H), 8.21 (dd, J = 8.8, 0.8Hz, 1H), 7.19 (d, J = 5.3Hz, 1H), 3.23-3.10 (m, 2H), 1.61 (s, 6H), 1.32 (d, J = 6.9Hz, 6H), 1.04-0.97 (m, 2H), 0.80-0.72 (m, 2H).

Biological examples Biological Example 1-Human CTPS1 Enzyme Inhibition

The enzyme inhibitory activity of the compounds of the present invention against the target of interest was determined using the ADP-Glo ^™ Max assay (Promega, UK). The analysis of human CTPS1 was performed in 1x analysis buffer containing 50 mM Tris, 10 mM MgCl ₂ , and 0.01% Tween-20 (pH adjusted to 8.0). Finally, L-cysteine was added to the 1x analysis buffer just before use to a final concentration of 2 mM. Unless otherwise stated, all reagents are from Sigma-Aldrich. Human full-length active C-terminal FLAG-His ₈ -labeled CTPS1 (UniProtKB-P17812, CTPS [1-591] -GGDYKDDDDKGGHHHHHHHH) was obtained from Proteros biostructures GmbH.

Analysis process

3x human CTPS1 protein was prepared in 1x analysis buffer to the final manipulated protein concentration required for the reaction. 3x human CTPS1 protein with 2uL volume per well and 3x test compound with 2uL per well (compounds are in 1x analysis buffer, relative to the concentration response curve designed for the test compound, and the appropriate final 3x compound concentration is made) at 25 ° C Mix for 10 minutes. Then add 2 uL volume of premixed substrate (UltraPure ATP from ADP-Glo ^TM Max kit (0.31mM), GTP (0.034mM), UTP (0.48mM) and L-glutamine (0.186mM)) to each well. Enzyme reaction was started, and the mixture was stirred at a constant speed of 500 revolutions per minute (rpm) at 25 ° C under a sealed disk condition, and cultured for an appropriate time in the determined linear reaction period. After adding ADP-Glo ^TM Max reagent for 60 minutes (6 μL per well), add ADP-Glo ^TM Max developing reagent for 60 minutes (12 uL per well), and then detect the signal in a microplate reader (EnVision® Multilabel Reader, Perkin Elmer). . During the analysis, each time each reagent was added, the analysis disc was quickly and briefly centrifuged at 500 rpm for 30 seconds.

In all cases, the enzyme converts ATP to form ADP, and the ADP-Glo ^™ Max reagent then consumes any residual intrinsic ATP in the reaction system. The ADP-Glo ^TM Max detection reagent converts the ADP produced by the enzyme reaction back to ATP, and uses ATP and luciferin as the acceptor of the luciferase enzyme, and the light produced becomes detectable luminescence. The measured luminescence signal is directly proportional to the amount of ADP produced by the enzyme reaction, and when the signal is reduced due to compound treatment, it is confirmed that there is an enzyme inhibitory effect. The following equations were used to calculate the percentage inhibition for each compound concentration:

Then the percentage inhibition relative to compound concentration was plotted from the obtained concentration - response curves measured 50% inhibitory concentration (IC _50).

The data for all experimental compounds of formula (I) are shown below.

It has been found in this assay that all tested compounds of the invention have been shown to inhibit the CTPS1 enzyme. These compounds are therefore expected to be useful for inhibiting CTPS1. The compounds of the present invention are also expected to have utility as research tools, for example, for CTPS analysis.

Biological Example 2-RapidFire / MS-Based Enzyme Selective Assay Analysis of Selectivity of Human CTPS1 to CTPS2 by RapidFire / MS Analysis

The optimized RapidFire high-throughput mass spectrometry (RF / MS) analysis mode can be used to determine the enzyme inhibitory activity of the compounds of the present invention on the target isoforms of interest. RF / MS analysis for both human CTPS1 and CTPS2 was performed in an analysis buffer consisting of 50 mM HEPES (Merck), 20 mM MgCl ₂ , 5 mM KCl, 1 mM DTT, 0.01% Tween-20 (pH to 8.0). Human full-length active C-terminal FLAG-His-tagged CTPS1 (UniProtKB-P17812, CTPS [1-591] -GGDYKDDDDKGGHHHHHHHH) is available from Proteros biostructures GmbH. Human full-length active C-terminal FLAG-His-Avi labeled CTPS2 (UniProtKB-Q9NRF8, CTPS2 [1-586] -DYKDDDDKHHHHHGLNDIFEAQKIEWHE) is available from Harker Bio.

Analysis process

Human CTPS (1 or 2) proteins can be made to the final manipulated protein concentration required for the reaction in 1x analysis buffer. Acoustic (ECHO) transmission method was used to mix 2x CTPS (1 or 2) protein per well with 40nL of compound in a volume of 2uL per well and incubate at 25 ° C for 10 minutes. Add 2uL of 2x substrate in assay buffer to each well to start each isozyme reaction. For hCTPS1: ATP (0.3 mM), UTP (0.2 mM), GTP (0.07 mM) and L-glutamine (0.1 mM) were used. For hCTPS2: ATP (0.1 mM), UTP (0.04 mM), GTP (0.03 mM) and L-glutamine (0.1 mM) were used. Each mixture can be cultured at 25 ° C for an appropriate period of time in accordance with the reaction linearity determined for each isotype. Add 60uL volume of stop solution (1% aqueous formic acid containing ^{_{0.5uM 13 C 9 - 15 N 3}} -CTP), rapid assay plate heat sealed, centrifuged for 10 minutes at 4,000rpm. After centrifugation, the analysis disk was loaded into an Agilent RapidFire microfluidic solid-phase extraction system and coupled with an API4000 three-section quadrupole mass spectrometer (RF / MS) for analysis.

In all cases, this enzyme converts UTP to CTP. It can be optimized by multiple reaction monitoring of high specificity and sensitivity (MRM) MS method to detect enzyme reaction product by ¹³ C ₉ CTP and appropriate isotopically-labeled product of the standard - ¹⁵ N ₃ -CTP of consumption. For reading and data analysis of the product CTP internal standard ¹³ C ₉ may be calculated - the ratio between the peak ¹⁵ N ₃ -CTP area. Data are reported using the following equations:

(R = ratio / reading, P = product signal area, IS = internal standard signal area)

The average value of the negative control group (DMSO) and the positive control group was used in each screening analysis plate to calculate the analysis window (S / B) and Z 'value. The median of each control group was used to calculate the percent inhibition according to the following equation:

(I = inhibitory, R _neg = median reading of negative control group, R _pos = median reading of negative control group, R _sample = sample reading value)

Compound concentration was then plotted by the relative percent inhibition by the resulting concentration - response curve determined 50% inhibitory concentration (IC _50).

The selectivity multiple between CTPS1 and CTPS2 is then calculated according to the following equation:

Certain compounds of formula (I) were tested in the analysis described above. The data for all test compounds are shown below.

All test compounds in the assay illustrated in Biological Example 2 have been found to be at least 2 times more selective for CTPS1 than CTPS2, and many compounds are more than 60 times more selective for CTPS1.

In particular, these compounds are expected to be useful in the treatment of diseases that may benefit from selective CTPS1 compounds.

Throughout this specification and the scope of the following patent applications, unless otherwise stated, the terms "including" and variations such as "include" and "include" mean that the meaning includes the stated integer, step, group of integers, or steps Group, but does not exclude any other integer, step, group of integers, or group of steps.

The application of this specification and the scope of patent application can form part of the priority basis for any subsequent application. The scope of patent application for these subsequent applications may relate to any feature or combination of features described herein. These may be in the form of products, compositions, processes, or use claims, and may include, for example, but not limited to, the following claims.

All publications excerpted from this specification, including (but not limited to) patent cases and patent applications, are incorporated herein by reference, and to the same extent as if it had been explicitly and individually indicated that the full text of each publication is cited The way is incorporated in general.

Projects of the invention:

Item 1. A compound of formula (I): Wherein A is an amidine linking group having the following structural formula: -C (= O) NH- or -NHC (= O)-; X is N or CH; Y is N or CR ₂ ; Z is N or CR ₃ ; But its limitation is that when at least one of X or Z is N, Y cannot be N; R ₁ is C _1-5 alkyl, C _0-2 alkyl, C _3-5 cycloalkyl (the cycloalkane (Optionally substituted with CH ₃ ), or CF ₃ ; R ₂ is H, halo, C _1-2 alkyl, OC _1-2 alkyl, C _1-2 haloalkyl, or OC _1-2 haloalkane R ₃ is H, halo, CH ₃ , OCH ₃ , CF ₃ , or OCF ₃ ; wherein at least one of R ₂ and R ₃ is H; R ₄ and R ₅ are independently H and C _1-6 alkane Alkyl, C _1-6 alkyl OH, C _1-6 haloalkyl, C _0-2 alkylalkyl C _3-6 cycloalkyl, C _0-2 alkyl alkyl C _3-6 heterocycloalkyl, C _1-3 alkylene OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; and when A is -NHC (= O)-: R ₄ and R ₅ may be additionally selected from: halo, OC _1-6 haloalkyl, OC _0-2 alkyl, C _3-6 cycloalkyl, OC _0-2 Alkyl C _3-6 heterocycloalkyl, OC _1-6 alkyl, and NR ₂₁ R ₂₂ ; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached Connect Ar1 to Amine was para; R ₁₀ is H, halo, C _1-3 alkyl, C _1-2 haloalkyl, OC _1-2 alkyl, OC _1-2 haloalkyl, or CN; R ₁₁ is H , F, Cl, C _1-2 alkyl, CF ₃ , OCH ₃ , or CN; R ₁₂ is attached to Ar2 in ortho or meta position relative to Ar1, and R ₁₂ is H, halo, C _{1- 4} alkyl, C _2-4 alkenyl, C _0-2 alkyl, C _3-5 cycloalkyl, OC _1-4 alkyl, OC _0-2 alkyl, C _3-5 cycloalkyl, C _{1 -4} haloalkyl, OC _1-4 haloalkyl, hydroxy, C _1-4 alkylOH, SO ₂ C _1-2 alkyl, C (O) N (C _1-2 alkyl) ₂ , NHC ( O) C _1-3 alkyl, or NR ₂₃ R ₂₄ ; and when A is -NHC (= O)-: R ₁₂ may be additionally selected from: CN, OCH ₂ CH ₂ N (CH ₃ ) ₂ and C _{3 -6} heterocycloalkyl (which is the point of attachment position of Ar2 comprises one nitrogen), or R ₁₂ is attached thereto together form N- oxides of nitrogen ^{(N + -O -); R} 13 is H or halogen R ₂₁ is H, C _1-5 alkyl, C (O) C _1-5 alkyl, C (O) OC _1-5 alkyl; R ₂₂ is H or CH ₃ ; R ₂₃ is H or C _1-2 alkyl; and R ₂₄ is H or C _1-2 alkyl; or a salt and / or a solvate and / or a derivative thereof.

Item 2. The compound according to item 1, which is a compound of the formula: Wherein R ₁ is a C _1-5 alkyl group or a C _0-2 alkylene group C _3-5 cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ ; R ₃ is H, a halogen group, or CH ₃ ; R ₄ And R ₅ are independently H, halo, C _1-6 alkyl, C _1-3 alkyl OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form C _{3 -6} cycloalkyl or C _3-6 heterocycloalkyl; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 opposite to amidine Position; R ₁₀ is H, halo, C _1-2 alkyl, OC _1-2 alkyl, OC _1-2 haloalkyl, or CN; R ₁₁ is H, F, CH ₃ , or OCH ₃ ; and R ₁₂ is attached to Ar2 in an ortho or meta position relative to Ar1, and R ₁₂ is H, halo, C _1-4 alkyl, OC _1-4 alkyl, OC _0-2 alkylene C _{3- 5} -cycloalkyl, CN, C _1-4 haloalkyl, OC _1-4 haloalkyl; or a salt and / or a solvate and / or a derivative thereof.

Item 3. Compounds of formula (I) according to item 1: Wherein R ₁ is a C _1-5 alkyl group or a C _0-2 alkylene group C _3-5 cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ ; R ₃ is H, a halogen group, or CH ₃ ; R ₄ And R ₅ are independently H, C _1-6 alkyl, C _1-3 alkyl OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form a C _3-6 ring Alkyl; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 in a para position relative to amidine; R ₁₀ is H, halo, C _{1 -2} alkyl, OC _1-2 alkyl, OC _1-2 haloalkyl, or CN; R ₁₁ is H, F, CH ₃ , or OCH ₃ ; and R ₁₂ is attached to Ar2 in an ortho position relative to Ar1 Or meta, and R ₁₂ is H, halo, C _1-4 alkyl, OC _1-4 alkyl, OC _0-2 alkyl, C _3-5 cycloalkyl, CN, C _1-4 haloalkane Radical, OC _1-4 haloalkyl; or a salt and / or a solvate and / or a derivative thereof.

Item 4. Compounds of formula (I) according to item 1: Wherein A is an amidine chain having the following structural formula: -C (= O) NH- or -NHC (= O)-; X is N or CH; Y is N or CR ₂ ; Z is N or CR ₃ ; But its limitation is that when at least one of X or Z is N, Y cannot be N; R ₁ is C _1-5 alkyl or C _0-2 alkylene C _3-5 cycloalkyl, the cycloalkane The group may be optionally substituted by CH ₃ ; R ₂ is H, C _1-2 alkyl or C _1-2 haloalkyl; R ₃ is H, halo or CH ₃ ; wherein at least one of R ₂ and R ₃ is H ; R ₄ and R ₅ are independently H, C _1-6 alkyl or C _1-3 alkyl OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom attached to form C _{3 -6} cycloalkyl or C _3-6 heterocycloalkyl; and when A is -NHC (= O)-: R ₄ and R ₅ may be additionally selected from: halo and OC _1-6 alkyl; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached to Ar1 in a para position relative to amidine; R ₁₀ is H, halogen, C _1-3 alkyl, C _1-2 haloalkyl, OC _1-2 alkyl, OC _1-2 haloalkyl, or CN; R ₁₁ is H, F, CH ₃ , or OCH ₃ ; R ₁₂ is attached to Ar2 relative to Ar1 Ortho or meta, and R ₁₂ is H, halo, C _1-4 alkyl, OC _1-4 alkyl, C _1-4 haloalkyl, OC _1-4 haloalkyl, C _0-2 alkylene C _3-5 cycloalkyl, OC _0-2 alkylene C _3-5 cycloalkyl, CN, or C _2-4 alkenyl; and R ₁₃ is H; or a salt thereof and / Or solvates and / or derivatives thereof.

Item 5. The compound according to item 1 or 4, wherein A is -C (= O) NH-.

Item 6. The compound according to item 1 or 4, wherein A is -NHC (= O)-.

Item 7. The compound according to any one of items 1 or 4 to 6, wherein X is N.

Item 8. A compound according to any one of items 1 or 4 to 6, wherein X is CH.

Item 9. The compound according to any one of items 1, 4 to 6 or 8, wherein Y is N.

Item 10. The compound according to any one of items 1 or 4 to 8, wherein Y is CR ₂ .

Item 11. A compound according to any one of items 1, 4 to 8 or 10, wherein Z is N.

Item 12. The compound according to any one of items 1 or 4 to 10, wherein Z is CR ₃ .

Item 13. The compound according to any one of items 1 or 4 to 12, wherein X is N, Y is CR ₂ , and Z is N.

Item 14. The compound according to any one of items 1 or 4 to 12, wherein X is N, Y is CR ₂ , and Z is CR ₃ .

Item 15. The compound according to any one of items 1 or 4 to 12, wherein X is CH, Y is N, and Z is CR ₃ .

Item 16. The compound according to any one of items 1 or 4 to 12, wherein X is CH, Y is CR ₂ , and Z is CR ₃ .

Item 17. The compound according to any one of items 1 or 4 to 12, wherein X is CH, Y is CR ₂ , and Z is N.

Item 18. The compound according to any one of items 1 to 17, wherein R ₁ is C _1-5 alkyl.

Item 19. The compound according to any one of items 1 to 17, wherein R ₁ is a C _0-2 alkylene C _3-5 cycloalkyl group, and the cycloalkyl group may be optionally substituted with CH ₃ .

Item 20. The compound according to item 19, wherein R ₁ is C _0-2 alkylene C _3-5 cycloalkyl.

Item 21. The compound according to item 19, wherein R ₁ is C _0-2 alkylene C _3-5 cycloalkyl, and the cycloalkyl is substituted with CH ₃ .

Item 22. The compound according to any one of items 19 to 21, wherein R ₁ is a C _3-5 cycloalkyl group _optionally substituted with CH ₃ .

Item 23. The compound according to any one of items 19 to 21, wherein R ₁ is a C ₁ alkylene C _3-5 cycloalkyl group optionally substituted with CH ₃ .

Item 24. The compound according to any one of items 19 to 21, wherein R ₁ is a C ₂ alkylene C _3-5 cycloalkyl group optionally substituted with CH ₃ .

Item 25. The compound according to any one of items 1 to 24, wherein R ₁ is cyclopropyl, cyclopropyl substituted with CH ₃ at the point of attachment, cyclobutyl, methyl or ethyl.

Item 26. The compound according to item 25, wherein R ₁ is cyclopropyl, methyl or ethyl.

Item 27. The compound according to item 26, wherein R ₁ is cyclopropyl.

Item 28. The compound according to any one of items 1 to 17, wherein R ₁ is CF ₃ .

Item 29. The compound according to any one of items 1 to 28, wherein R ₂ is H.

Item 30. The compound according to any one of items 1 to 28, wherein R ₂ is a halogen group, such as: F, Cl, or Br, such as: Cl or Br.

Item 31. The compound according to any one of items 1 to 28, wherein R ₂ is C _1-2 alkyl, such as: CH ₃ .

Item 32. The compound according to any one of items 1 to 28, wherein R ₂ is OC _1-2 alkyl, such as: OCH ₃ .

Item 33. The compound according to any one of items 1 to 28, wherein R ₂ is a C _1-2 haloalkyl group, such as: CF ₃ .

Item 34. The compound according to any one of items 1 to 28, wherein R ₂ is OC _1-2 haloalkyl, such as OCF ₃ .

Item 35. The compound according to any one of items 1 to 34, wherein R ₃ is H.

Item 36. The compound according to any one of items 1 to 34, wherein R ₃ is a halogen group.

Item 37. The compound according to item 36, wherein R ₃ is fluorine.

Item 38. The compound according to any one of items 1 to 34, wherein R ₃ is CH ₃ .

Item 39. The compound according to any one of items 1 to 34, wherein R ₃ is OCH ₃ .

Item 40. The compound according to any one of items 1 to 34, wherein R ₃ is CF ₃ .

Item 41. The compound according to any one of items 1 to 34, wherein R ₃ is OCF ₃ .

Item 42. The compound according to any one of items 1 to 41, wherein at least one of R ₂ and R ₃ is H.

Item 43. The compound according to any one of items 1 to 42, wherein R ₄ is H.

Item 44. The compound according to any one of items 1 to 42, wherein R ₄ is C _1-6 alkyl.

Item 45. The compound according to item 44, wherein R ₄ is methyl or ethyl.

Item 46. The compound according to any one of items 1 to 42, wherein R ₄ is C _1-6 alkylOH.

Item 47. The compound according to any one of items 1 to 42, wherein R ₄ is a C _1-6 haloalkyl group, such as: CF ₃ .

Item 48. The compound according to any one of items 1 to 42, wherein R ₄ is C _0-2 alkylene C _3-6 cycloalkyl.

Item 49. The compound according to any one of items 1 to 42, wherein R ₄ is C _0-2 alkylene C _3-6 heterocycloalkyl.

Item 50. The compound according to any one of items 1 to 42, wherein R ₄ is C _1-3 alkylene OC _1-3 alkyl.

Item 51. The compound according to item 50, wherein R ₄ is C ₂ alkylene OC _1-3 alkyl.

Item 52. The compound according to item 51, wherein R ₄ is CH ₂ CH ₂ OCH ₃ .

Item 53. The compound according to any one of items 1 to 42, wherein R ₄ is a halogen group.

Item 54. The compound according to item 53, wherein R ₄ is fluorine.

Item 55. The compound according to any one of items 1 or 6 to 42, wherein R ₄ is OC _1-6 haloalkyl, such as: OC _1-4 haloalkyl.

Item 56. The compound according to any one of items 1 or 6 to 42, wherein R ₄ is OC _0-2 alkylene C _3-6 cycloalkyl.

Item 57. The compound according to any one of items 1 or 6 to 42, wherein R ₄ is OC _0-2 alkylene C _3-6 heterocycloalkyl.

Item 58. The compound according to any one of items 1, 4 or 6 to 42, wherein R ₄ is OC _1-6 alkyl, in particular OC _1-4 alkyl.

Item 59. The compound according to any one of items 1 or 6 to 42, wherein R ₄ is NR ₂₁ R ₂₂ .

Item 60. The compound according to item 59, wherein R ₂₁ is H, CH ₃ , C (O) CH ₃ , C (O) OCH ₃ or C (O) O third butyl.

Item 61. The compound according to item 59, wherein R ₂₂ is H or CH ₃ , such as H.

Item 62. The compound according to any one of items 59 to 61, wherein R ₂₁ is C (O) OCH ₃ and R ₂₂ is H, R ₂₁ is C (O) CH ₃ and R ₂₂ is H, and R ₂₁ and R _{22 is} both CH ₃ , or both R ₂₁ and R ₂₂ are H.

Item 63. The compound according to any one of items 1 to 42, wherein R ₄ is H, C _1-6 alkyl, C _1-6 alkylOH, C _1-6 haloalkyl, C _0-2 butane C _3-6 cycloalkyl, C _0-2 alkyl, C _3-6 heterocycloalkyl, C _1-3 alkyl, OC _1-3 alkyl, or R ₄ and R ₅ with their attached The carbon atoms together form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl.

Item 64. The compound according to any one of items 1 to 42, wherein R ₄ is halo, OC _1-6 haloalkyl, OC _0-2 alkyl, C _3-6 cycloalkyl, OC _0-2 Alkyl C _3-6 heterocycloalkyl, OC _1-6 alkyl, or NR ₂₁ R ₂₂ .

Item 65. The compound according to any one of items 1 to 64, wherein R ₅ is H.

Item 66. The compound according to any one of items 1 to 64, wherein R ₅ is C _1-6 alkyl.

Item 67. The compound according to item 66, wherein R ₅ is methyl or ethyl.

Item 68. The compound according to any one of items 1 to 64, wherein R ₅ is C _1-6 alkylOH.

Item 69. The compound according to any one of items 1 to 64, wherein R ₅ is C _1-6 haloalkyl, such as: CF ₃ .

Item 70. The compound according to any one of items 1 to 64, wherein R ₅ is C _0-2 alkylene C _3-6 cycloalkyl.

Item 71. The compound according to any one of items 1 to 64, wherein R ₅ is C _0-2 alkylene C _3-6 heterocycloalkyl.

Item 72. The compound according to any one of items 1 to 64, wherein R ₅ is C _1-3 alkylene OC _1-3 alkyl, such as: C ₂ alkylene OC _1-3 alkyl, for example: CH ₂ CH ₂ OCH ₃ .

Item 73. The compound according to any one of items 1 to 64, wherein R ₅ is halo.

Item 74. The compound according to item 73, wherein R ₅ is fluorine.

Item 75. The compound according to any one of items 1 or 6 to 64, wherein R ₅ is OC _1-6 haloalkyl, such as: OC _1-4 haloalkyl.

Item 76. The compound according to any one of items 1 or 6 to 64, wherein R ₅ is OC _0-2 alkylene C _3-6 cycloalkyl.

Item 77. The compound according to any one of items 1 or 6 to 64, wherein R ₅ is OC _0-2 alkylene C _3-6 heterocycloalkyl.

Item 78. A compound according to any one of items 1, 4 or 6 to 64, wherein R ₅ is OC _1-6 alkyl, in particular OC _1-4 alkyl.

Item 79. The compound according to any one of items 1 or 6 to 64, wherein R ₅ is NR ₂₁ R ₂₂ .

Item 80. The compound according to item 79, wherein R ₂₁ is H, CH ₃ , C (O) CH ₃ , C (O) OCH ₃ or C (O) O third butyl.

Item 81. The compound according to item 79, wherein R ₂₂ is H or CH ₃ , such as H.

Item 82. The compound according to any one of items 79 to 81, wherein R ₂₁ is C (O) OCH ₃ and R ₂₂ is H, R ₂₁ is C (O) CH ₃ and R ₂₂ is H, and R ₂₁ and R _{22 is} both CH ₃ , or both R ₂₁ and R ₂₂ are H.

Item 83. The compound according to any one of items 1 to 64, wherein R ₅ is H, C _1-6 alkyl, C _1-6 alkylOH, C _1-6 haloalkyl, C _0-2 butane C _3-6 cycloalkyl, C _0-2 alkyl, C _3-6 heterocycloalkyl, C _1-3 alkyl, OC _1-3 alkyl, or R ₄ and R ₅ with their attached The carbon atoms together form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl.

Item 84. The compound according to any one of items 1 to 64, wherein R ₅ is halo, OC _1-6 haloalkyl, OC _0-2 alkyl, C _3-6 cycloalkyl, OC _0-2 Alkyl C _3-6 heterocycloalkyl, OC _1-6 alkyl, or NR ₂₁ R ₂₂ .

Item 85. The compound according to any one of items 1 to 84, wherein R ₄ and R ₅ are both H.

Item 86. The compound according to any one of items 1 to 84, wherein R ₄ and R ₅ are both methyl.

Item 87. The compound according to any one of items 1 to 84, wherein R ₄ and R ₅ are both ethyl.

Item 88. The compound according to any one of items 1 to 84, wherein R ₄ and R ₅ are both fluorine.

Item 89. The compound according to any one of items 1 to 84, wherein R ₄ is ethyl, and R ₅ is H.

Item 90. The compound according to any one of items 1 to 84, wherein R ₄ is fluorine, and R ₅ is ethyl.

Item 91. The compound according to any one of items 1 to 84, wherein R ₄ is CH ₂ CH ₂ OCH ₃ , and R ₅ is H.

Item 92. The compound according to any one of items 89 to 91, wherein R ₄ and R ₅ are arranged in an S configuration.

Item 93. The compound according to any one of items 1 to 42, wherein R ₄ and R _{5 together} with the carbon atom to which they are attached form a C _3-6 cycloalkyl group.

Item 94. The compound according to item 93, wherein R ₄ and R _{5 together} with the carbon atom to which they are attached form a cyclopropyl ring or a cyclopentyl ring, such as a cyclopentyl ring.

Item 95. The compound according to any one of items 1 to 42, wherein R ₄ and R ₅ is attached thereto, etc. of carbon atoms together form a C ₃ - ₆ heterocycloalkyl, such as: Heterocyclic hexyl group, such as: tetrahydropyran Piran.

Item 96. The compound according to any one of items 1 to 95, wherein Ar1 is phenyl.

Item 97. The compound according to any one of items 1 to 95, wherein Ar1 is 2-pyridyl.

Item 98. The compound according to any one of items 1 to 95, wherein Ar1 is 3-pyridyl.

Item 99. The compound according to any one of items 1 to 98, wherein Ar2 is 3-pyridyl.

Item 100. The compound according to any one of items 1 to 98, wherein Ar2 is 2,5-pyridine base.

Item 101. The compound according to any one of items 1 to 100, wherein R ₁₀ is H.

Item 102. The compound according to any one of items 1 to 100, wherein R ₁₀ is a halogen group, such as fluorine or chlorine.

Item 103. The compound according to any one of items 1 to 100, wherein R ₁₀ is C _1-3 alkyl.

Item 104. The compound according to item 103, wherein R ₁₀ is C _1-2 alkyl, such as: CH ₃ .

Item 105. The compound according to any one of items 1 to 100, wherein R ₁₀ is a C _1-2 haloalkyl group, such as: CF ₃ .

Item 106. The compound according to any one of items 1 to 100, wherein R ₁₀ is OC _1-2 alkyl, such as: OCH ₃ .

Item 107. The compound according to any one of items 1 to 100, wherein R ₁₀ is OC _1-2 haloalkyl, such as: OCF ₃ .

Item 108. The compound according to any one of items 1 to 100, wherein R ₁₀ is CN.

Item 109. The compound according to any one of items 1 to 108, wherein R ₁₁ is H.

Item 110. The compound according to any one of items 1 to 108, wherein R ₁₁ is F.

Item 111. The compound according to any one of items 1 to 108, wherein R ₁₁ is Cl.

Item 112. The compound according to any one of items 1 to 108, wherein R ₁₁ is C _1-2 alkyl.

Item 113. The compound according to item 112, wherein R ₁₁ is CH ₃ .

Item 114. A compound according to any one of items 1 to 108, wherein R ₁₁ is CF ₃ .

Item 115. The compound according to any one of items 1 to 108, wherein R ₁₁ is OCH ₃ .

Item 116. The compound according to any one of items 1 to 108, wherein R ₁₁ is CN.

Item 117. The compound according to any one of items 1 to 116, wherein R ₁₂ is H.

Item 118. The compound according to any one of items 1 to 116, wherein R ₁₂ is a halogen group, such as fluorine or chlorine.

Item 119. The compound according to any one of items 1 to 116, wherein R ₁₂ is C _1-4 alkyl, such as: CH ₃ .

Item 120. The compound according to any one of items 1 to 116, wherein R ₁₂ is C _2-4 alkenyl.

Item 121. The compound according to any one of items 1 to 116, wherein R ₁₂ is C _0-2 alkylalkyl C _3-5 cycloalkyl, such as: C ₀ alkyl alkyl C ₃ cycloalkyl.

Item 122. The compound according to any one of items 1 to 116, wherein R ₁₂ is OC _1-4 alkyl, such as: methoxy, ethoxy, or isopropoxy.

Item 123. The compound according to any one of items 1 to 116, wherein R ₁₂ is OC _0-2 alkylalkyl C _3-5 cycloalkyl, such as: OC ₀ alkyl alkyl C ₃ cycloalkyl.

Item 124. The compound according to any one of items 1 to 116, wherein R ₁₂ is a C _1-4 haloalkyl group, such as: CF ₃ .

Item 125. The compound according to any one of items 1 to 116, wherein R ₁₂ is OC _1-4 haloalkyl, such as: OCH ₂ CF ₃ or OCHF ₂ .

Item 126. The compound according to any one of items 1 to 116, wherein R ₁₂ is OH.

Item 127. The compound according to any one of items 1 to 116, wherein R ₁₂ is C _1-4 alkylOH.

Item 128. The compound according to any one of items 1 to 116, wherein R ₁₂ is SO ₂ C _1-2 alkyl.

Item 129. The compound according to any one of items 1 to 116, wherein R ₁₂ is NHC (O) C _1-3 alkyl.

Item 130. The compound according to any one of items 1 to 116, wherein R ₁₂ is NR ₂₃ R ₂₄ .

Item 131. The compound according to item 130, wherein R ₂₃ is H or C _1-2 alkyl, such as: H or CH ₃ .

Item 132. A compound according to item 130 or 131, wherein R ₂₄ is H or C _1-2 alkyl, such as: CH ₃ or ethyl.

Item 133. The compound according to any one of items 130 to 132, wherein R ₂₃ is H and R ₂₄ is ethyl; or R ₂₃ is CH ₃ and R ₂₄ is CH ₃ .

Item 134. The compound according to any one of items 1, 4 or 6 to 116, wherein R ₁₂ is CN.

Item 135. The compound according to any one of items 1 or 6 to 116, wherein R ₁₂ is OCH ₂ CH ₂ N (CH ₃ ) ₂ .

Item 136. The compound according to any one of items 1 or 6 to 116, wherein R ₁₂ is a C _3-6 heterocycloalkyl group which contains a nitrogen at the position of the attachment point to Ar ₂ .

Item 137. The compound according to any one of items 1 to 6 or 16, wherein R ₁₂ is attached thereto together form N- oxides of nitrogen (N ⁺ -O ^-).

Item 138. The compound according to any one of items 1 to 116, wherein R ₁₂ is C (O) N (C _1-2 alkyl) ₂ .

Item 139. The compound according to any one of items 1 to 138, wherein R ₁₃ is H.

Item 140. The compound according to any one of items 1 to 138, wherein R ₁₃ is a halogen group, such as: fluorine or chlorine, for example: fluorine.

Item 141. The compound according to any one of items 1 to 140, when R ₁ is methyl, at least one of R ₄ , R ₅ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ is not H.

Item 142. The compound according to any one of items 1 to 141, wherein at least one of any C _3-6 heterocycloalkyl ring (eg, only one C _3-6 heterocycloalkyl ring) (eg, only A) The nitrogen atom is substituted, for example: via C _1-4 alkyl, C (O) H, C (O) C _1-4 alkyl, C (O) OC _1-4 alkyl, C (O) OC _1-4 alkylaryl (such as: C (O) OBz), C (O) NHC _1-4 alkyl, C (O) NHC _1-4 alkylaryl (such as: C (O) NHBz) , Fmoc group, C (O) C _1-4 haloalkyl, C (O) OC _1-4 haloalkyl or C (O) NHC _1-4 haloalkyl, such as: C (O) OtBu.

Item 143. The compound according to any one of items 1 to 141, wherein all nitrogen atoms of all C _3-6 heterocycloalkyl rings are unsubstituted.

Item 144. The compound according to any one of items 1 to 143, wherein at least one of any C _3-6 heterocycloalkyl ring (eg, only one C _3-6 heterocycloalkyl ring) (eg, only A) The nitrogen atom is substituted, for example: substituted with one oxygen atom to form S = O, or substituted with two oxygen atoms to form S (O) ₂ .

Item 145. The compound according to any one of items 1 to 143, wherein all sulfur atoms of all C _3-6 heterocycloalkyl rings are unsubstituted.

Item 146. Compounds as in Examples P1 to P111.

Item 147. Compounds as in Examples P112 to P115.

Item 148. Compounds as in Examples P116 to P225.

Item 149. A compound of formula (II) : Wherein R ₁ , R ₃ , R ₄ and R ₅ are as defined in any of the foregoing items, and R is H, C _1-6 alkyl (for example, methyl and ethyl) or benzyl, or Salt, such as its pharmaceutically acceptable salt.

Item 150. A compound of formula (III) : Wherein Ar1, Ar2, R ₁₀ , R ₁₁ and R ₁₂ are as defined in any of the foregoing items, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 151. A compound of formula (XX) : Wherein _{Ar1, Ar2, R 1, R} 3, R 4, R 5, R 10, R 11 and R ₁₂ lines preceding items defined in any of, and P is a nitrogen protecting group (such as: p-methoxybenzyl Methyl), or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 152. A compound of formula (XXIV) : Wherein _{Ar1, Ar2, R 1, R} 3, R 4, R 5, R 10, R 11 and R ₁₂ lines preceding items defined in any of, and P is a nitrogen protecting group (such as: p-methoxybenzyl Methyl), or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 153. A compound of formula (II) : Where R ₁ , X, Y, Z, R ₄ and R ₅ are as defined in any of the preceding items, and R is H, C _1-6 alkyl (for example: methyl and ethyl) or benzyl , Or a salt thereof, such as: a pharmaceutically acceptable salt thereof.

Item 154. A compound of formula (III) : Wherein R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined in any one of the foregoing items, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 155. A compound of formula (XX) : Wherein _{Ar1, Ar2, R 1, X} , Y, Z, R 4, R 5, R 10, R 11, R 12 and R ₁₃ lines preceding items defined in any of, and P is a nitrogen protecting group (e.g. : P-methoxybenzyl), or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 156. A compound of formula (XXIV) : Wherein _{Ar1, Ar2, R 1, X} , Y, Z, R 4, R 5, R 10, R 11, R 12 and R ₁₃ lines preceding items defined in any of, and P is a nitrogen protecting group (e.g. : P-methoxybenzyl), or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 157. A compound of formula (XXXI) : Wherein Ar1, Ar2, X, Y, Z, R ₄ , R ₅ , R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined in any of the foregoing items, or a salt thereof, such as: pharmaceutically acceptable Of salt.

Item 158. A compound of formula (XXXXII) : Wherein R ₁ , X, Y, Z, R ₄ and R ₅ are as defined in any one of the foregoing items, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 159. A compound of formula (XXXXIII) : Wherein Ar1, Ar2, R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined in any one of the foregoing items, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 160. A compound of formula (LI) : Wherein Ar1, Ar2, R ₄ and R ₅ are as defined in any of the foregoing items, and X is Cl or Br, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 161. A compound of formula (LVIII) : Wherein R ₁ , Ar1, X, Y, Z, R ₄ and R ₅ are as defined in any one of the foregoing items, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 162. A compound of INTC1 to INTC177, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 163. A compound of INTD1 to INTD86, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

Item 164. The compound according to any one of items 1 to 161, wherein each heterocycloalkyl group is a fully saturated hydrocarbon ring containing a specified number of carbon atoms, and may include a carbon atom attached to a cycloalkyl group, wherein at least one of the rings The carbon atom is replaced by a heteroatom (eg, N, S, or O).

Item 165. The compound according to any one of items 1 to 148 or 164, which is used as a medicine.

Item 166. The compound according to item 165, which is used to inhibit CTPS1 for an individual.

Item 167. The compound according to item 165, which is used to reduce T-cell and / or B-cell proliferation for an individual.

Item 168. The compound according to item 165 for the treatment or prevention of: inflammatory skin diseases such as: psoriasis or lichen planus; acute and / or chronic GVHD, such as: steroid-resistant acute GVHD; acute lymphoblastic syndrome (ALPS); systemic lupus erythematosus, lupus nephritis, or cutaneous lupus; or transplantation.

Item 169. A compound according to item 165 for use in the treatment or prevention of myasthenia gravis, multiple sclerosis, and scleroderma / systemic sclerosis.

Item 170. A method for inhibiting CTPS1 in an individual, comprising administering to the individual an effective amount of a compound according to any one of items 1 to 148 or 164.

Item 171. Use of a compound according to any one of items 1 to 148 or 164 for use in the manufacture of a medicament for the inhibition of CTPS1 in an individual.

Item 172. The compound according to item 165, which is used to treat cancer.

Item 173. A method of treating cancer in an individual by administering a compound according to any one of items 1 to 148 or 164 to an individual in need thereof.

Item 174. The use of a compound according to any one of items 1 to 148 or 164 for the manufacture of a medicament for the treatment of cancer in an individual.

Item 175. The compound according to item 172, the method according to item 173, or the use according to item 174, wherein the cancer is a blood cancer.

Item 176. The compound, method or use according to item 175, wherein the blood cancer is selected from the group consisting of: acute myeloid leukemia, vascular immunoblast T-cell lymphoma, B-cell acute lymphoblastic Leukemia, Sweet syndrome, T-cell Non-Hodgkins lymphoma (including natural killer / T-cell lymphoma, adult T-cell leukemia / lymphoma, bowel disease type T -Cell lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma (including Burkitt lymphoma , Diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), hairy cell leukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphoid plasma cells Lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, myelodysplastic syndrome, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (such as chronic myeloid leukemia, original Myelofibrosis, polycythemia present state of platelets, red blood cells true multi disease) and chronic lymphocytic leukemia.

Item 177. The compound according to item 172, the method according to item 173, or the use according to item 174, wherein the cancer is a non-blood cancer such as: bladder cancer, breast cancer, melanoma, neuroblastoma, malignant costal mesothelioma , And sarcomas, such as: breast cancer and melanoma.

Item 178. The compound according to item 165, which is used to promote recovery from vascular injury or surgery for an individual, and to reduce the morbidity and mortality associated with neointimal and postoperative restenosis.

Item 179. A method for promoting recovery from vascular injury or surgery for individuals and reducing the morbidity and mortality associated with neointimal and postoperative restenosis, which is administered to individuals in need according to items 1 to A compound of any one of 148 or 164.

Item 180. Use of a compound according to any one of items 1 to 148 or 164 for use in the manufacture of medicine for the individual to promote recovery from vascular injury or surgery, and to reduce neointimal and postoperative restenosis Relevant morbidity and mortality.

Item 181. A pharmaceutical composition comprising a compound according to any one of items 1 to 148 or 164.

Item 182. The compound, method or use according to any one of items 165 to 180, which is administered to a human individual.

Item 183. The compound, method, use or composition according to any one of items 165 to 182, which is administered in combination with other pharmaceutically acceptable active ingredients or ingredient groups.

Item 184. The compound, method, use or composition according to any one of items 165 to 183, which is administered topically to the skin, eyes, or intestines.

Item 185. The compound according to any one of items 1 to 148 or 164, which is a natural isotope type.

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Fairbanks, LD et al. Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. Disproportionate expansion of pyrimidine pools and contrasting effects of de novo synthesis inhibitors. J. Biol. Chem. 270, 29682-29689 (1995).

Higgins, MJ et al. Regulation of human cytidine triphosphate synthetase 1 by glycogen synthase kinase 3. J. Biol. Chem. 282, 29493-29503 (2007).

Kursula, P. et al. Structure of the synthetase domain of human CTP synthetase, a target for anticancer therapy. Acta Crystallogr Sect F Struct Biol Cryst Commun. 62 (Pt7): 613-617 (2006).

Lieberman I. Enzymatic amination of uridine triphosphate to cytidine triphosphate. The J. Biol. Chem. 222 (2): 765-75 (1956).

Martin E. et al. CTP synthase 1 deficiency in humans reveals its central role in lymphocytes proliferation. Nature. Jun 12; 510 (7504): 288-92 (2014). Erratum in: Nature. Jul 17; 511 (7509): 370 (2014).

McCluskey GD et al., Exploring the Potent Inhibition of CTP Synthase by Gemcitabine-5 ' -Triphosphate. Chembiochem. 17, 2240-2249 (2016).

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Claims (33)

A compound of formula (I): Wherein A is an amidine linking group having the following structural formula: -C (= O) NH- or -NHC (= O)-; X is N or CH; Y is N or CR ₂ ; Z is N or CR ₃ ; But its limitation is that when at least one of X or Z is N, Y cannot be N; R ₁ is C _1-5 alkyl, C _0-2 alkyl, C _3-5 cycloalkyl (the cycloalkane (Optionally substituted with CH ₃ ), or CF ₃ ; R ₂ is H, halo, C _1-2 alkyl, OC _1-2 alkyl, C _1-2 haloalkyl, or OC _1-2 haloalkane R ₃ is H, halo, CH ₃ , OCH ₃ , CF ₃ , or OCF ₃ ; wherein at least one of R ₂ and R ₃ is H; R ₄ and R ₅ are independently H and C _1-6 alkane Alkyl, C _1-6 alkyl OH, C _1-6 haloalkyl, C _0-2 alkylalkyl C _3-6 cycloalkyl, C _0-2 alkyl alkyl C _3-6 heterocycloalkyl, C _1-3 alkylene OC _1-3 alkyl, or R ₄ and R _{5 together} with the carbon atom to which they are attached form a C _3-6 cycloalkyl or C _3-6 heterocycloalkyl; and when A is -NHC (= O)-: R ₄ and R ₅ may be additionally selected from: halo, OC _1-6 haloalkyl, OC _0-2 alkyl, C _3-6 cycloalkyl, OC _0-2 Alkyl C _3-6 heterocycloalkyl, OC _1-6 alkyl, and NR ₂₁ R ₂₂ ; Ar1 is 6-membered aryl or heteroaryl; Ar2 is 6-membered aryl or heteroaryl and is attached Connect Ar1 to Amine was para; R ₁₀ is H, halo, C _1-3 alkyl, C _1-2 haloalkyl, OC _1-2 alkyl, OC _1-2 haloalkyl, or CN; R ₁₁ is H , F, Cl, C _1-2 alkyl, CF ₃ , OCH ₃ , or CN; R ₁₂ is attached to Ar2 in ortho or meta position relative to Ar1, and R ₁₂ is H, halo, C _{1- 4} alkyl, C _2-4 alkenyl, C _0-2 alkyl, C _3-5 cycloalkyl, OC _1-4 alkyl, OC _0-2 alkyl, C _3-5 cycloalkyl, C _{1 -4} haloalkyl, OC _1-4 haloalkyl, hydroxy, C _1-4 alkylOH, SO ₂ C _1-2 alkyl, C (O) N (C _1-2 alkyl) ₂ , NHC ( O) C _1-3 alkyl, or NR ₂₃ R ₂₄ ; and when A is -NHC (= O)-: R ₁₂ may be additionally selected from: CN, OCH ₂ CH ₂ N (CH ₃ ) ₂ and C _{3 -6} heterocycloalkyl (which is the point of attachment position of Ar2 comprises one nitrogen), or R ₁₂ is attached thereto together form N- oxides of nitrogen ^{(N + -O -); R} 13 is H or halogen R ₂₁ is H, C _1-5 alkyl, C (O) C _1-5 alkyl, C (O) OC _1-5 alkyl; R ₂₂ is H or CH ₃ ; R ₂₃ is H or C _1-2 alkyl; and R ₂₄ is H or C _1-2 alkyl; or a salt and / or a solvate and / or a derivative thereof.     A compound as claimed in claim 1, wherein A is -C (= O) NH-.         A compound as claimed in claim 1, wherein A is -NHC (= O)-.     A compound as claimed in any one of claims 1 to 3, wherein X is N, Y is CR ₂ , and Z is CR ₃ . A compound as claimed in any one of claims 1 to 3, wherein X is CH, Y is N, and Z is CR ₃ . A compound according to any one of claims 1 to 3, wherein X is CH, Y is CR ₂ and Z is N. A compound according to any one of claims 1 to 6, wherein R ₁ is a C _3-5 cycloalkyl group _optionally substituted with CH ₃ . A compound according to any one of claims 1 to 7, wherein R ₂ is H. A compound according to any one of claims 1 to 8, wherein R ₃ is H. The compound according to any one of claims 1 to 9, wherein R ₄ is selected from the group consisting of halo (e.g. fluorine), C _1-6 alkyl (e.g. methyl or ethyl), C _1-3 butane OC _1-3 alkyl (such as: CH ₂ CH ₂ OCH ₃ ), or OC _1-6 alkyl (such as: OCH ₃ ). A compound according to any one of claims 1 to 10, wherein R ₅ is H, fluorine, methyl or ethyl. The compound according to any one of claims 1 to 9, wherein R ₄ and R _{5 together} with the carbon atom to which they are attached form a cyclopropyl ring or a cyclopentyl ring, such as a cyclopentyl ring. The compound of any one of claims 1 to 9, wherein R ₄ and R _{5 together} with the carbon atom to which they are attached form a tetrahydropiperanyl ring.     A compound according to any one of claims 1 to 13, wherein Ar1 is phenyl or 2-pyridyl.     A compound according to any one of claims 1 to 14, wherein Ar2 is 3-pyridyl or 2,5-pyridine base. A compound according to any one of claims 1 to 15, wherein R ₁₀ is H, F, Cl, CH ₃ , OCH ₃ , OCF ₃ or CN, for example: H or F. A compound according to any one of claims 1 to 16, wherein R ₁₁ is H or F, for example: H. A compound according to any one of claims 1 to 17, wherein R ₁₂ is H, F, Cl, CH ₃ , methoxy, ethoxy, isopropoxy, OC ₀ alkyl, C ₃ cycloalkyl, CN, CF ₃ , OCHF ₂ or OCH ₂ CF ₃ , for example: methoxy, ethoxy, isopropoxy, OC ₀ alkyl, C ₃ cycloalkyl, CF ₃ , OCHF ₂ or OCH ₂ CF ₃ . A compound according to any one of claims 1 to 18, wherein R ₁₃ is H.     The compound according to any one of claims 1 to 19, which is used as a medicine.         The compound of claim 20, which is used to reduce T-cell and / or B-cell proliferation for an individual.         A compound as claimed in claim 20, for the treatment or prevention of: inflammatory skin diseases, such as: psoriasis or lichen planus; acute and / or chronic GVHD, such as: steroid-resistant acute GVHD; acute lymphoproliferative syndrome (ALPS ); Systemic lupus erythematosus, lupus nephritis, or cutaneous lupus; or transplantation.         The compound of claim 20, which is used for treating or preventing: myasthenia gravis, multiple sclerosis or scleroderma / systemic sclerosis.         A compound according to claim 20, which is used for treating cancer.         The compound of claim 24, wherein the cancer is a blood cancer.         The compound, method or use according to claim 25, wherein the blood cancer is selected from the group consisting of acute myeloid leukemia, vascular immunoblast T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet syndrome, T-cell non-Hodgkins lymphoma (including natural killer / T-cell lymphoma, adult T-cell leukemia / lymphoma, enteric T-cell Lymphoma, hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma (including Burkitt lymphoma, diffuse Large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), hair cell leukemia, Hodgkin's lymphoma, lymphoblastic lymphoma, lymphoplasmic lymphoma Tumor, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, myelodysplastic syndrome, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorders (such as chronic myelogenous leukemia, primary Sex bone marrow Fibrosis, idiopathic thrombocytosis, polycythemia vera) and chronic lymphocytic leukemia.         The compound of claim 20, which is used to promote recovery from vascular injury or surgery for an individual, and to reduce the morbidity and mortality associated with neointimal and postoperative restenosis.         A pharmaceutical composition comprising the compound according to any one of claims 1 to 19.     A compound of formula (II) : Where R ₁ , X, Y, Z, R ₄ and R ₅ are as defined in any of the preceding claims, and R is H, C _1-6 alkyl (for example: methyl and ethyl) or benzyl Base, or a salt thereof, such as a pharmaceutically acceptable salt thereof. A compound of formula (III) : Wherein Ar1, Ar2, R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined in any one of the preceding claims, or a salt thereof, such as a pharmaceutically acceptable salt thereof. A compound of formula (XXXXII) : Wherein R ₁ , X, Y, Z, R ₄ and R ₅ are as defined in any one of the preceding claims, or a salt thereof, such as a pharmaceutically acceptable salt thereof. A compound of formula (XXXXIII) : Wherein Ar1, Ar2, R ₁₀ , R ₁₁ , R ₁₂ and R ₁₃ are as defined in any one of the preceding claims, or a salt thereof, such as a pharmaceutically acceptable salt thereof. A compound selected from the group consisting of the compounds of formula (XX) : Compound of formula (XXIV) : Compound of formula (XXXI) : Compound of formula (LI) : Wherein X is Cl or Br; and a compound of formula (LVIII) : Wherein any of the above _{compounds, Ar1, Ar2, R 1,} X, Y, Z, R 4, R 5, R 10, R 11, R 12 and R ₁₃ are as previously defined system described in any one of the request, and P is a nitrogen protecting group, such as: p-methoxybenzyl; or a salt thereof, such as a pharmaceutically acceptable salt thereof.