Aminopyrimidine derivatives as CTPS1 inhibitors

Abstract

To provide CTPS1 inhibitors.SOLUTION: The present invention provides a compound of formula (I), or its salt and / or solvate, and / or its derivative. An illustrative example of this is a compound of the following formula.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Field of invention) The present invention includes novel compounds, processes for making the compounds, related intermediates, and the compounds. and the use of such compounds, particularly in the treatment or prevention of disorders related to cell proliferation. and its use as inhibitors of thymidine triphosphate synthase 1. [Background technology]

[0002] BACKGROUND OF THE INVENTION Nucleotides are essential for cellular metabolic processes such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. Nucleotides contain either purine or pyrimidine bases. There are two types of ATP, both of which are important for metabolic processes. Many therapeutic approaches targeting different aspects of nucleotide synthesis have been developed, some of which are protease inhibitors. Inhibits the production of phosphorus nucleotides and some pyrimidine nucleotides or both It is something.

[0003] The pyrimidine nucleotide cytidine 5' triphosphate (CTP) is essential for the assimilation of DNA and RNA. CTP is not only a precursor for sialylation of phospholipids but also a necessary precursor for sialylation of phospholipids and proteins. It is dependent on two enzymes, CTP synthase (or synthetase) 1 and 2 (CTPS1 and CTPS2). It arises from two sources: the Rubesi pathway and de novo synthesis pathway (Evans and Guy et al., 2004; Hi ggins et al. 2007; Ostrander et al. 1998).

[0004] CTPS1 and CTPS2 are involved in the synthesis of uridine triphosphate (UTP) and glutamine, and the synthesis of cytidine triphosphate (CTP). and catalyzes the conversion to L-glutamate: [ka] .

[0005] Both enzymes contain two domains, an N-terminal synthetase domain and a C-terminal glutaminase domain. The synthetase domain is responsible for the synthesis of adenosine triphosphate (ADT). Transfer of phosphate from ATP to the 4th position of UTP to form an activated intermediate, 4-phospho- The glutaminase domain contains a conserved active site cysteine. Ammonia is generated from glutamine via a bound thioester intermediate, and glutamate is released. This ammonium is transported from the glutaminase domain to the synthetase domain. It is transported through tunnels to the NH4+ complex, but can also originate from external ammonium. This ammonium is used by the synthetase domain to convert 4-phospho-UTP to CTP. generated (Lieberman, 1956).

[0006] CTPS exists as two isozymes, CTPS1 and CTPS2, in humans and other eukaryotes. However, the functional differences between the two isozymes have not yet been fully elucidated (van Kuil enburg et al. 2000).

[0007] The immune system provides protection from infection, so it is important to They have evolved to respond rapidly to a wide variety of pathogens. This response can take many forms. However, the expansion and differentiation of immune cell populations is a key factor, which leads to rapid cell proliferation. Among them, CTP synthase activity is involved in DNA synthesis and lymphocyte function after activation. It has been shown to play an important role in the rapid expansion of the sphere (Fairbanks et al. 1995; van den Berg et al. 1995).

[0008] Strong clinical validation that CTPS1 is a key enzyme in human lymphocyte proliferation is provided by the This was accompanied by the identification of a homozygous loss-of-function mutation (rs145092287) in It causes a profound and life-threatening immune deficiency that is mediated by antigen receptors. Activated CTPS1 deficiency is characterized by impaired proliferation of activated T and B cells. In cells, the CTP level was reduced. Expression of wild-type CTPS1 or addition of cytidine reduced the CTP level. Normal T cell proliferation was restored in PS1-deficient cells. CTPS1 expression is low in resting lymphocytes. was found to be rapidly upregulated after activation of these cells. CTPS1 expression was generally low in various tissues. CTPS2 is ubiquitously expressed in various cells and tissues. It appears to be expressed, but at low levels, and mutated CTP The inability to compensate for S1 may be a key factor in determining whether CTPS1 is responsible for the adverse effects on patients with immune cells. Supporting that it is an enzyme (Martin et al. 2014).

[0009] Overall, these findings suggest that CTPS1 is a CTP required by several important immune cell populations. This suggests that it is a key enzyme needed to meet supply demand.

[0010] Normally, the immune response is tightly regulated to ensure protection from infection and to target host tissues. In certain situations, control of this process is ineffective, leading to immune-mediated disease. A wide range of human diseases are mediated by various components of the immune system. This is likely due to an inappropriate response such as:

[0011] The role that T and B lymphocytes play in a wide range of autoimmune and other diseases Given its likely role, CTPS1 represents a target for a new class of immunosuppressive drugs. Inhibition of CTPS1 inhibits lymphocytes, as well as natural killer cells and mucosal-associated invariant T cells (MAI). T), and other immune cell populations selected from invariant natural killer T cells, etc. A novel approach to inhibiting the activation of cell populations that are attracting attention as phenotypes of patients with mutations. provide roaches (Martin et al. 2014).

[0012] Cancer can affect many cell types and tissues, but the underlying cause is cell division. This process is highly complex and requires careful coordination of multiple pathways. Many of these have been fully characterized. Cell division involves the transfer of the cell's DNA and other Efficient replication of components is required. Targeting nucleic acid synthesis enhances the replicative capacity of the cell. Blocking this force has been a central approach in cancer treatment for many years. Examples of treatments that employ 6-thioguanine, 6-mercaptopurine, 5-fluorouracil, Cytarabine, gemcitabine, and pemetrexed be.

[0013] As mentioned above, the pathways involved in providing the major building blocks for nucleic acid replication are purine and pi Pyrimidine synthesis pathway, pyrimidine biosynthesis is upregulated in tumor and neoplastic cells It has been observed that

[0014] CTPS activity is upregulated in a range of tumor types of both hematologic and non-hematologic origin. Although the incidence of HIV-1 infection has been reported, heterogeneity among patients has been observed. There is also a link with drug resistance.

[0015] Currently, the exact roles that CTPS1 and CTPS2 play in cancer are not entirely clear. Selective CTPS inhibitors have been developed for oncology indications up to Phase I / II clinical trials. , was discontinued due to toxicity and efficacy issues.

[0016] Many of the inhibitors developed are kinases involved in pyrimidine biosynthesis; uridine / cytidine kinases, nucleoside monophosphate kinases (NMP kinases) and nucleoside diphosphates Nucleosides converted to active triphosphorylated metabolites by kinases (NDP kinases) The remaining inhibitors (Azauridine, CPEC, Carbodine) are analogue prodrugs. Acivicin (DON) irreversibly inhibits the glutaminase domain of CTPS. Gemcitibine, a reactive analogue of glutamine, also has anti-CTPS properties. It has been reported that it has some inhibitory activity (McClusky et al., 2016).

[0017] Therefore, it is clear that CTPS is an important target in the field of cancer. The nature of these compounds suggests that their effects on other pathways may contribute to their efficacy in tumor inhibition. That's what happens.

[0018] Therefore, selective CTPS inhibitors offer an attractive alternative approach for the treatment of tumors. Compounds with different potencies towards CTPS1 and CTPS2 may be related to the dependence on these enzymes. This may offer important opportunities to target different tumors depending on gender.

[0019] CTPS1 also plays a role in vascular smooth muscle cell proliferation after vascular injury or surgery. (Tang et al. 2013).

[0020] To date, no selective CTPS1 inhibitors have been developed. A selective inhibitory peptide, CTpep-3, was identified. However, this inhibitory effect of CTpep-3 was ineffective. This peptide was confirmed in cell assays but not in a cellular environment. Therefore, it was difficult to develop it as a treatment. was not an unexpected result (Sakamoto et al. 2017).

[0021] In summary, available information and data suggest that inhibitors of CTPS1 may have therapeutic potential in many immune and cancer cells. It reduces proliferation of vascular smooth muscle cells and may have similar effects on other selected cell types, such as vascular smooth muscle cells. Therefore, CTPS1 inhibitors may be effective in inhibiting the proliferation of these cells. These compounds would be expected to be useful in the treatment or prevention of a wide range of conditions in which pathology is caused by .

[0022] CTPS1 inhibitors are thought to be effective in inhibiting the immune system of various tissues and, in general terms, the immune system of transplanted cells and tissues. immune system disorders, such as tissue rejection, transplant-related diseases or disorders, allergies and autoimmune diseases Novel Approaches to Inhibit Selected Components of Stem-Associated Conditions or Pathological Symptoms Furthermore, CTPS1 inhibitors have potential for treating various cancer conditions, as well as vascular damage and Accelerate recovery from surgery and reduce morbidity and mortality associated with neointima and restenosis Offers therapeutic possibilities. Summary of the Invention

[0023] (Summary of the Invention) The present invention provides compounds of formula (I): [ka] (In the formula, A is an amide linker having the structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2; Z is N or CR3; provided that if at least one of X or Z is N, then Y is not N; R1 is C 1-5 C alkyl, cycloalkyl optionally substituted with CH3 0-2 Alkire N C 3-5 cycloalkyl, or CF3; R2 is H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 Haloal It is a kill; R3 is H, halo, CH3, OCH3, CF3, or OCF3; provided that at least one of R2 and R3 is H; R4 and R5 are each independently H, C 1-6 Alkyl, C 1-6 Alkyl OH, C 1-6 Haloalkyl , C 0-2 Alkylene C 3-6 Cycloalkyl, C0-2 Alkylene C 3-6 Heterocycloalkyl, C 1-3 Alkylene OC 1-3 alkyl, or R4 and R5 together with the carbon atoms to which they are attached to C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)-: R4 and R5 are halo, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0- 2 alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21 R 22 Select additionally from May be; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a six-membered aryl or heteroaryl bonded to Ar1 in the para position relative to the amide. Congruent; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 Hello Aruki le, or CN; R 11 are H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 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 C3-5 Cycloalkyl, C 1-4 Haloalkyl, OC 1-4 Haloalkyl, hydroxy, C 1-4 Alkyl OH, SO2C 1-2 Alkyl, C(O)N(C 1-2 alkyl)2, NHC(O)C 1-3 Alkyl or N R 23 R 24 and When A is -NHC(=O)-: R 12 is a C-substituted aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2. 3-6 heterocycloalkyl; or R 12 is the nitrogen atom to which it is attached. N-oxide (N + -O - ) may be formed; 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 is alkyl; R 22 is H or CH3; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 alkyl).

[0024] Suitably, the present invention provides a compound of formula (I): [ka] (In the formula, R1 is C 1-5 C alkyl or cycloalkyl optionally substituted with CH 0-2 Al Kiren C 3-5is cycloalkyl; R3 is H, halo, or CH3; R4 and R5 are each independently H, halo, C 1-6 Alkyl, C 1-3 Alkylene OC 1-3 Alkyl or R4 and R5 together with the carbon atom to which they are attached are C 3-6 Cycloalkyl or Kuha C 3-6 forming a heterocycloalkyl; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a six-membered aryl or heteroaryl bonded to Ar1 in the para position relative to the amide. Has been; R 10 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 is H, F, CH3, or OCH3; and R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1- 4 alkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, CN, C 1-4 Hello Aruki Le, O.C. 1-4 haloalkyl).

[0025] The present invention also provides a compound of formula (I): [ka] (In the formula, R1 is C 1-5 C alkyl or cycloalkyl optionally substituted with CH 0-2 Al Kiren C 3-5 is cycloalkyl; R3 is H, halo, or CH3; R4 and R5 are each independently H, C 1-6 Alkyl, C 1-3 Alkylene OC 1-3 is alkyl or R4 and R5 together with the carbon atom to which they are attached form a C 3-6 Forming a cycloalkyl; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a six-membered aryl or heteroaryl bonded to Ar1 in the para position relative to the amide. Has been; R 10 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 is H, F, CH3, or OCH3; and R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1- 4 alkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, CN, C 1-4 Hello Aruki Le, O.C. 1-4 haloalkyl).

[0026] The present invention also provides a compound of formula (I): [ka] (In the formula, A is an amide linker having the structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2; Z is N or CR3; provided that if at least one of X or Z is N, then Y is not N; R1 is C 1-5 C alkyl or cycloalkyl optionally substituted with CH 0-2 Al Kiren C 3-5 is cycloalkyl; R2 is H, C 1-2 Alkyl or C 1-2 is haloalkyl; R3 is H, halo, or CH3; provided that at least one of R2 and R3 is H; R4 and R5 are each independently H, C 1-6 Alkyl or C 1-3 Alkylene OC 1-3 With alkyl or R4 and R5 together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl or is C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)-: R4 and R5 are halo and OC 1-6 may additionally be selected from alkyl; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a six-membered aryl or heteroaryl bonded to Ar1 in the para position relative to the amide. Has been; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 Hello Aruki le, or CN; R 11 is H, F, CH3, or OCH3; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1- 4 alkyl, OC 1-4 Alkyl, C 1-4 Haloalkyl, OC 1-4Haloalkyl, 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).

[0027] The compounds of formula (I) may be used in the form of their salts and / or solvates and / or derivatives thereof. Preferably, the compound of formula (I) can be provided in the form of a pharmaceutically acceptable salt thereof. and / or solvates and / or derivatives thereof. The compounds of formula (I) may be used in the form of pharmaceutically acceptable salts, such as pharmaceutically acceptable salts, and / or It may be provided in the form of a solvate.

[0028] Also provided is a compound of formula (I) or a compound thereof for use as a pharmaceutical. Pharmaceutically acceptable salts and / or solvates and / or derivatives thereof, particularly to inhibit CTPS1 or to reduce T cell and / or B cell proliferation in a subject for use in the prevention or treatment of related diseases or disorders in which it would be beneficial to be.

[0029] Furthermore, compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, and / or derivatives thereof to a subject in need thereof, Inhibiting CTPS1, which is involved in T cell proliferation, or reducing T cell and / or B cell proliferation, would be beneficial. Methods for preventing or treating such related diseases or disorders are provided.

[0030] Additionally provided are methods for inhibiting CTPS1 in a subject or for inhibiting T cells and / or or to prevent or treat a related disease or disorder in which reducing B cell proliferation is beneficial. a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating The use of salts and / or solvates thereof and / or derivatives thereof.

[0031] Preferably, the disease or disorder is an inflammatory skin disease, such as psoriasis or lichen planus; acute and / or or chronic GVHD, such as steroid-resistant acute GVHD; acute lymphoproliferative syndrome (ALPS); systemic lupus erythematosus, lupus nephritis or cutaneous lupus; and transplantation. The disease or disorder is selected from myasthenia gravis, multiple sclerosis, and scleroderma / systemic sclerosis. It is possible.

[0032] Also provided is a compound of formula (I) or a medicament thereof for use in treating cancer. and / or a suitable salt and / or solvate thereof, and / or a derivative thereof.

[0033] Furthermore, compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, and / or derivatives thereof to a subject in need thereof, Methods for treating cancer in a subject are provided.

[0034] Additionally provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or or solvates thereof, and / or derivatives thereof, for the treatment of cancer in a subject - Patent application Use in the manufacture of

[0035] Also provided are compounds of formula (I) or pharmaceutically acceptable salts and / or derivatives thereof. or solvates thereof, and / or derivatives thereof, in a subject after vascular injury or surgery. and to promote the recovery of these tissues and reduce the morbidity and mortality associated with neointima and restenosis. be.

[0036] Furthermore, compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, and / or derivatives thereof to a subject in need thereof, and promote recovery from vascular injury or surgery, and reduce morbidity and mortality associated with neointima and restenosis. and methods for reducing mortality.

[0037] Additionally provided are methods for promoting recovery from vascular injury or surgery in a subject, and for promoting new In the manufacture of pharmaceuticals for reducing morbidity and mortality associated with vivisection and restenosis A compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, and / or or the use of derivatives thereof.

[0038] Also provided are compounds of formula (I) or pharmaceutically acceptable salts and / or derivatives thereof. or solvates and / or derivatives thereof, and a pharmaceutically acceptable carrier or A pharmaceutical composition comprising an excipient.

[0039] Also provided are compounds of formula (I) and compounds used to prepare compounds of formula (I). This is a process for producing a novel intermediate. DETAILED DESCRIPTION OF THE INVENTION

[0040] (Detailed Description of the Invention) The present invention provides compounds of formula (I): [ka] (In the formula, A is an amide linker having the structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2; Z is N or CR3; provided that if at least one of X or Z is N, then Y is not N; R1 is C 1-5 C alkyl, cycloalkyl optionally substituted with CH3 0-2 Alkire N C 3-5 cycloalkyl, or CF3; R2 is H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, C 1-2 Haloalkyl or OC 1-2 Haloal It is a kill; R3 is H, halo, CH3, OCH3, CF3, or OCF3; provided that at least one of R2 and R3 is H; R4 and R5 are each independently H, C 1-6 Alkyl, C 1-6 Alkyl OH, C 1-6 Haloalkyl , 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 R4 and R5 together with the carbon atoms to which they are attached to C 3-6 Cycloalkyl or C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)-: R4 and R5 are halo, OC 1-6 Haloalkyl, OC 0-2 Alkylene C 3-6 Cycloalkyl, OC 0- 2 alkylene C3-6 Heterocycloalkyl, OC 1-6 Alkyl and NR 21 R 22 Select additionally from May be; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a six-membered aryl or heteroaryl bonded to Ar1 in the para position relative to the amide. Congruent; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 Hello Aruki le, or CN; R 11 are H, F, Cl, C 1-2 alkyl, CF3, OCH3 or CN; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 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 Alkyl OH, SO2C 1-2 Alkyl, C(O)N(C 1-2 alkyl)2, NHC(O)C 1-3 Alkyl or N R 23 R 24 and When A is -NHC(=O)-: R 12 is a C-substituted aryl group containing CN, OCH2CH2N(CH3)2, and one nitrogen atom at the point of attachment to Ar2. 3-6 heterocycloalkyl, or R 12 is the nitrogen to which it is attached N-oxide (N + -O - ) may be formed; 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 is alkyl; R 22 is H or CH3; R 23 is H or C 1-2 is alkyl; and R 24 is H or C 1-2 alkyl); or a salt and / or solvate thereof, and / or a derivative thereof.

[0041] Suitably, the present invention provides a compound of formula (I): [ka] (In the formula, R1 is C 1-5 C alkyl or cycloalkyl optionally substituted with CH 0-2 Al Kiren C 3-5 is cycloalkyl; R3 is H, halo, or CH3; R4 and R5 are each independently H, halo, C 1-6 Alkyl, C 1-3 Alkylene OC 1-3 Alkyl or R4 and R5 together with the carbon atom to which they are attached are C 3-6 Cycloalkyl or Kuha C 3-6 forming a heterocycloalkyl; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a six-membered aryl or heteroaryl bonded to Ar1 in the para position relative to the amide. Congruent; R 10 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 is H, F, CH3, or OCH3; and R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1- 4 alkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, CN, C 1-4 Hello Aruki Le, O.C. 1-4 haloalkyl); or a salt and / or solvate thereof, and / or a derivative thereof.

[0042] The present invention also provides a compound of formula (I): [ka] (In the formula, R1 is C 1-5 C alkyl or cycloalkyl optionally substituted with CH 0-2 Al Kiren C 3-5 is cycloalkyl; R3 is H, halo, or CH3; R4 and R5 are each independently H, C 1-6 Alkyl, C 1-3 Alkylene OC 1-3 is alkyl or R4 and R5 together with the carbon atom to which they are attached form a C 3-6 Forming a cycloalkyl; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a six-membered aryl or heteroaryl bonded to Ar1 in the para position relative to the amide. Congruent; R 10 H, halo, C 1-2 Alkyl, OC 1-2 Alkyl, OC 1-2 haloalkyl, or CN; R 11 is H, F, CH3, or OCH3; and R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 H, halo, C 1- 4 alkyl, OC 1-4 Alkyl, OC 0-2 Alkylene C 3-5 Cycloalkyl, CN, C 1-4 Hello Aruki Le, O.C. 1-4 haloalkyl); or a salt and / or solvate thereof, and / or a derivative thereof.

[0043] The present invention also provides a compound of formula (I): [ka] (In the formula, A is an amide linker having the structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2; Z is N or CR3; provided that if at least one of X or Z is N, then Y is not N; R1 is C 1-5 C alkyl or cycloalkyl optionally substituted with CH 0-2 Al Kiren C 3-5 is cycloalkyl; R2 is H, C 1-2 Alkyl or C 1-2 is haloalkyl; R3 is H, halo, or CH3; provided that at least one of R2 and R3 is H; R4 and R5 are each independently H, C 1-6 Alkyl or C 1-3 Alkylene OC 1-3 With alkyl or R4 and R5 together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl or is C 3-6 forming a heterocycloalkyl; and When A is -NHC(=O)-: R4 and R5 are halo and OC 1-6 may additionally be selected from alkyl; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a six-membered aryl or heteroaryl bonded to Ar1 in the para position relative to the amide. Congruent; R 10 H, halo, C 1-3 Alkyl, C 1-2 Haloalkyl, OC 1-2 Alkyl, OC 1-2 Hello Aruki le, or CN; R 11 is H, F, CH3, or OCH3; R 12 is bonded to Ar2 at the ortho or meta position relative to Ar1, and R 12 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 and / or solvate thereof, and / or a derivative thereof.

[0044] As used herein, the term "alkyl" refers to any group, e.g., C 1-3 Alkyl, C 1-4 Alkyl, C 1-5 a Rukill or C 1-6 The alkyl group may be a single group or an O-alkyl group (e.g., OC 1-3 Alkyl, OC 1-4 Alkyl and OC 1-5 The specific number, whether or not it is part of a larger group such as alkyl, Examples of alkyl groups include: C 1-5 Alkyl groups, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and n-pentyl, sec-pentyl and 3-pentyl, especially C 1-3 The alkyl groups include methyl, ethyl, n-propyl and iso-propyl. References include n-propyl and iso-propyl, and references to "butyl" include n-butyl, isobutyl, Examples of O-alkyl groups include OC-butyl, sec-butyl, and tert-butyl. 1-4 Alkyl group, meth oxy, ethoxy, propoxy (including n-propoxy and iso-propoxy), and butoxy (n This specification includes oxy groups such as 1-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. As used herein, C6 alkyl groups may be used alone or as part of a larger group such as an OC6 alkyl group. fully saturated straight-chain or branched-chain hydrocarbons containing six carbon atoms, regardless of whether they comprise Examples of C6 alkyl groups include n-hexyl, 2-methylpentyl, 3-methylpentyl, Includes 2,2-dimethylbutyl and 2,3-dimethylbutyl.

[0045] As used herein, the term "alkylene" refers to any group, e.g., 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 etc. are specific numbers It is a difunctional, straight or branched, fully saturated hydrocarbon chain containing carbon atoms. 0-2 Alkire Examples of alkyl groups are those where the group is absent (i.e., C0), or is a methylene (C1) and ethylene (C 2).

[0046] As used herein, the term "alkenyl" refers to any group, such as C 2-4 Alkenyl etc. is a group with a specific number of carbon atoms It is a straight or branched hydrocarbon chain containing atoms and carbon-carbon double bonds.

[0047] As used herein, the term "cycloalkyl" refers to a group such as C 3-5 Cycloalkyl or C 3-6 S Chloroalkyl etc. may be used alone or in combination with OC 3-5 Cycloalkyl or C 0-2 Alkylene C 3-5 Cyclo Contains a specified number of carbon atoms, whether or not it forms part of a larger group such as alkyl, It is a fully saturated hydrocarbon ring. Examples of cycloalkyl groups include C 3-6 Cycloalkyl groups, cyclo Propyl, cyclobutyl, cyclopentyl and cyclohexyl, especially C 3-5 cycloalkyl Groups include cyclopropyl, cyclobutyl and cyclopentyl: [ka] .

[0048] As used herein, the term "heterocycloalkyl" refers to any group, such as C 3-6 Heterocycloalkane L or C 0-2 Alkylene C 3-6 Heterocycloalkyl and the like are fully saturated groups containing a specified number of carbon atoms. a hydrocarbon ring containing a carbon atom through which a cycloalkyl group is attached In this case, at least one carbon atom in the ring may be a heteroatom such as N, S or O. If necessary, the nitrogen atom is bonded to a hydrogen atom to form an NH group. The nitrogen atom may be, for example, C 1-4 Alkyl, C(O)H, C(O)C 1-4 Alkyl, C(O)OC1 -4 Alkyl, C(O)OC 1-4 Alkylaryl, e.g., 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 by haloalkyl, such as C(O)OtBu, etc. (e.g., one If the ring heteroatom is S, the term "heteroatom" is used. "Hydroxycycloalkyl" means a group in which the S atom is replaced by one or two oxygen atoms (e.g., one S atom). This includes cases where the child is replaced (i.e., S(O) or S(O)2). Alternatively, C 3-6 Heterothymic Any sulfur atom in the alkyl ring is not substituted.

[0049] C 3-6 Examples of heterocycloalkyl groups include those containing one heteroatom, e.g., one heteroatom. containing a heteroatom (e.g., oxygen) or two heteroatoms (e.g., two oxygen atoms, or It includes those containing one oxygen atom and one nitrogen atom. MuC 3-6 Specific examples of heterocycloalkyl include oxiranyl, oxetanyl, 3-dioxo thiazole, morpholinyl, 1,4-oxathiazole, tetrahydropyranyl, 1,4-thioxanyl and 1,3,5-trioxanyl. 3-6 Examples of heterocycloalkyl include those having one acid These include those containing oxygen atoms, such as those containing one oxygen atom or those containing two oxygen atoms. C containing one oxygen atom 3-6 Specific examples of heterocycloalkyl include oxiranyl. , oxetanyl, 3-dioxolanyl, morpholinyl, 1,4-oxathianiyl, tetrahydro These include pyranyl, 1,4-thioxanyl, and 1,3,5-trioxanyl.

[0050] In one embodiment, the term "heterocycloalkyl" as used herein, e.g., C 3-6 Heterocycloalkyl and the like are fully saturated hydrocarbon rings containing a specified number of carbon atoms, It may contain a carbon atom to which a cycloalkyl group is bonded through a ring. At least one carbon atom in C is replaced with a heteroatom such as N, S, or O. 3-6 F Examples of tetracycloalkyl groups include those containing one heteroatom, e.g., one heteroatom (e.g., oxygen) or containing two heteroatoms (e.g., two oxygen atoms, or one and one nitrogen atom).

[0051] The heterocycloalkyl group can have the structure: [ka] wherein each Q is a heteroatom independently selected from O, N, or S. When Q is N, In this case, depending on the valence requirements, the nitrogen atom may be bonded to a hydrogen atom to form an NH group. Alternatively, the nitrogen atoms may be substituted (e.g., one nitrogen atom is substituted, etc.). , e.g. C 1-4 Alkyl, C(O)H, C(O)C 1-4 Alkyl, C(O)OC 1-4 Alkyl, C(O)OC 1-4 Al alkylaryl, e.g., C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC 1-4 alkylaryl, For example, C(O)NHBz, Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C(O)N HC 1-4 It can be substituted by haloalkyl, such as C(O)OtBu, etc. Any Q can be S In this case, the S atom is replaced by one or two oxygen atoms (e.g., one S atom is replaced (i.e., S(O) or S(O)2). Alternatively, C 3-6 Heterocycloa Any sulfur atom in the alkyl ring is not substituted.

[0052] The heterocycloalkyl group can also have the structure: [ka] (wherein each Q is independently selected from O, N, or S, such as O or N). When Q is N, If valence requires, the nitrogen atom may be bonded to a hydrogen atom to form an NH group. Alternatively, the nitrogen atoms may be substituted (e.g., one nitrogen atom is substituted, etc.); 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 Archi aryl, e.g., C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC 1-4 Alkylaryl, e.g. For example, C(O)NHBz, Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C(O)NHC 1-4 It can be substituted by haloalkyl, such as C(O)OtBu. In this case, the S atom is replaced by one or two oxygen atoms (e.g., one S atom is replaced (i.e., S(O) or S(O)2). Alternatively, C 3-6 Heterocycloar None of the sulfur atoms in the alkyl ring are substituted.

[0053] A is —C(═O)NH and R4 and / or R5 are C0 alkylene C 3-6 Heterocycloalkyl or R4 and R5 together with the carbon atom to which they are attached are C 3-6 Heterocycloalkyl If formed, any heteroatom in the heterocycloalkyl may be bonded to R4 and R5. It will not bond directly to the carbon atom.

[0054] Preferably, the heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms. At least one carbon atom is replaced with a heteroatom, such as N, S, or O. If necessary, any nitrogen atom is bonded to a hydrogen atom, and the sulfur atom is bonded to an oxygen atom. It does not exist as an oxide.

[0055] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine. Particular examples of halo are fluorine and chlorine, especially fluorine. As used herein, the term "haloalkyl" refers to any group, such as C 1-6 Haloalkyl, e.g., C 1-4 Haloalkyl may be alone or may be O haloalkyl groups such as O-C. 1-6 Haloalkyl, etc. BaOC 1-4 A specific number of carbon atoms, whether part of a larger group such as haloalkyl, atom and at least one halogen atom, such as fluoro or chloro, in particular fluoro, An example of a haloalkyl is CF3. Further examples of haloalkyl include CHF2 and CH2CF3. Examples of O haloalkyl include OCF3, O Includes CHF2 and OCH2CF3.

[0056] As used herein, the term "6-membered aryl" refers to a phenyl ring. As used herein, the term "six-membered heteroaryl" refers to a group containing at least one heteroatom. An exemplary six-membered heteroaryl is a six-membered aromatic ring containing one atom (e.g., nitrogen). Nitrogen atom (pyridinyl), two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl) and and three nitrogen atoms (triazinyl).

[0057] As used herein, the phrase "para to the amide" refers, for example, to the position of Ar. means that a compound having the following structure is formed: [ka] wherein, as permitted by the definitions provided for compounds of formula (I), W1 is N, CH, CR 10 or CR 11 in W2 may be N, CH or CR 12 W2 may be any of the groups defined for compounds of formula (I). As long as CR 13 is also acceptable).

[0058] As used herein, for example, R on Ar 12 Used to define the position of Ar1 The terms "ortho" and "meta" used herein refer to the relationship that the following structures would form: [ka] .

[0059] The phrase "A is an amide linker having the structure: -C(=O)NH- or -NHC(=O)-" refers to The following structural forms are meant: [ka] .

[0060] In one embodiment, A is -C(=O)NH-. In another 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 CR2. In one embodiment, Z is N. In another embodiment, Z is CR3.

[0061] Preferably, X is N, Y is CR2, and Z is CR3. Alternatively, X is CH and Y is is N and Z is CR3; or X is CH, Y is CR2, and Z is CR3; or , X is CH, Y is CR2, and Z is N. Alternatively, X is N, Y is CR2, and Z is N. be.

[0062] In one embodiment of the invention, R1 is C 1-5 alkyl. R1 is C 1-5 For alkyl, R1 is , methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isopropyl) n-butyl, sec-butyl or tert-butyl) or pentyl (e.g., n-pentyl, sec-pentyl, It may also be 3-pentyl or 3-pentyl.

[0063] In a second embodiment of the present invention, R1 is a cycloalkyl optionally substituted with CH3. RuC 0-2 Alkylene C 3-5 In some embodiments, R is C 0-2 Archi Ren C 3-5 In another embodiment, R1 is cycloalkyl, wherein cycloalkyl is substituted by CH3. Substituted C 0-2 Alkylene C 3-5 R1 is cycloalkyl. C replaced by CH3 3-5 R1 may be cycloalkyl. R1 may be cycloalkyl. C1 alkylene C substituted by CH3 3-5 R1 may be cycloalkyl. C2 alkylene C optionally substituted with CH3 3-5 It may be cycloalkyl. R1 is a C in which cycloalkyl is optionally substituted with CH 0-2 Alkylene C3 Cycloalkyl R1 may be a C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32 0-2 Alkylene C4 R1 may be a C1-C12 alkyl group, where the cycloalkyl group is optionally substituted with CH3. 0-2 a It may be alkylene C5 cycloalkyl. 0-2 Alkylene C 3-5 Cycloalkyl is When CH3 is optionally replaced by C 3-5 Cycloalkyl C 0-2 Bond to alkylene It exists at the same point.

[0064] In a third embodiment, R1 is CF3. Preferably, R1 is cyclopropyl, cyclopropyl substituted at the attachment site with CH3. , cyclobutyl, CH3, or CH2CH3. In particular, R1 is cyclopropyl, cyclobutyl, C H3, or CH2CH3, especially cyclopropyl.

[0065] In one embodiment, R2 is H. In a second embodiment, R2 is halo, such as F, Cl, or Br. etc., for example Cl or Br. In a third embodiment, R2 is C 1-2 It is alkyl. R2 is C 1-2 In the case of alkyl, R2 may be methyl or ethyl, such as methyl. In this embodiment, R2 is OC 1-2 R2 is alkyl. 1-2 In the case of alkyl, OCH3 or OEt, e.g. In a fifth embodiment, R2 is C 1-2 haloalkyl. R2 is C 1-2 Hello In the case of alkyl, R2 may be CF3 or CH2CF3, such as CF3. In a sixth embodiment, R2 is OC 1-2 Haloalkyl. R2 is OC 1-2 For haloalkyl, R2 is OCF3 or OCH2CF3, e.g., O CF3 etc. may also be used. Suitably, R2 is H, CH3 or CF3, such as H or CH3, especially H.

[0066] In one embodiment, R3 is H. In a second embodiment, R3 is halo, particularly chloro or fluoro. In a third embodiment, R3 is CH3. In a fourth embodiment, R3 is CH3. In a fifth embodiment, R3 is OCH3. In a sixth embodiment, R3 is CF3. 3 is OCF3. Suitably, R3 is H, halo, particularly chloro or fluoro, especially fluoro, CH3, or More preferably, R3 is H or F, such as H. Preferably, at least one of R2 and R3 is H.

[0067] In one embodiment, R4 and R5 together with the carbon atom to which they are attached form a C 3-6 Cycloalkane cyclopropyl, cyclobutyl or cyclopentyl, in particular cyclopropyl or or cyclopentyl. In a second embodiment, R4 and R5 form the radicals to which they are attached. C with the carbon atom 3-6 Heterocycloalkyl, such as heterocyclohexyl, especially tetracyclohexyl. Forms a dihydropyranyl. Any nitrogen atom, e.g., C 3-6 Heterocycloalkyl ring One nitrogen atom in the 1-4 Alkyl, C(O)H, C(O)C 1-4 Alkyl, C(O)OC 1-4 a Rukill, C(O)OC 1-4 Alkylaryl, e.g., C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC1 -4 Alkylaryl, such as C(O)NHBz, Fmoc group, C(O)C 1-4Haloalkyl, C(O)OC 1-4 Ha alkyl, or C(O)NHC 1-4 It can be substituted by haloalkyl, such as C(O)OtBu. Preferably, C 3-6 Any nitrogen atom in the heterocycloalkyl ring is unsubstituted. In three embodiments, R4 is C 1-6 Alkyl, especially C 1-4 Alkyl, e.g., methyl, ethyl, proton butyl (n-propyl or isopropyl), or butyl (n-butyl, isobutyl, sec-butyl) In a fourth embodiment, R4 is C 1-3 Alkylene OC 1-3 Al Kills, especially C 1-2 Alkylene OC 1-2 Alkyl, for example, C1 alkylene, C1 alkyl, C2 alkyl C1 alkylene OC2 alkyl, C2 alkylene OC2 alkyl, etc. In a sixth embodiment, R4 is H. In a sixth embodiment, R4 is halo, such as chloro or fluoro. In a seventh embodiment, R4 is C 1-6 Haloalkyl, e.g., CF3 or CH2CF3, etc. In an eighth embodiment, R4 is C 0-2 Alkylene C 3-6 cycloalkyl, For example, C 3-6 Cycloalkyl, C1 alkylene C 3-6 Cycloalkyl, C2 alkylene C 3-6 Cyclo Alkyl, C 0-2 Alkylene C3 cycloalkyl, C 0-2 Alkylene C4 cycloalkyl, C 0-2 a alkylene C5 cycloalkyl, or C 0-2 Alkylene C6 cycloalkyl, etc. In an embodiment, R4 is C0-2 Alkylene C 3-6 Heterocycloalkyl, e.g., C 3-6 Heterocycloar Kyl, C1 alkylene C 3-6 Heterocycloalkyl, C2 alkylene C 3-6 Heterocycloalkyl , C 0-2 Alkylene C3 heterocycloalkyl, C 0-2 Alkylene C4 heterocycloalkyl, C0 -2 alkylene C5 heterocycloalkyl, or C 0-2 Alkylene C6 heterocycloalkyl etc. Preferably, heterocycloalkyl is heterocyclopropyl, heterocyclobutyl. , heterocyclopentyl, or heterocyclohexyl ring, e.g., a heterocyclohexyl ring etc. Preferably, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Preferably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom, e.g., C 3-6 One nitrogen atom in a heterocycloalkyl ring 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 Alkylaryl, e.g., C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC 1-4 Alkyl Ally C(O)NHBz, Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C (O)NHC 1-4 It can be substituted by haloalkyl, such as C(O)OtBu. 3-6 In a tenth embodiment, any nitrogen atom in the heterocycloalkyl ring is unsubstituted. , R4 is C 1-6 alkylOH, such as CH2OH or CH2CH2OH. In an eleventh embodiment, R4 is O.C. 1-6 Haloalkyl, e.g., OC 1-4 haloalkyl, for example, OCF3 or OCHF2. In a twelfth embodiment, R4 is O-C 0-2 Alkylene C 3-6 Cycloalkyl, e.g., OC 3-6 Cyclo Alkyl, OC1 alkylene C 3-6 Cycloalkyl, OC2 alkylene C 3-6 Cycloalkyl, OC 0- 2 alkylene C3 cycloalkyl, OC 0-2 Alkylene C4 cycloalkyl, OC 0-2 Alkylene C5 Cycloalkyl or OC 0-2 alkylene C6 cycloalkyl, etc. In the thirteenth embodiment, R4 is OC 1-6 Alkyl, especially OC 1-4 Alkyl, for example, methoxy, ethoxy, propoxy (n-propoxy or isopropoxy), or butoxy (n-butoxy, isobutoxy, sec- In a fourteenth embodiment, R4 is OC 0-2 Alkire N C 3-6 Heterocycloalkyl, e.g., OC 3-6 Heterocycloalkyl, OC1 alkylene C 3-6 F Tetracycloalkyl, OC2 alkylene C 3-6 Heterocycloalkyl, OC 0-2 Alkylene C3 Cycloalkyl, OC 0-2 Alkylene C4 heterocycloalkyl, OC 0-2 Alkylene C5 Hetero Cycloalkyl or OC 0-2alkylene C6 heterocycloalkyl, etc. Heterocycloalkyl includes heterocyclopropyl, heterocyclobutyl, and heterocyclopentyl. cyclohexyl, or heterocyclohexyl ring, for example, heterocyclohexyl ring. The heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. , the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Nitrogen atoms, e.g., C 3-6 One nitrogen atom in a heterocycloalkyl ring may be, for example, C 1-4 a Rukill, C(O)H, C(O)C 1-4 Alkyl, C(O)OC 1-4 Alkyl, C(O)OC 1-4 alkylaryl, For example, C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC 1-4 Alkylaryl, e.g., C(O)NHBz etc., Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C(O)NHC 1-4 Haloal It can be replaced by a alkyl, for example, C(O)OtBu. 3-6 Heterocycloa In a fifteenth embodiment, R4 is NR 21 R 22 in be.

[0068] When A is -NHC(=O)- or -C(=O)NH-, preferably R4 is H, C 1-6 Alkyl, C 1-6 Haloal Kill, C 1-6 Alkyl OH, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Hetero Cycloalkyl, C 1-3 Alkylene OC 1-3 alkyl, or R4 and R5 are bonded together C with the carbon atom 3-6 Cycloalkyl or C 3-6 Forming a heterocycloalkyl When A is -NHC(=O)-, preferably R4 is additionally selected from halo, OC 1-6 Haloalkyl, OC 0-2 Al Kiren C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl or NR 21 R 22 You can choose from:

[0069] Suitably R4 is H, fluoro, CH3, ethyl, OCH3, or CH2CH2OCH3, e.g. fluoro, ethyl, OCH3 or CH2CH2OCH3, etc. Suitably R4 is H, CH3, ethyl or CH2CH2OCH3, especially CH3 or ethyl. Preferably, R4 and R5 together with the carbon atoms to which they are attached are cyclopropyl or cyclopentyl. cyclopentyl, especially cyclopentyl.

[0070] Preferably, R4 and R5 together with the carbon atom to which they are attached form heterocyclohexyl, e.g. For example, it forms tetrahydropyranyl or piperidinyl, especially tetrahydropyranyl. Any nitrogen atom, e.g., C 3-6 A nitrogen atom in a heterocycloalkyl ring may be, for example, BaC 1-4 Alkyl, C(O)H, C(O)C 1-4 Alkyl, C(O)OC 1-4 Alkyl, C(O)OC 1-4 Alkyria Reels, such as C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC 1-4 Alkylaryl, e.g., C (O)NHBz etc., Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C(O)NHC 1-4 Ha It can be substituted by alkyl, such as C(O)OtBu. 3-6 Heterogeneity Any nitrogen atom in the chloroalkyl ring is not substituted.

[0071] Preferably, R4 and R5 together with the carbon atom to which they are attached form a heterocyclobutyl, e.g. For example, azetidinyl. Any nitrogen atom, e.g., C 3-6 Heterocycloalkyl ring One nitrogen atom in the 1-4 Alkyl, C(O)H, C(O)C 1-4 Alkyl, C(O)OC 1-4 a Rukill, C(O)OC 1-4 Alkylaryl, e.g., C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC1 -4 Alkylaryl, such as C(O)NHBz, Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Ha alkyl, or C(O)NHC 1-4 It can be substituted by haloalkyl, such as C(O)OtBu. Preferably, C 3-6 Any nitrogen atom in a heterocycloalkyl ring is unsubstituted.

[0072] R4 is NR 21 R 22 In one embodiment, R 21 is H. In a second embodiment, R 21 teeth, C1-5 Alkyl, such as methyl, ethyl or propyl, especially methyl. In R 21 is C(O)C 1-5 alkyl, such as C(O)CH. In a fourth embodiment, R 21 is C (O)OC 1-5 Alkyl, such as C(O)OCH3 or C(O)O tert-butyl. R4 is NR 21 R 22 In one embodiment, R 22 is H. In a second embodiment, R 22 Hame It's chill.

[0073] For example, R4 can be NH2, N(CH3)2, NHC(O)CH3, NHC(O)OCH3, NHC(O)Otert-butyl, and CH2CH 2OH, in particular N(CH3)2, NHC(O)CH3, NHC(O)OCH3. Preferably, R 21 is C(O)OCH3, and R 22 is H. Preferably, R 21 is C(O)CH3, and R 22 is H Preferably, R 21 and R 22 are both CH3. Preferably, R 21 and R 22 are both H is.

[0074] In one embodiment, R5 is C 1-6 Alkyl, especially C 1-4 alkyl, e.g., methyl, ethyl, Propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl) In a second embodiment, R5 is C 1-3 Alkylene OC 1-3 Alkyl, especially C 1-2Alkylene OC 1-2 Alkyl, for example, C1 alkylene, C1 alkyl, C2 alkyl alkylene OC1 alkyl, C1 alkylene OC2 alkyl, or C2 alkylene OC2 alkyl. In a third embodiment, R5 is H. In a fourth embodiment, R5 is halo, such as chloro or is fluoro, and the like, in particular fluoro. In a fifth embodiment, R5 is C 1-6 Haloalkyl, e.g. For example, CF3 or CH2CF3. In a sixth embodiment, R5 is C 0-2 Alkylene C 3-6 Cycloa Lukil, for example, C 3-6 Cycloalkyl, C1 alkylene C 3-6 Cycloalkyl, C2 alkylene C3 -6 Cycloalkyl, C 0-2 Alkylene C3 cycloalkyl, C 0-2 Alkylene C4 cycloalkyl , C 0-2 Alkylene C5 cycloalkyl, or C 0-2 Alkylene C6 cycloalkyl, etc. In seven embodiments, R5 is C 0-2 Alkylene C 3-6 Heterocycloalkyl, e.g., C 3-6 Hetero Cycloalkyl, C1 alkylene C 3-6 Heterocycloalkyl, C2 alkylene C 3-6 Heterothymic Roalkyl, C 0-2 Alkylene C3 heterocycloalkyl, C 0-2 Alkylene C4 heterocyclo Lukil, C 0-2 alkylene C5 heterocycloalkyl, or C 0-2 Alkylene C6 heterocyclo Preferably, heterocycloalkyl is heterocyclopropyl, heterocycloalkyl, etc. a heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl ring, e.g., a heterocyclo Preferably, the heterocyclopentyl ring is a tetrahydrofuranyl or Preferably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom, e.g., C 3-6 One in the heterocycloalkyl ring The nitrogen atom of, 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 Alkylaryl, e.g., C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC 1-4 Archi aryl, such as C(O)NHBz, Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Hello Aruki or C(O)NHC 1-4 It can be substituted by haloalkyl, for example, C(O)OtBu. Preferably, C 3-6 Any nitrogen atom in the heterocycloalkyl ring is not substituted. In an embodiment, R5 is C 1-6 Alkyl-OH, such as CHOH or CHCHOH. Ninth embodiment So, R5 is OC 1-6 Haloalkyl, e.g., OC 1-4 Haloalkyl, for example, OCF3 or OCHF2 In a tenth embodiment, R5 is OC 0-2 Alkylene C 3-6 Cycloalkyl, e.g., OC 3-6 Cycloalkyl, OC1 alkylene C 3-6 Cycloalkyl, OC2 alkylene C 3-6 cycloalkyl , O.C. 0-2 Alkylene C3 cycloalkyl, OC 0-2 Alkylene C4 cycloalkyl, OC0-2 Archi C5 cycloalkyl or OC 0-2 Alkylene C6 cycloalkyl, etc. In embodiments, R5 is OC 1-6 Alkyl, especially OC 1-4 Alkyl, for example, methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, In a twelfth embodiment, R5 is O-C, such as sec-butoxy or tert-butoxy. 0-2 a Rukiren C 3-6 Heterocycloalkyl, e.g., OC 3-6 Heterocycloalkyl, OC1 alkylene C 3-6 Heterocycloalkyl, OC2 alkylene C 3-6 Heterocycloalkyl, OC 0-2 Alkylene C3 heterocycloalkyl, OC 0-2 Alkylene C4 heterocycloalkyl, OC 0-2 Alkylene C5 Heterocycloalkyl, or OC 0-2 alkylene C6 heterocycloalkyl, etc. Heterocycloalkyl includes heterocyclopropyl, heterocyclobutyl, heterocyclopropyl, cyclohexyl or heterocyclohexyl rings, such as heterocyclohexyl rings. In some embodiments, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Preferably, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom, e.g., C 3-6 One nitrogen atom in a heterocycloalkyl ring may be, for example, C1 -4 Alkyl, C(O)H, C(O)C 1-4 Alkyl, C(O)OC 1-4 Alkyl, C(O)OC 1-4 Alkyl Ally C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC 1-4 Alkylaryl, e.g., C(O)N HBz etc., Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C(O)NHC 1-4 Hello It can be substituted by alkyl, for example, C(O)OtBu. 3-6 Heterocyclo In a thirteenth embodiment, R5 is NR 21 R 22 is.

[0075] When A is -NHC(=O)- or -C(=O)NH-, preferably R5 is H, C 1-6 Alkyl, C 1-6 Haloal Kill, C 1-6 Alkyl OH, C 0-2 Alkylene C 3-6 Cycloalkyl, C 0-2 Alkylene C 3-6 Hetero Cycloalkyl, C 1-3 Alkylene OC 1-3 alkyl, or R4 and R5 are bonded together C with the carbon atom 3-6 Cycloalkyl or C 3-6 Forming a heterocycloalkyl When A is -NHC(=O)-, preferably R5 is additionally selected from halo, OC 1-6 Haloalkyl, OC 0-2 Al Kiren C 3-6 Cycloalkyl, OC 0-2 Alkylene C 3-6 Heterocycloalkyl, OC 1-6 Alkyl or NR 21 R 22 You can choose from:

[0076] R5 is NR 21 R 22 In one embodiment, R 21 is H. In a second embodiment, R 21 teeth, C 1-5 Alkyl, such as methyl, ethyl or propyl, especially methyl. In your opinion, R 21 is C(O)C 1-5 alkyl, such as C(O)CH. In a fourth embodiment, R 21 is C(O)OC 1-5 Alkyl, such as C(O)OCH3 or C(O)O tert-butyl. R5 is NR 21 R 22 In one embodiment, R 22 is H. In a second embodiment, R 22 Hame It's chill.

[0077] For example, R5 can be NH2, N(CH3)2, NHC(O)CH3, NHC(O)OCH3, NHC(O)Otert-butyl, and CH2 CH2OH, in particular N(CH3)2, NHC(O)CH3, NHC(O)OCH3. Preferably, R 21 is C(O)OCH3, and R 22 is H. Preferably, R 21 is C(O)CH3, and R 22 is H Preferably, R 21 and R 22 are both CH3. Preferably, R 21 and R 22 are both H is. Suitably R5 is H, F, CH3, or ethyl, such as H, CH3, or ethyl.

[0078] Preferably R4 is H, CH3, ethyl, or CH2CH2OCH3, and R5 is H, CH3 or ethyl, especially R4 is CH3 or ethyl, and R5 is H, methyl, or ethyl. For example, R4 and R5 are H, R4 and R5 is methyl, R4 and R5 are ethyl, or R4 is CH2CH2OCH3 and R5 is H. Preferably, R4 is F and R5 is ethyl. Preferably, R4 is F and R5 is also F. Preferably, R4 is ethyl and R5 is H.

[0079] Preferably, R4 and R5 are arranged in the following configuration: [ka] .

[0080] In one embodiment, Ar1 is a 6-membered aryl, i.e., phenyl. Ar1 is a 6-membered heteroaryl, especially one nitrogen atom (pyridyl) or two nitrogen atoms. Contains an atom (pyridazinyl, pyrimidinyl or pyrazinyl).

[0081] In particular, Ar1 is phenyl, 2-pyridyl, or 3-pyridyl, e.g., phenyl or 2-pyridyl. The position numbering for Ar1 is based on the amide, with the carbon at the attachment point being the 1st position, The numbers other than indicate the relative position of the nitrogen atom, e.g.: [ka] .

[0082] In one embodiment, R 10 is H. In a second embodiment, R 10 is halo, e.g. fluoro or chloro, etc. In a third embodiment, R 10 is C 1-3 Alkyl, e.g., C 1-2 Alkyl etc., such as CH3 or ethyl etc. In a fourth embodiment, R 10 is O.C. 1-2 Alkyl, e.g. In a fifth embodiment, R 10 is O.C. 1-2 Haloalkyl, e.g. OCF3, etc. In a sixth embodiment, R 10 In a seventh embodiment, R 10 is C 1-2 Ha and alkyl, such as CF3.

[0083] Preferably, R 10 is H, fluoro, chloro, CH3, CF3, OCH3, OCF3 or CN, e.g., H, fluoro, chloro Fluoro, chloro, CH3, OCH3, OCF3 or CN, in particular H, fluoro, chloro, OCH3, OCF3 or CN, especially H or fluoro. Preferably, R 10 is H, F or CH3.

[0084] In one embodiment, R 11 is H. In a second embodiment, R 11 is F. Third embodiment In your opinion, R 11 is C 1-2 Alkyl, such as CH3 or Et, for example CH3. So, R 11 is OCH3. In a fifth embodiment, R 11 In a sixth embodiment, R1 is Cl. 1 is Et. In a seventh embodiment, R 11 In an eighth embodiment, R 11 is CN do. Preferably, R 11 is H, F, CH3 or OCH3, such as H, F or CH3, for example H or F, e.g. For example, H.

[0085] In one embodiment, R 10 is in the ortho position relative to the amide. 10 Haa Preferably, R 10 is in the ortho position relative to the amide. In one embodiment, R 11 is in the ortho position relative to the amide. 11 Haa Preferably, R 11 is in the ortho position relative to the amide.

[0086] In one embodiment, Ar2 is a six-membered aryl, i.e., phenyl. Ar2 is a 6-membered heteroaryl, especially one nitrogen atom (pyridyl) or two nitrogen atoms. Contains an atom (pyridazinyl, pyrimidinyl or pyrazinyl).

[0087] The numbering of positions on Ar2 is relative to the point of attachment to Ar1, for example: [ka] . In particular, Ar2 is 3-pyridyl or 2,5-pyrazinyl, especially 2,5-pyrazinyl.

[0088] In one embodiment, R 12 is H. In a second embodiment, R 12 is halo, e.g. fluoro or chloro. In a third embodiment, R 12 is C 1-4 Alkyl, e.g., methyl, ethyl , propyl (n-propyl or isopropyl), or butyl (n-butyl, isobutyl, sec- butyl or tert-butyl). In a fourth embodiment, R 12 is O.C. 1-4 Alkyl, e.g. For example, OCH3, ethoxy, isopropoxy, or n-propoxy. In a fifth embodiment, R 12 is O.C. 0-2 Alkylene C 3-5 Cycloalkyl, e.g., OC 3-5 Cyclo Alkyl (e.g., cyclopropoxy or cyclobutoxy), OC1 alkylene C 3-5 Cycloa alkyl, or OC2 alkylene C 3-5 In a sixth embodiment, R 12 is CN In a seventh embodiment, R 12 is C 1-4 haloalkyl, such as CF3. In the embodiment, R 12 is O.C. 1-4 haloalkyl, such as OCF3, OCHF2, or OCH2CF3. In ninth embodiment, R 12 is C 2-4 Alkenyl, for example, C(=CH2)CH3. Tenth embodiment In your opinion, R 12 is C 0-2 Alkylene C 3-5 Cycloalkyl, e.g., C 3-5 Cycloalkyl, C1 alkyl Rukiren C 3-5 Cycloalkyl, C2 alkylene C 3-5 Cycloalkyl, C 0-2 Alkylene C3 Cyclo Roalkyl, C 0-2 Alkylene C4 cycloalkyl, or C 0-2 Alkylene C5 cycloalkyl etc. In an eleventh embodiment, R 12 In a twelfth embodiment, R 12 is C 1-4 alkylOH, such as CHOH. In a thirteenth embodiment, R 12 is SO2C 1-2 Al In a fourteenth embodiment, R 12 is C(O)N(C 1-2 alkyl)2, For example, C(O)N(CH). In a fifteenth embodiment, R 12 is NHC(O)C 1-3 It is alkyl. In a sixteenth embodiment, R 12 is NR 23 R 24 In a seventeenth embodiment, R 12 is OCH2CH2N(CH 3) 2. In an eighteenth embodiment, R 12 is a C with one nitrogen atom at the point of attachment to Ar2 3-6 Preferably, the heterocycloalkyl is a heterocyclopropane. propyl, heterocyclobutyl, heterocyclopentyl, or heterocyclohexyl ring, e.g. For example, a heterocyclohexyl ring. Preferably, the heterocyclopentyl ring is a pyrrolidinyl ring. Preferably, the heterocyclohexyl ring is piperidinyl or piperazinyl. Any nitrogen atom, e.g. C 3-6 One nitrogen atom in a heterocycloalkyl ring, e.g., 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, e.g., C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC 1-4 Alkylaryl, e.g. For example, 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. 3-6 Haitai In a nineteenth embodiment, R is substituted with any nitrogen atom in the cycloalkyl ring. 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) is formed.

[0089] When A is -NHC(=O)- or -C(=O)NH-, preferably R 12 is in the ortho or meta position with respect to Ar1 is bonded to Ar2 by R 12 H, halo, C 1-4 Alkyl, C 2-4 Alkenyl, C 0-2 Al Kiren 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 Alkyl OH, SO2C 1-2 Alkyl, C( O)N(C 1-2 alkyl)2, NHC(O)C 1-3 Alkyl or NR 23 R 24 is.

[0090] When A is -NHC(=O)-, preferably R 12 at the attachment points to CN, OCH2CH2N(CH3)2, and Ar2. C containing one nitrogen atom located 3-6 may additionally be selected from heterocycloalkyl; is R 12 together with the nitrogen atom to which it is attached form an N-oxide (N + -O - ) can be formed.

[0091] The present invention provides N-oxides of compounds of formula (I). Suitably, R 12 But it is bound N-oxide (N + -O - ), the following example structure is formed: [ka] .

[0092] R 12 is preferably H, F, Cl, CH3, OCH3, OEt, OiPr, Ocyclopropyl, CN, CF3, OCHF2 , or OCH2CF3. In particular, R 12 is Cl, CN, CF3, OCHF2, OCH2CF3, OCH3, OEt, OiPr, Ocyclopropyl, such as CF3, OCHF2, OCH2CF3, OCH3, OEt, OiPr, Ocyclopropyl, etc. For example, OEt.

[0093] R 12 is preferably H, F, Cl, CH3, iPr, OCH3, OEt, OiPr, Ocyclopropyl, CN, CF3, OCHF2, OCH2CF3, C3 cycloalkyl, or C(=CH2)CH3. In particular, R 12 are Cl, iPr, and OC H3, OEt, OiPr, Ocyclopropyl, CN, CF3, OCHF2, OCH2CF3, C3 cycloalkyl, or C (=CH2)CH3, e.g. Cl, OCH3, OEt, OiPr, Ocyclopropyl, CF3, OCHF2, OCH2CF3 or C3 Cycloalkyl and the like, for example OEt. When A is -C(=O)NH-, preferably R 12 is CF3, OEt, or OiPr, such as OEt or OiPr, do. Preferably R 12 is the meta position of Ar2. Alternatively, R 12 is the ortho position of Ar2.

[0094] In one embodiment, R13 is H. In another embodiment, R 13 is halo, such as F or Cl, Preferably it is F. In one embodiment, R 13 is in the ortho position relative to Ar. 13 is Ar1 In another embodiment, R 13 is in the meta position with respect to Ar1.

[0095] In one embodiment, R 23 is H. In another embodiment, R 23 is C 1-2 Alkyl, e.g., methyl Chill et al. In one embodiment, R 24 is H. In another embodiment, R 24 is C 1-2 Alkyl, e.g., methyl Chill et al. Preferably, R 23 is H and R 24 is ethyl. Preferably, R 23 is CH3 and R 24 is CH3 do. Desirably, the compound of formula (I) is 2-(6-(methylsulfonamido)pyrazin-2-yl)-N-(4- (pyridin-3-yl)phenyl)acetamide is not included.

[0096] In one embodiment, at least one R 10 , R 11 , R 12 , and R 13 is other than H. Preferably, at least one of R4, R5, R 10 , R 11 , R 12 , and R 13 is other than H. More preferably, when R1 is methyl, at least one of R4, R5, R 10 , R 11 , R 12, and R 13 is other than H.

[0097] Throughout the specification, Ar1 and Ar2 can be represented as follows: [ka] .

[0098] All statements regarding Ar1 are of equal value, and all statements regarding Ar2 are of equal value, Unless the context dictates otherwise, the descriptions of Ar1 and Ar2 exclude the presence of heteroatoms or substitutions. should not be construed as

[0099] The present invention provides a compound according to any one of Examples P1 to P111. The present invention also provides the compounds described in any one of Examples P112 to P115. The present invention also provides the compounds described in any of Examples P116 to P225.

[0100] The present invention provides the following compounds: N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-cyclopropanesulfonamido)pyridin (midin-4-yl)butanamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)phenyl)cyclopentanecarboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazine-2 -yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(5-(trifluoromethyl)-2- ... (Oromethyl)pyridin-3-yl)phenyl)propanamide; 2-Methyl-N-(2-methyl-4-(6-methylpyrazin-2-yl)phenyl)-2-(2-methylsulfonyl) (mido)pyrimidin-4-yl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyrazine- 2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(trifluoromethyl) 1)pyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl) (I)pyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropoxypyridine) (pyridin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)phenyl)-2-ethylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-trifluoromethyl)-pyrimidin-4-yl)- (fluoromethyl)pyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropyl) (2-hydroxypyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(trifluoromethyl) phenyl)pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(2,2,2-trifluoromethyl)-2-pyrimidin-4-yl)- (Iroethoxy)pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)-N-(4-(pyridine- 3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)- Nyl)acetamide; N-([1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl) r) acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazine-2 -yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(2,2,2-trifluoromethyl)-2-pyrimidin-4-yl)- (2-chloroethoxy)pyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropoxypyridine) Zin-2-yl)phenyl)acetamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2- yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropyl) (2-(2-hydroxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2- yl)-2-methylphenyl)-2-methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazine-2- (yl)phenyl)-2-methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2- (yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)-3-fluoropyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5'-ethoxy-[3,3'-bipyridin-4-yl] Lysine]-6-yl)-2-methylpropanamide; N-([3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl) (I)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(5-(6-(trifluoromethyl)-2- ... (Oromethyl)pyrazin-2-yl)pyridin-2-yl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6- ... radin-2-yl)pyridin-2-yl)-2-methylpropanamide; N-(2-chloro-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-cyclopropanesulfone) Amido)pyrimidin-4-yl)-2-methylpropanamide; N-(2-cyano-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-cyclopropanesulfone) Amido)pyrimidin-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(5-isopropyl) (3-hydroxypyridin-3-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyridine- 3-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-trifluoromethyl)-pyrimidin-4-yl)- (fluoromethyl)pyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropyl) (2-propyl)pyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-fluoro-5-methylphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2,6-difluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyrazine- 2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(2-methyl-4-(6- (Trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2,3-dimethylphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-5-fluoro-2-methylphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2,5-dimethylphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-(trifluoromethoxy)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-5-fluoro-2-methoxyphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-methoxyphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(pyrimidine- 5-yl)phenyl)propanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-cyclopropanesulfonamido)pyridin (midin-4-yl)-2-methylpropanamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyridin) (midin-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-fluoropyridine-3 -yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(5-methylpyrimidin-4-yl) Lysin-3-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(difluoromethacrylamide) C) pyridin-3-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-methoxypyridine-3 -yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-ethoxypyridine-3 -yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-isopropoxypyrimidin-4-yl)- (diphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(pyridine-3- (yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(3'-(trifluoromethyl)-2- ... (trimethyl)-[1,1'-biphenyl]-4-yl)propanamide; N-(3'-chloro-[1,1'-biphenyl]-4-yl)-2-(2-cyclopropanesulfonamido)pyrimidin Zin-4-yl)-2-methylpropanamide; N-(3'-cyano-[1,1'-biphenyl]-4-yl)-2-(2-(cyclopropanesulfonamido)pyrimidinyl) Zin-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3'-ethoxy-[1,1'-biphenyl] [phenyl]-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl)-2- ... (Oromethyl)pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6- ... radin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropoxypyridine) Zin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)-N-(4-(6-ethoxy) Sipirazin-2-yl)phenyl)-2-methylpropanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((1-methylcyclopropane )-1-sulfonamido)pyrimidin-4-yl)propanamide; 2-(2-(cyclopropanesulfonamido)-5-methylpyrimidin-4-yl)-N-(4-(6-ethoxy) Pyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(pyrazine-2- (yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-(2-ethylsulfonamide) pyrimidin-4-yl)-2-methylpropanamide; 2-(2-(ethylsulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(trifluoromethyl) (I)pyrazin-2-yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2-(ethylsulfonamido)pyrimidine- 4-yl)-2-methylpropanamide; N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2-methyl-2-(2-(methyl (sulfonamido)pyrimidin-4-yl)propanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methyl-2-(2-methylsulfonyl) (mido)pyrimidin-4-yl)propanamide; N-(2-fluoro-4-(5-isopropoxypyridin-3-yl)phenyl)-2-methyl-2-(2-methyl sulfonamido)pyrimidin-4-yl)propanamide; N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-methyl Sulfonamido)pyrimidin-4-yl)propanamide; 2-methyl-N-(2-methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2-(2-(methyl Thilsulfonamido)pyrimidin-4-yl)propanamide; 2-Methyl-2-(2-(methylsulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl) (I)pyrazin-2-yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-methylsulfonamido)pi rimidin-4-yl)propanamide; 2-(2-((1,1-dimethylethyl)sulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyridine) Zin-2-yl)phenyl)-2-methylpropanamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)phenyl)cyclopropanecarboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5'-(trifluoromethyl) -[3,3'-bipyridin]-6-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5'-(2,2,2-trifluoromethyl)pyrimidin-4-yl)- Ethoxy)-[3,3'-bipyridin]-6-yl)butanamide; N-([3,3'-bipyridin]-6-yl)-2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl) l) butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-(trifluoromethyl) yl)pyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropoxypyridine) (pyridin-2-yl)pyridin-2-yl)butanamide; N-(4-(5-chloropyridin-3-yl)-2-fluorophenyl)-2-(2-cyclopropanesulfone) Amido)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-isopropyl) (3-hydroxypyridin-3-yl)phenyl)butanamide; 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)-pyrimidin-4-yl)- (fluoromethyl)pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-methoxy) Sipirazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-isopropyl) (2-hydroxypyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(6-(2,2,2- Trifluoroethoxy)pyrazin-2-yl)phenyl)butanamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyridin) (midin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(2,2,2-trifluoromethyl)-2-pyrimidin-4-yl)- (isoethoxy)pyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-isopropoxypyrimidin-4-yl)- Zin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)- nil)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl) (I)pyrazin-2-yl)phenyl)butanamide; N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(2-(cyclopropanesulfonamido)pyri (midin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazine-2 -yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropoxypyridine) Zin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(2,2,2-trifluoromethyl)-2-pyrimidin-4-yl)- (2-chloroethoxy)pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyrazin-2-yl)phenyl)- nil)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)phenyl)-4-methoxybutanamide; and 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(pyridin-3-yl)phenyl)- Nyl)propanamide.

[0101] The present invention also provides the following compound: 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)-2-(R)-fluorobutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)-2-(S)-fluorobutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)-2-fluorobutanamide; and 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide.

[0102] The present invention also provides the following compound: 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropylpyrazine) (2-methyl-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-fluorophenyl)-2,2-difluoroacetamide; N-((2-(cyclopropanesulfonamido)pyrimidin-4-yl)methyl)-4-(6-ethoxypyrazole) Zin-2-yl)benzamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(5-(6-(propan-1-yl)methyl)-2- ... -en-2-yl)pyrazin-2-yl)pyridin-2-yl)propanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(5-(6-ethoxy) Pyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-( 5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyridine) (pyridin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(6-(6-ethoxypyrazine-2 -yl)pyridin-3-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropylpyridine) Zin-2-yl)-2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4-(6-ethoxy) Pyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-( 4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6-(propan-1-yl)methyl)-2-methyl) -en-2-yl)pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-isopropylpyrazine) (phenyl-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(dimethylamino)pyrimidin-4-yl)- radin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4-(6-ethoxy) Pyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin-4-yl)-N-( 4-(6-ethoxypyrazin-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-ethoxypyrazine-2 -yl)pyridin-2-yl)cyclopentane-1-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)phenyl)tetrahydro-2H-pyran-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(methylsulfonamido)pyridin-2-yl)- (imidin-4-yl)piperidine-4-carboxamide; tert-Butyl 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-((5-(6-ethoxy) pyrazin-2-yl)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)piperidine-4-carboxamide; tert-Butyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-3-((5-(6-ethoxy) pyrazin-2-yl)pyridin-2-yl)carbamoyl)azetidine-1-carboxylate; tert-Butyl 4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)-4-(2-( Methylsulfonamido)pyrimidin-4-yl)piperidine-1-carboxylate; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-fluorophenyl)tetrahydro-2H-pyran-4-carboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)-3-fluoropyridin-2-yl)-4-methoxybutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)-4-methoxybutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-fluorophenyl)-4-methoxybutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methyl-2-(2-(methyl (sulfonamido)pyrimidin-4-yl)butanamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-2-(2-cyclopropanesulfonamido)pyrimidin (din-4-yl)butanamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-2-(2-cyclopropanesulfonamido)pyrimidin Zin-4-yl)-2-fluorobutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyridine) (Pyridin-2-yl)pyridin-2-yl)-2-fluorobutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-methylsulfone) Amido)pyrimidin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)-3-methylpyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-cyclopropylpyridine) (pyridin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-(2,2,2-trifluoromethyl)pyrimidin-4-yl ... (Ethoxy)pyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3-fluoro-5-(6-methoxy) Sipirazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-methoxypyrazine-2 -yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-cyclopropylpyridine) Zin-2-yl)-2-fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-methylphenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)-3-fluoropyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)-2-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)-2-fluoro-3-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)-2-fluorophenyl)-3-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)-3-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine-2 -yl)phenyl)-2-methoxyacetamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-methylsulfone) Amido)pyrimidin-4-yl)-(R)-butanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-methylsulfone) Amido)pyrimidin-4-yl)-(S)-butanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6-cyclopropanesulfonamido)pyridin Zin-2-yl)acetamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(6-(cyclopropanesulfonamido)pyridin) Zin-2-yl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-fluoropyridine-3- (yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-methoxypyridine-3- (yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(pyridin-3-yl)phenyl)- r) acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-(trifluoromethyl) Pyrazin-2-yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-methoxypyrazine-2-yl) (yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(pyrazin-2-yl)phenyl) r) acetamide; N-([3,3'-bipyridin]-6-yl)-2-(6-(cyclopropanesulfonamido)pyridin-2-yl) -2-methylpropanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6-cyclopropanesulfonamido)pyridin Zin-2-yl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-fluoropyridine-3- (yl)phenyl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5-ethoxypyridine-3- (yl)phenyl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4-(pyridin-3-yl) (phenyl)propanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(2-fluoro-4-(pyrazine-2-yl) (yl)phenyl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4-(6-(trifluoromethyl)-2-methyl- (trimethyl)pyrazin-2-yl)phenyl)propanamide; N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(6-cyclopropanesulfonamido)pyri Zin-2-yl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazine-2-yl) (yl)phenyl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-methoxypyrazine-2-yl) (yl)phenyl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4-(pyrazine-2-yl) (phenyl)propanamide; 4-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-(trifluoromethyl) Pyrazin-2-yl)pyridin-2-yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)butanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6-cyclopropanesulfonamido)pyridin Zin-2-yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazine-2-yl) (yl)-2-fluorophenyl)butanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6-ethoxypyrazine-2-yl) yl)phenyl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)- r) acetamide; 2-(6-(ethylsulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetate Toamide; 2-(6-(methylsulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3-yl)phenyl)acetate Toamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazine-2-yl) (yl)phenyl)-2-methylpropanamide; 4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)-4-methoxy-2-methylbutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methyl-2-(6-methyl (sulfonamido)pyrazin-2-yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)-2-fluorobutanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazine-2-yl) yl)phenyl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)-2-methoxyacetamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6-ethoxypyrazine-2-yl) (yl)phenyl)-2-methoxyacetamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)-2-methoxypropanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)-2-(R)-fluorobutanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6-ethoxypyrazine-2-yl) yl)pyridin-2-yl)-2-(S)-fluorobutanamide; 2-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6-ethoxypyrazine-2 -yl)pyridin-2-yl)butanamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)cyclopropyl)-4-(6-ethoxy)- (2-thoxypyrazin-2-yl)-2-fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-5-(6-ethoxy Pyrazin-2-yl)picolinamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-2-fluoro-4-( 5-(trifluoromethyl)pyridin-3-yl)benzamide; 4-(5-chloropyridin-3-yl)-N-(1-(2-(cyclopropanesulfonamido)pyrimidine-4- (yl)propyl)-2-fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(5-(trifluoromethyl)-2-pyrimidin-4-yl)propyl) (Oromethyl)pyridin-3-yl)benzamide; 4-(5-chloropyridin-3-yl)-N-(1-(2-(cyclopropanesulfonamido)pyrimidine-4- (yl)propyl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-ethoxy Pyrazin-2-yl)-2-(trifluoromethyl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-ethoxy Pyrazin-2-yl)-2-fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-(trifluoromethyl)-2-pyrimidin-4-yl)propyl) (Oromethyl)pyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-isopropyl (poxypyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4-(6-ethoxy pyrazin-2-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butan-2-yl)-4-(6-ethoxy) xypyrazin-2-yl)-2-fluorobenzamide; N-(2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl)-2-fluoro rho-4-(6-isopropoxypyrazin-2-yl)benzamide; N-(2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl)-4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl) (trifluoromethyl)pyrazin-2-yl)benzamide; N-(1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6-ethoxypyrazole) radin-2-yl)-2-fluorobenzamide; N-(1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6-ethoxypyrazole) (R)-2-(radin-2-yl)-2-(R)-fluorobenzamide; and N-(1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6-ethoxypyrazole) radin-2-yl)-2-(S)-fluorobenzamide.

[0103] The compounds of the present invention may be pharmaceutically acceptable salts and / or solvates thereof, and / or can be provided in the form of their derivatives. In particular, the compounds of formula (I) can be used as pharmaceuticals Provide it in the form of an acceptable salt and / or solvate, such as a pharmaceutically acceptable salt. can be done.

[0104] Compounds of the invention of particular interest are those that inhibit the CTPS1 enzyme using the methods of the Examples (or equivalent methods). IC<1uM, especially IC<100nM 50 This shows that.

[0105] Compounds of the invention of particular interest are those that bind to select CTPS1 receptors using the methods of the Examples (or equivalent methods). The selectivity is 2 to 30 times, preferably >30 to 60 times, or more preferably >60 times, that of CTPS2. Desirably, the selectivity of human CTPS1 is greater than that of human CTPS2.

[0106] Salts of the compounds of formula (I) for pharmaceutical use should be pharmaceutically acceptable. It will be understood that non-pharmaceutically acceptable salts of compounds of formula (I) are salts of compounds of formula (I) It may be used in other cases, such as during the preparation of the compound. Salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts are those described in Berge et al. (1977) Such pharmaceutically acceptable salts include those described in the acid and base addition salts. Pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid or phosphoric acid, etc., and organic acids such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalenesulfonic acid Other salts, such as oxalates or formates, can also be formed, e.g. Compounds of formula (I) may be used in isolated form and are within the scope of the present invention.

[0107] Some compounds of formula (I) may be reacted with an equimolar or greater amount of an acid or base to form an acid or base addition salt. The present invention encompasses all possible stoichiometric and non-stoichiometric forms thereof. Included in the range. The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and if crystalline, , optionally solvated, for example as a hydrate. The present invention relates to stoichiometric solvates. Also within the scope are compounds containing various amounts of solvent (e.g., water), as well as compounds containing various amounts of solvent (e.g., water). include.

[0108] The present invention includes pharmaceutically acceptable derivatives of the compounds of formula (I), which are within the scope of the present invention. It should be understood that the terms "a", "b", "c", "d" and "e" are included within the scope of the present invention. As used herein, a "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable derivative. Prodrugs thereof also include, for example, esters of the compounds of formula (I) or salts of such esters. , which, when administered to a recipient, produce compounds of formula (I) or their active metabolites or capable of providing (directly or indirectly) residues.

[0109] The present invention includes all isomers of formula (I) and their pharmaceutically acceptable derivatives: All geometric, tautomeric and optical isomeric forms, and mixtures thereof (e.g., It should be understood that the term "racemic mixture" includes compounds of formula (I). When present in a compound, the present invention includes within its scope all possible diastereoisomers and their The different isomeric forms can be separated or resolved one from the other by conventional methods. or any given isomer can be obtained by conventional synthetic methods or by stereospecific synthesis. It can also be obtained by chiral or asymmetric synthesis.

[0110] The present disclosure includes all isotopic forms of the compounds of the invention described herein, which may be in the form Regardless of the atomic number, (i) all atoms of a given atomic number have a mass number that is predominant in nature ( or a mixture of mass numbers) form (referred to herein as "natural isotopes"); or (ii) 1 These atoms have the same atomic number but have a mass number different from the mass number of the atom that predominates in nature. forms in which atoms corresponding to the hydroxyl group are substituted (referred to herein as "non-natural variant isotopes") It is understood that an atom may exist in nature as a mixture of multiple mass numbers. The term "non-natural variant isotopes" also refers to isotopes that are known to be less common in nature. An atom of a given atomic number having a mass number that is known (herein referred to as an "uncommon isotope") is The proportion of atoms with that atomic number is increased relative to the natural type, for example, by >20% , including embodiments where the level is >50%, >75%, >90%, >95% or >99%. (The latter embodiment is referred to as an "isotopically enriched variant.") The term "non-naturally occurring variant" "Isotope" also includes embodiments in which the proportion of uncommon isotopes is reduced relative to the natural form. Isotopes are available in radioactive forms (i.e., they incorporate a radioactive isotope) and non-radioactive forms. The radioactive form will usually be an isotopically enriched variant.

[0111] Thus, a non-natural variant isotope of a compound may contain one or more artificial or uncommon isotopes, e.g. For example, deuterium ( 2 H or D), carbon 11 ( 11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen 13( 13N), 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) etc., one or more elements The isotopes may be present in the element, and may be enriched in an amount greater than the amount predominant in nature. It may also contain the above atoms.

[0112] Non-natural variant isotopes, including radioactive isotopes, may be used, for example, to enhance the tissue composition of the drug and / or substrate. It can be used for fabric research. 3 H, and carbon 14, i.e. 14 C is particularly useful for this purpose due to its ease of incorporation and the availability of detection methods. Deuterium, that is, 2 Unnatural variant isotopes incorporating H or D have better metabolic stability. A particular therapeutic advantage resulting from a higher concentration of hydroxybenzoates, such as a longer in vivo half-life or This may be preferable in some circumstances as it may result in a reduction in dosage. Non-natural variant isotopes include positron-emitting isotopes, e.g. 11 C. 18 F, 15 O and 13 Incorporating N etc. and positron emission tomography (PET) to examine substrate receptor occupancy. It will be useful to

[0113] In one embodiment, the compounds of the invention are provided with natural isotopes. In one embodiment, the compounds of the present invention are provided in non-natural variant isotopes. In an embodiment, non-natural variant isotopes are those in which hydrogen is substituted into one or more atoms of a compound of the invention. Deuterium (i.e., 2 H or D) is incorporated. In one embodiment, the atoms of the compounds of the present invention are isotopes that are not radioactive. In an embodiment, one or more atoms of a compound of the invention are isotopes that are radioactive. The radioisotope is a stable isotope. Preferably, a non-natural variant isotope is used as a pharmaceutical. This is an acceptable form.

[0114] In one embodiment, the compounds of the present invention comprise a non-natural variant isotope at only one atom of the compound. In another embodiment, the compounds of the present invention are provided as Non-natural variants are provided as isotopes.

[0115] Non-naturally occurring isotopic variants are generally prepared by conventional techniques known to those skilled in the art or by methods disclosed herein. The processes described herein, for example those described in the examples for preparing natural isotopes, Therefore, non-natural isotopic variants can be prepared by processes similar to those of The compound may be a suitable isotopic variant (or labeled) instead of the conventional reagent employed in this example. The compounds of formula (I) are intended for use as pharmaceutical compositions. As shown, each of them is preferably in substantially pure form, e.g., 60% pure. More preferably, the purity is 75% or more, and more preferably 85% or more, and particularly preferably 98% or more (% is It will be readily understood that impure preparations of the compounds are provided on a weight / weight basis. It can be used to prepare the purer forms used in pharmaceutical compositions.

[0116] In general, compounds of formula (I) can be prepared by organic synthesis techniques known to those skilled in the art, as well as by the methods shown below. The compounds can be prepared by the representative methods described above, those in the Examples, and modifications thereof.

[0117] (General route) General routes by which exemplary compounds of the present invention can be conveniently prepared are outlined below. Scheme 1a [ka] Scheme 1b [ka]

[0118] Generally, Scheme 1a (wherein R1, R3, Ar1 and Ar2 are as defined above and R4 is H or Et), or Scheme 1b (wherein R1, R2, R3, Ar1 and Ar2 are as defined above, As shown in the formula (I), the compound of formula (I) can be prepared by the 2,4-dichloro- It can be prepared in 4 or 5 steps starting from a pyrimidine derivative. ester derivative to displace the more reactive chloride to give a compound of formula (VII) ) can form an intermediate compound of the formula: Such a reaction is most effective in the presence of a strong base such as sodium hydride. If mono-alkylation is desired, an intermediate Compound (VII) is reacted with an inorganic base such as sodium hydroxide and an alkylating agent such as ethyl iodide (EtI). Treatment in the presence of methyl groups affords compounds of general formula (V). In this case, the compound of general formula (VII) can be directly converted to the compound of general formula (IV) (see below). (see note).

[0119] Palladium-catalyzed sulfamination of 2-chloropyrimidine derivatives (VII) and (V) Using catalysts such as [t-BuXPhosPd(allyl)]OTf and substituted sulfonamide nucleophiles (VI), This reaction can be carried out in the presence of an inorganic base, such as potassium carbonate, to form the intermediate derivative (IV). This compound can then be converted to hydroxybenzoates via decarboxylation initiated by the use of a strong acid such as TFA. The intermediate derivative (II) can be obtained by deprotection. Such reactions are carried out at temperatures ranging from 0°C to room temperature. The reaction is carried out in DCM at 37°C.

[0120] Compounds of general formula (I) can be prepared by converting intermediate (II) in a one-step or two-step process. First, saponification using a reagent such as TMSOK gives the intermediate carboxylic acid derivative, followed by and reacting it with an activating agent to give a reactive electrophilic carboxylic acid derivative, which is then reacted with an amine of formula (III) or a suitably protected derivative thereof. ,2,4,6-Trioxatriphosphorinane-2,4,6-trioxide (T3P) is a carboxyl group-activated Another approach is to use trimethylaluminum (usually in toluene). or a 2.0 M solution in heptane) to directly activate the ester moiety and add the amine (III) These reactions are usually carried out in a solvent such as toluene at 80-100°C for several hours. do.

[0121] If an alkoxy (R4 = OMe) linker is required, the compound may be a 2,4-dichloro It can be prepared in four steps starting from a pyrimidine derivative (Scheme 1b). Derivative (VIII) has the symmetric malonate to form an intermediate compound of formula (VII) where R4 = OMe. This compound can then be coupled with a primary sulfonamide under the conditions previously described. Compounds of formula (IV) in which the alkyl group is methyl can be decarboxylated using an alkali metal base. The intermediate carboxylate can be deprotected to give the intermediate derivative (XXVI). The sylate derivative (XXVI) can be converted to the final compound of formula (I) via amide coupling as described above. A compound can be obtained.

[0122] Scheme 2a [ka] Scheme 2b [ka]

[0123] Preferably, when R2 is H, (IX) is reacted with a base and an alkyl halide or X-CH2-(CH2)nX (formula where n=1, 2, 3) to (X) to obtain compounds of general formula (I) in a five-step process. do.

[0124] Generally, as shown in Schemes 2a and 2b, compounds of general formula (I) can be prepared by reacting two compounds of general formula (VIII) It may be obtained in a five or six step process from a 4-dichloropyrimidine derivative. Conductor (VIII) can be reacted with an unsymmetrical malonate as shown in Scheme 1a, 1b, 2a or 2b. This intermediate compound can then be deprotected at this stage and reacted with a strong acid such as TFA. The intermediate derivative (IX) can be obtained via decarboxylation starting with R3 = H. Some intermediates, such as (IX), are commercially available. Methyl 2-(2-chloro)-2-methylpropanol of general formula (IX) The reaction of the (pyrimidin-4-yl)acetate derivative with an inorganic base such as potassium carbonate gives the alkyl In the presence of alkylating agents, this leads to α-alkylation to esters. Both mono- and di-alkylation It will be understood by those skilled in the art that this can be achieved by careful control of reaction conditions. For a more reliable synthesis of the monoalkylated product, an alternative procedure (as in Scheme 1a) As mentioned above, (IX) to (X) are combined with R4 and R5 to form C 3-6 Cycloalkane Such compounds can be reacted with 1, By double alkylation with dihaloalkanes such as 2-dibromoethane or 1,3-dibromobutane It may be prepared.

[0125] Palladium-catalyzed sulfamination of intermediate (X) can be carried out using [t-BuXPhosPd(allyl)]OTf or The catalytic activity of t-BuXPhos-Pd-G3 and substituted sulfonamide nucleophiles (VI) was investigated. This can be carried out in the presence of an organic base, such as potassium carbonate, to form the intermediate derivative (II). The conversion of intermediate (II) to compounds of general formula (I) can be carried out by annealing the intermediate (II) in trimethylaluminum (usually 2.0 M trimethylaluminum). The ester moiety is activated using a solvent such as toluene or heptane, and then the amine (III) (commercially available available or can be prepared according to Schemes 6a, 6b, 7a, or 7b) It can be prepared by converting

[0126] Compounds of general formula (VII) where R2 is O-alkyl can be obtained from commercially available 2,4,6 -trichloropyrimidine derivatives can be accessed in two steps. Reaction of this with methyltrimethylsilyl can give compounds such as (VII), which can then be reacted with sodium methoxide, etc. alkoxide base to displace the more reactive chloride and form the R2 = O-alkyl Such compounds can then be reacted with the above-mentioned scrubs to produce compounds of the general formula (VII) The final compound of formula (I) can be obtained by following the steps described in Section 2a or 2b. do.

[0127] A compound of general formula (I) (wherein R1, Ar1 and Ar2 are as defined above, and R4 and R5 are each independently C together with the carbon atom to which they are attached 3-6 forming a heterocycloalkyl) is represented by the general formula ( VIII) can be prepared in four steps. First, an alkyl ester of general formula (XXVII) The ter is treated with a strong base such as LHMDS and then reacted with a 2,4-dichloropyrimidine such as derivative (VIII). Such compounds can then be further synthesized using the method described in Scheme 2b to give the final product. If any protecting groups remain after amide coupling, TF Treatment with a strong acid such as A can provide the final compound of formula (I).

[0128] R5 is a halo such as F and R4 is C 1-6 For compounds that are alkyl, a two-step procedure is carried out to prepare the compound of formula (IX) can be converted to (X), see Scheme 2b. First, to the ester Mono-α-alkylation of the compound is carried out in the presence of an inorganic base such as potassium carbonate and an alkylating agent. This can be achieved by reacting these products with a strong base such as LHMDS followed by N-fluoro exposure to a fluorinating agent such as rho-N-(phenylsulfonyl)benzenesulfonamide; A compound of formula (X) can be obtained.

[0129] Scheme 3 [ka]

[0130] Generally, as shown in Scheme 3, compounds of general formula (I) (wherein R3 is H) can be prepared by the synthesis of As specified in schemes 4 and 5, from the aniline of formula (III), R4 and / or R5 are alkyl groups. can be obtained in a 7-step process when R4 = R5 = H (or a 5-step process when R4 = R5 = H). First, aniline (III) is reacted with 4-methoxybenzaldehyde, followed by direct Reduction with a reducing agent such as sodium triacetoxyborohydride affords aniline (III ) can be protected with a suitable nitrogen protecting group such as a para-methoxybenzyl ether group. The protected aniline was then reacted with 3-(tert-butoxy)-3-oxopropionic acid (XIV) as described by HATU et al. By reacting in the presence of a coupling reagent, intermediate (XV) can be obtained. Intermediate (XV) can be prepared by the reaction of 2,4-dichloropyrimidine (VIII) (where R3 = H) with a strong base such as NaH. Bottom, S N The intermediate (XVI) can then be converted into pyrimidine of formula (XVI) by two subsequent transformations. Exchange can be carried out.

[0131] First, decarboxylation with a strong acid such as TFA gives the intermediate of formula (XVIII), followed by K2CO3 to form a compound of formula (XIX). The sulfonamidation of intermediate (XIX) can be carried out using a catalytic system such as Pd-174 to give sulfonamide (VI). The aniline is prepared in the presence of a strong acid system such as TFA / triflic acid to give the compound of formula (XX). Deprotection of the phosphorus nitrogen provides compounds of formula (I).

[0132] Alternatively, the compound of formula (XVI) can be converted to a sulfonamide by the addition of a sulfonamide of type (VI). followed by double deprotection using a strong acid system such as TFA / triflic acid to give the compound of formula (I). A compound can be obtained.

[0133] Scheme 4a [ka] Scheme 4b [ka] Preferably, R2 is H, R3 is H, R4 is F, and R5 is C. 1-6 It is alkyl.

[0134] Generally, as shown in Scheme 4a, compounds of general formula (I) (wherein R1, Ar1 and Ar2 are as defined above) can be prepared by the following procedure: where P is a nitrogen protecting group such as PMB, R4 is halo such as F, and R5=C 1-6 Alkyl can be prepared starting from the methyl ester (II), which can be reacted with PMB-Cl or the like to give intermediate (XXI), which is then treated with a suitable base such as LHMDS to give N-fluoro-N Fluorination using a fluorinating reagent such as -(phenylsulfonyl)benzenesulfonamide The intermediate (XXII) is salted with an inorganic base such as LiOH to obtain the intermediate (XXIII), Then, in the presence of a base, it is activated with a coupling reagent such as T3P to couple with an aniline such as (III). This can be followed by a final deprotection step to give the final protected compound (XXIV). In the second step, strong acid conditions such as TFA in DCM provide the desired final compound of general formula (I).

[0135] As shown in Scheme 4b, intermediates of formula (XXI) can also be prepared starting from pyrimidine (IV). This can be prepared by protecting the intermediate (XXVIII) with PMB-Cl or the like. In the case of u, decarboxylation can be carried out with a strong acid such as TFA to give the derivative of formula (XXI). Alternatively, if the alkyl group is methyl, decarboxylation can be carried out using a chloride ion source such as LiCl. In an aprotic polar solvent such as DMSO, at a high temperature such as 140°C, Krapcho conditions are used. which can be carried out below to give derivatives of general formula (XXI).

[0136] R4 is C 1-6 For compounds where R4 is alkyl but R5 is not equal to R5, the derivative of general formula (XXI) , in the presence of an inorganic base such as potassium carbonate and an alkylating agent to give a compound of formula (XXII) Such compounds may be converted to the final compounds using the methods described above in Scheme 4a. It can be exchanged.

[0137] To determine compounds where R4 = H, compounds of formula (XXI) can be analyzed by a suitable reagent such as TMSOK as described above. By treatment with an appropriate reagent, the intermediate (XXIII) can be directly converted to a carboxylic acid salt such as (XXIII). , which may be converted to compounds of formula (I) as described above, or (XXII) may be converted to compounds of formula (I) by activating AlMe, etc. in the presence of an agent, followed by direct coupling of (XXIV) with an amine of formula (III) to a carboxylic acid of formula (I) as previously described. This may be carried out in two steps to convert the compound into

[0138] Scheme 5a [ka]

[0139] Scheme 5b [ka] Preferably, X is N, Y is CH, R3 is H, and (IX) is a compound of a base and formula (XXV) where n1=n2= 2) to (X), where hal is Cl, alkyl is methyl, and R4 and R5 are and form a tetrahydropyranyl ring together with the carbon atom to which they are attached, and The compound is converted to a compound of formula (I) using AlMe3 and a compound of formula (III).

[0140] A compound of general formula (I) (wherein R1, Ar1 and Ar2 are as defined above, and R4 and R5 are each independently C together with the carbon atom to which they are attached 3-6 forming a heterocycloalkyl) is represented by the general formula ( IX) can be prepared in three steps starting from the intermediate IX, see Scheme 5a. The compound (IX) is reacted with a symmetrical dibromoether of general formula (XXV) as shown in Scheme 5a. The α-ring compound of formula (X) can be obtained by further treating the intermediate thus obtained with Reaction with a sulfonamide of general formula (VI) gives a compound of formula (II). Derivative (II) is reacted with AlMe3 in the presence of aniline type (III) to give compounds of general formula (I) can be obtained.

[0141] A compound of general formula (I) (wherein R1, R3, Ar1 and Ar2 are as defined above, and X=Y=CH or X=CH and Y=N, hal=Br or Cl, R4 is C 1-6 alkyl, and R5 is H or C 1-6 alkyl) can be prepared in three or four steps starting from an intermediate of general formula (IX). The compound is reacted with an inorganic base such as potassium carbonate in the presence of an alkylating agent to form the α- - alkylation to give compounds of formula (X). For both mono- and di-alkylation, the reaction conditions are It will be understood by those skilled in the art that this can be achieved by careful control of the following: and advancing the compound to the final compound of formula (I) according to the steps described in Scheme 5b above. can be done.

[0142] A compound of general formula (I) (wherein R1, R3, Ar1 and Ar2 are as defined above, and X=Y=CH or X=CH and Y=N, R4 and R5 together with the carbon atoms to which they are attached are C 3-6 Heterocyclo The compound (forming an alkyl group) can be prepared in the same manner as for the compound where X=N and Y=CH. Cut.

[0143] A compound of general formula (II) (wherein R1 and R3 are as defined above, R4 = R5 = H, X and Y = CH can also be prepared by reacting a commercially available amine of formula (XXIX) with the appropriate sulfonyl chloride (XXX) in pyridine. The intermediate (II) can then be hydrolyzed by the above method. can be used for amide coupling.

[0144] A compound of general formula (I) (wherein R1, R3, Ar1 and Ar2 are as defined above, X=CH and Y= N, hal=Br or Cl, R4 is C 1-6 alkyl and R5 is F) can be obtained from an intermediate of general formula (IX) First, mono-α-alkylation to the ester is carried out in the presence of an alkylating agent. This can be achieved by treating these products with an inorganic base such as potassium carbonate. followed by reaction with a strong base such as N-fluoro-N-(phenylsulfonyl)benzenesulfonyl Exposure to a fluorinating agent such as methylimide can be carried out to give compounds of formula (X). The product can then be carried forward to compounds of formula (I) according to the steps described above in Scheme 5b.

[0145] Scheme 6a [ka] Scheme 6b [ka] An intermediate of formula (III) (wherein Ar1, R 10 , R 11 and R 12 is as defined above, and Ar2 is a non-substituted The boronates of general formula (XII) (wherein R 12 is before Z is a dihydroxyboryl or dialkyloxyboryl group, typically 4 ,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group) under Suzuki conditions to give the compound of formula (XI) (wherein X represents a halide) Coupling by the Suzuki method can be carried out, for example, by the reaction of [1,1'-bis(diphenylphosphino)phenyl] In the presence of a catalyst such as [ferrocene]dichloropalladium(II) complex, dichloromethane and potassium carbonate The reaction is carried out by heating with an inorganic base such as ammonium in a mixed solvent of dioxane and water.

[0146] Scheme 7a [ka] Scheme 7b [ka] An intermediate of formula (III) (wherein Ar1, R 10 , R 11 and R 12 is as defined above, and Ar2 is a non-substituted The 2,5-pyrazinyl ring is a substituted or substituted 2,5-pyrazinyl ring, and the aromatic halide of the general formula (XII) wherein Z represents a halide) is converted under Suzuki conditions into a boronate of general formula (XI) It represents a hydroxyboryl or dialkyloxyboryl group, usually 4,4,5,5-tetramethyl-1 ,3,3,2-dioxaborolan-2-yl group). Coupling by the method can be carried out using, for example, tetrakis(triphenylphosphine)palladium or Catalysts such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and By heating in a mixed solvent of dioxane and water in the presence of an inorganic base such as potassium carbonate, Carry out.

[0147] Scheme 8 [ka] Generally, as shown in Scheme 8, a compound of formula (I) (wherein R1, R3, Ar1 and Ar2 are as defined above) can be prepared. As defined above, X=N and Y=CH, R4=H, C 1-6 alkyl or CH2CH2OMe, where R5=H (VIII) can be prepared in four or five steps starting from an intermediate of general formula (VII). The intermediate (VII) is reacted with an inorganic base such as sodium hydroxide and an alkylating agent such as ethyl iodide. This can be achieved by treating in the presence of methyl methyl acrylate, to give the compound of formula (V). The carboxylation can be initiated with a strong acid such as TFA to give an intermediate of formula (X). This intermediate is then subjected to saponification and amide coupling according to the method described in Scheme 1 to give a compound of formula (XXXI) The final compound of formula (I) can be obtained by reacting an intermediate of formula (XXXI) as shown in Scheme 1 above. It can be accessed by coupling with a primary sulfonamide.

[0148] Generally, as shown in Scheme 8, a compound of formula (I) (wherein R1, R3, Ar1 and Ar2 are as defined above) can be prepared. where X=CH and Y=N, R4=H or CH2CH2OMe, and R5=H or Me) Starting from an intermediate of general formula (VIII), in scheme 8, the compound as described for the case where X=N and Y=CH If a linker where R5=Me is required, it can be prepared according to the same method as that described above. The alkylation of intermediate (Xa) can be carried out by treating with an alkylating agent in the presence of a base to give intermediates such as (Xa). Compounds of formula (Xa) can then be converted to the final compounds via a three-step procedure as described in Scheme 8. Cut.

[0149] The compound of general formula (XXXI) (wherein R4 = R5 = H, X = CH and Y = N) can also be prepared by the above-mentioned amides. By coupling of commercially available acids of formula (XXXII) with anilines of formula (III) under coupling conditions Compounds of this type can then be prepared by sulfamidation using the sulfamidation conditions described above to give compounds of formula (I) ) compounds.

[0150] Scheme 9 [ka] Generally, as shown in Scheme 9, compounds of general formula (I) (wherein R1, Ar1 and Ar2 are as defined above) can be prepared by The compound ethyl 2,2-difluoro-2-(2-methyl-2,2-difluoro-2-methyl ... It can be prepared in three steps from the (thio)pyrimidin-4-yl)acetate (XXXIII). Thioethers can be prepared by oxidizing protons such as MeOH at room temperature in the presence of an oxidizing agent such as Oxone®. In a polar carboxylic acid solvent, the sulfone group can be converted to a primary sulfonamide (VI). ), followed by ester hydrolysis to give the acid of general formula (XXXV). This can be done in a one-pot procedure in an aprotic polar solvent such as DMF in the presence of a base. The acid derivative (XXXV) is then activated with a coupling reagent such as HATU in the presence of a base to give (III). and the like to give the final compound of formula (I).

[0151] Scheme 10 [ka] Generally, as shown in Scheme 10, a compound of general formula (X) (wherein R1, R3, Ar1 and Ar2 is as defined above and R4=OMe) is a 2,4-dichloropyrazine derivative of general formula (VIII) The derivative (VIII) can be prepared in four, five or six steps starting from the symmetrical maleic acid derivative (VIII). phosphate ester (wherein R4 = OMe) in the presence of a strong base such as sodium hydride and a solvent such as DMF. The reaction can be carried out in a polar solvent to form an intermediate compound of formula (V). Compounds of general structure (X) can be obtained by first using an alkali metal hydroxide such as NaOH. Saponification of the biscarboxylic acid affords the biscarboxylic acid, which is then oxidized once to undergo spontaneous decarboxylation. The resulting monocarboxylic acid is then reacted with thiochloride in the presence of an alcoholic solvent such as methanol. The derivative of formula (X) can be converted to an ester of formula (X) by treatment with an activating agent such as benzoyl. The methods described in Scheme 5 can be used to convert to the final compounds of formula (I).

[0152] Scheme 11 [ka] Generally, as shown in Scheme 11, a compound of formula (XXVIII) and R4 = H or Et) can be obtained from 2,4-dichloropyrimidine derivatives of general formula (VIII) Derivative (VIII) can be prepared in seven steps starting from the sulfonamide (VI) and potassium carbonate. When reacted in the presence of an inorganic base such as , the more reactive chloride is displaced to form a compound of formula (X The compound of formula (XXXVI) can be protected using, for example, PMB-Cl to form an intermediate compound of formula (XXVI). to obtain the compound of formula (XXXVII).

[0153] This compound can then be reacted with an unsymmetrical malonate to form a dimethicone in the presence of a base such as cesium carbonate. By treating in a solvent such as diethane, it can be converted to a compound of general formula (XXXVIII). If mono-alkylation is desired, intermediate (XXXVIII) can then be reacted with an inorganic acid such as potassium carbonate. Treatment with a base in the presence of an alkylating agent such as EtI gives a compound of general formula (XXVIII). This compound can then be converted to the final compound of formula (I) using the methods described in Scheme 4 above. do. When R4 = H, the compound of general formula (XXXVIII) can be directly converted (as described above) to a compound of general formula (I) It can be said that:

[0154] (benzamidopyrimidine) Scheme 12 [ka] Compounds of general formula (I) can be obtained in a four-step process as shown in Scheme 12. 2-Chloropyrimidine-4-carbonitrile (XXXIX) can be prepared by the procedure reported in Scheme 1 above. Using radium-catalyzed sulfamination conditions, the compounds were converted to the corresponding sulfonamides (XXXX). The reaction of nickel(II) chloride and di-tert-butyl dicarbonate using sodium borohydride can be carried out. Reduction of the nitrile group in the presence of methylprecipitate affords the protected benzylamine derivative of general formula (XXXXI) Deprotection is achieved by acid hydrolysis using HCl in dioxane. Then, the benzylamine derivative of the general formula (XXXXII) can be obtained. Amide coupling conditions are employed to convert the derivative (XXXXII) to an amide of general formula (I). The conditions are as follows: coupling reagent is converted to biaryl carboxylic acid (XXXXIII) (commercially available and is prepared in Scheme 19.

[0155] Scheme 13 [ka]

[0156] Compounds of general formula (I) (wherein R1, Ar1 and Ar2 are as defined above, X=N and Y=CH, R 3 is H, R4 is C1-6 Alkyl, R5 is H or C 1-6 alkyl, or R4 and R5 are C together with the carbon to which it is bonded 3-6 cycloalkyl) can be obtained by Scheme 13 (and At a certain stage, it can be obtained in a six-step process as shown in Scheme 12. Then, the derivative (IX) is reacted with an alkyl halide to give a compound of the general formula (X) (wherein R4=alkyl). Alternatively, the derivative (IX) can be obtained by the addition of an alkylbishalogeno group. and reacting with a fluoride to give a compound of general formula (X) (wherein R4 and R5 are bonded together as defined above). TeC 3-6 A carboxylic acid (which may form a heterocycloalkyl ring) can be obtained. XXXII) was prepared by using an alkali metal base such as lithium hydroxide in a mixed solvent such as THF / MeOH. It can be obtained by hydrolysis of the methyl ester (X). For example, diphenylphosphoryl Curtius rearrangement using azide in the presence of triethylamine and tert-butanol can be carried out to give carbamates such as (XXXXIV). The amide (XXXXI) was then catalyzed by palladium catalysis using the conditions previously reported in Scheme 1. The carbamates of formula (XXXXI) can then be obtained by sulfamination according to Scheme 12. This can then be carried forward to the final compound of formula (I).

[0157] A compound of general formula (I) (wherein R1, Ar1 and Ar2 are as defined above, X=CH and Y=N, R 4 is C 1-6 alkyl and R5 is H) can be prepared by starting from a commercially available acid of formula (XXXII) It can be obtained in a four-step process following the steps described in Scheme 13.

[0158] Scheme 14 [ka] Pyrimidin-4-yl(propan-2-yl)benzamide derivatives of formula (I) (wherein R1, R3, Ar1 and Ar2 are as defined above, R4 = alkyl, R5 = H) are shown in Scheme 14 It may be prepared by two different routes, both of which involve the use of 2-bromopyridinyl groups. The conversion of limidine to the corresponding ketone (XXXXVI) is initiated by suitable amines such as TMPMgCl LiCl. This is achieved by treatment with an appropriate base followed by exposure to a Weinreb amide derivative. The pathways later converge at compounds of general formula (L), which then lead to the final class of compounds by a subsequent two-step process. Reaching the similarity.

[0159] Route A: The ketone derivative (XXXXVI) is treated with ammonium trifluoroacetate, followed by water Reduction with sodium borohydride gives the benzylamine (L). can. Route B: Ketones of general formula (XXXXVI) are treated with a Lewis acid such as titanium isopropoxide. Subsequent exposure to sulfinamines such as 2-methylpropane-2-sulfinamide This is converted to sulfinamide (XXXXVII) and reduced with sodium borohydride to afford The intermediate of formula (XXXXVIII) can then be reacted with HCl to give sulfinamide (XXXXVIII). However, HCl tends to induce halogen exchange, and the amine of general formula (L) This gives the compound (where X=Cl).

[0160] The amide coupling conditions reported in Scheme 12 were then employed to afford the benzylamine derivative (L) may be converted to an amide of general formula (LI) by palladium catalyzed sulfamination: Compounds of general formula (I) can be obtained as described in Scheme 12.

[0161] Scheme 15 [ka] Generally, as shown in Scheme 15, compounds of general formula (XXXXII) can be prepared by reacting compounds of general formula (XXXXVI) It can be obtained from the ketone derivative in a three-step process. Sulfamidation of derivative (XXXXVI) can be carried out using the conditions described in Scheme 12 to give compounds of formula (LII). The subsequent oxime formation with hydroxyamine is carried out in the presence of a suitable catalyst such as Pd / C under an H2 gas atmosphere. The amine derivative of general formula (XXXXII) is obtained by reduction in a protic polar solvent such as MeOH under atmospheric pressure. Amines of this type can be carried forward to the final compound according to Scheme 12.

[0162] Scheme 16 [ka] Alternatively, compounds of general formula (XXXXII) can be prepared in a three step process as shown in Scheme 16. N-(2-(2-bromopyrimidin-4-yl)butan-2-yl)-2-methylpropanol can be obtained by Pan-2-sulfinamide (XXXXVII) can be synthesized as previously described (Scheme 14). The imine of can be exposed to a nucleophile such as MeMgBr to give intermediates such as (XXXXVIII). The corresponding sulfonamides (LIII) can then be prepared by palladium-catalyzed sulfonation as described in Scheme 1. Deprotection can be achieved by acid hydrolysis using HCl to give the compound of general formula (XXXX The benzylamine derivative II) can then be synthesized into the final compound according to Scheme 12. It can be transformed into something.

[0163] Scheme 17 [ka] A benzamide derivative of formula (I) (wherein R1, R3, Ar1 and Ar2 are as defined above, and R4 = R5 = alkyl) can be prepared in five steps as shown in Scheme 17, and its preparation is shown in Scheme 18. Using the sulfamidation conditions described in 1, commercially available aromatic chlorides such as (LIV) and primary sulfonates were prepared. This is then carried out by coupling with an aprotic amide such as THF. A Ritter-type reaction can then be carried out in a dilute solvent to form an intermediate of formula (LVI). This can be done using alkyl nitriles such as methyltrimethylsilane in the presence of an acid such as H2SO4. The intermediate of formula (LVII) is reduced with thiourea in the presence of acetic acid in a protic solvent such as ethanol. The benzylamine derivative (XXXXII) can be obtained by deprotection by heating under reflux. The final compounds of formula (I) can be obtained using the amide coupling conditions reported in Scheme 12. Can be reached using

[0164] Scheme 18 [ka] Generally, as shown in Scheme 18, compounds of general formula (I) can be prepared by a three-step process using intermediate It can be prepared by first saponifying (II) with a reagent such as TMSOK to give the intermediate carboxylate. to give the carboxylic acid derivative, which is then reacted with an activating agent such as T3P and a bromoaniline of formula (XI) The intermediate of formula (LVIII) can then be reacted with a boronate ester of general formula (XII) to form a Suzuki reaction product. The boronate is converted to a compound of the present invention by coupling under conditions of general formula (I). , usually a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5-tetrahydroboryl group. The coupling by the Suzuki method is, for example, For example, catalysts such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and heating in a mixed solvent of dioxane and water in the presence of an inorganic base such as potassium carbonate. Numerous catalysts and conditions can be employed for such coupling. , as will be understood by those skilled in the art.

[0165] Scheme 19 [ka] An intermediate of formula (XXXXIII) (wherein Ar2 is an unsubstituted or substituted 2-pyrazine ring or 3-pyrazine ring) The diazyl ring can be synthesized as shown in Scheme 19, but the synthesis is carried out under Suzuki conditions. and an aromatic halide of general formula (XII) (wherein R 12 and R 13 is as defined above, and Z represents Br or Cl) and a boronate of general formula (XI) 10 and R 11 is as defined above. X is a dihydroxy group such as 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group. By coupling with a boryl or dialkyloxyboryl group, The coupling is, for example, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium. In the presence of a catalyst such as ammonium(II)-CH2Cl2 adduct and an inorganic base such as cesium carbonate, The reaction is carried out by heating in a mixed solvent of ethanol and water under an inert atmosphere such as a nitrogen atmosphere, and the reaction product is obtained by the following reaction: The carboxylic acid of general formula (XXXXIII) can be obtained by cleaving the carboxylic acid with a strong acid such as TFA in a solvent of CH2Cl2. Deprotection of t-butyl esters using an alkaline metal ion such as NaOH in a mixed solvent such as THF / MeOH Hydrolysis of methyl esters using metal hydroxides or nitrite using strong acids such as concentrated HCl It can be obtained by either hydrolysis of methyl methyl acrylate or methyl methyl acrylate.

[0166] (Intermediate of the present invention) The present invention also relates to novel intermediates in the synthesis of the compounds of formula (I), such as the compounds of formulas (II) to (LVIX). Of particular interest are compounds of formula (II) to (XXV), such as compounds of formula (II) to (XX). The intermediates that can be used are of the general formula: As defined for compounds of formula (I): Compounds of formula (II): [ka] (Wherein R represents H, C 1-6 alkyl (e.g., methyl and ethyl), or benzyl); Compounds of formula (III): [ka] Compounds of formula (XX): [ka] Compound of formula (XXIV): [ka] where P is a nitrogen protecting group such as paramethoxybenzyl.

[0167] Also of note are the following compounds, with the variables and associated preferences being as described above: As defined below for compounds of formula (I): Formula (II): [ka] (Wherein R represents H, C 1-6 alkyl (e.g., methyl and ethyl) or benzyl; Compounds of formula (III): [ka] Compounds of formula (XX): [ka] Compound of formula (XXIV): [ka] Compounds of formula (XXXI): [ka] Compound of formula (XXXXII): [ka] Compounds of formula (XXXXIII): [ka] Compounds of formula (LI): [ka] Compounds of formula (LVIII): [ka] .

[0168] Embodiments of the present invention include all novel intermediates described in the examples: Intermediates INTC1 to INTC47; and Intermediates INTD1 to INTD51, Also included.

[0169] Also provided are intermediates INTC48-INTC53. Also provided are intermediates INTC54-INTC177. Also provided are intermediates INTD52-INTD86.

[0170] As an embodiment of the present invention, any of the intermediates disclosed herein, such as those of formula (II) to (LVIX), and the like. The term "compounds" includes salts such as pharmaceutically acceptable salts of, such as any of the compounds of.

[0171] (Treatment method) The compounds of formula (I) of the present invention have utility as inhibitors of CTPS1. Accordingly, the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or and / or their derivatives, which are useful as pharmaceuticals. and is intended for use in treating diseases or disorders in which an inhibitor of CTPS1 would be beneficial, e.g. For example, in the treatment or prevention of these diseases and disorders listed herein below. It is intended to be used as a product.

[0172] The present invention relates to a method for treating diseases or disorders in which an inhibitor of CTPS1 is beneficial, such as those listed herein below. A method for the treatment or prevention of diseases and disorders, comprising using a compound of formula (I) or a compound thereof as a medicament The availability of acceptable salts and / or solvates (e.g., salts), and / or derivatives thereof The method comprises administering to a subject in need thereof an amount of

[0173] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvent thereof. and / or derivatives thereof for diseases or disorders in which an inhibitor of CTPS1 is beneficial, e.g., For the treatment or prevention of these diseases and disorders, for example, those listed herein below. The present invention provides for the use of the compound in the manufacture of a product.

[0174] More preferably, the disease or disorder for which an inhibitor of CTPS1 is beneficial is a disease or disorder that affects T cell and / or B cell proliferation. These are diseases or disorders in which it is beneficial to reduce proliferation.

[0175] The present invention also provides a compound of formula (I), or a compound thereof, for use in inhibiting CTPS1 in a subject. Pharmaceutically acceptable salts and / or solvates (e.g., salts) and / or derivatives thereof provide.

[0176] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof: administering to a subject an effective amount of a compound (e.g., a salt), and / or a derivative thereof, Methods for inhibiting CTPS1 in a subject are provided.

[0177] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvent thereof. and / or derivatives thereof for the manufacture of pharmaceuticals for the inhibition of CTPS1 in a subject. The present invention provides for use in the manufacture of

[0178] The present invention also provides a method for reducing T cell and / or B cell proliferation in a subject. or a pharmaceutically acceptable salt and / or solvate thereof (e.g. , salts), and / or derivatives thereof.

[0179] The present invention provides a method of reducing T cell and / or B cell proliferation in a subject, comprising administering to a subject an antibody of formula (I) compounds or pharmaceutically acceptable salts and / or solvates thereof (e.g., salts), and and / or a derivative thereof to a subject.

[0180] The present invention also provides a method for the manufacture of a medicament for reducing T cell and / or B cell proliferation in a subject. The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g. The present invention provides for the use of the compounds of formula (I) and / or derivatives thereof, such as salts thereof.

[0181] More preferably, the disease or disorder for which an inhibitor of CTPS1 is beneficial is a disease or disorder that inhibits T cell and / or B cell proliferation. It is a disease or disorder whose reduction is beneficial.

[0182] As used herein, the term "treatment" or "treating" refers to the control of a disease state or its symptoms. , mitigation, relief, or regulation. As used herein, the terms "prophylaxis" or "prevention" refer to the treatment of a disease or disorder in a subject. or preventing the recurrence of symptoms of a disease or disorder in an affected subject, The purpose of this is not limited to the complete prevention of

[0183] Preferably, the disease or disorder is rejection of transplanted cells and tissue, transplant-associated disease or disorder. The disease is selected from allergies, allergies, and autoimmune diseases.

[0184] In one embodiment, the disease or disorder is rejection of transplanted cells and tissues. Heart, kidney, lung, liver, pancreas, pancreatic islet, brain tissue, stomach, large intestine, small intestine, cornea, skin, trachea, bone, Bone marrow (or hematopoietic cells mobilized from bone marrow to peripheral blood cells or umbilical cord blood cells, hematopoietic progenitor cells and stem cells from other sources), muscle, or bladder The compounds of the present invention may be used to treat donor tissue, may be useful in preventing or suppressing immune responses associated with cell, graft or organ transplant rejection good.

[0185] In a further embodiment, the disease or disorder is a transplant-associated disease or disorder. Related diseases or disorders include graft-versus-host disease (GVHD), such as bone marrow transplant-related GVHD, and Organs, tissues, including skin, muscle, neuron, pancreatic islet, organ, and liver parenchymal cell grafts, etc. or transplantation of cell grafts (e.g., tissue or cell allografts or xenografts) This includes immune disorders resulting from or associated with rejection, as well as host-versus-graft disease (HVGD). The compounds are useful in preventing or inhibiting acute rejection of such transplants in recipients. and / or prevent rejection of such transplants in the recipient (e.g. For example, insulin-producing pancreatic islet cells from a donor to a diabetic intended recipient. It may also be useful in long-term maintenance therapy for the prevention of transplant rejection. The compounds of the invention are useful in preventing both host-versus-graft disease (HVGD) and graft-versus-host disease (GVHD). do.

[0186] The CTPS1 inhibitor can be administered to the subject before, during, and / or after transplantation. In some embodiments, the CTPS1 inhibitor is administered to the subject on a timed basis before and / or after transplantation. It is possible. In another embodiment, the disease or disorder is an allergy.

[0187] In additional embodiments, the immune-related disease or disorder is an autoimmune disease. As used herein, an "autoimmune disease" is a disease or disorder that targets a subject's own tissues. Examples of autoimmune diseases include, but are not limited to, Addison's disease, adult-onset Still's disease, and Alopecia areata, Alzheimer's disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, ankylosing spondylitis, anti Phospholipid syndrome (Hughes syndrome), aplastic anemia, arthritis, asthma, atherosclerosis atherosclerotic plaque, atopic dermatitis, autoimmune hemolytic anemia, autoimmune Infectious hepatitis, autoimmune hypophysitis (lymphocytic hypophysitis), autoimmune inner ear disease, autoimmune Lymphoproliferative syndrome, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis, autoimmune Autoimmune orchitis, autoinflammatory diseases requiring immunosuppressive treatment, azoospermia, Behcet's disease, Burger's disease, bullous pemphigoid, cardiomyopathy, cardiovascular disease, and intractable celiac disease (types I and II) including celiac disease, chronic fatigue and immune dysfunction syndrome (CFIDS), chronic idiopathic polyneuropathy, chronic chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy (Guillain-Barré syndrome), Churg-Strauss syndrome (CSS), cicatricial pemphigoid, cold agglutinin disease (CAD), chronic obstructive pulmonary disease disease (COPD), CREST syndrome, cryoglobulin syndrome, cutaneous lupus, dermatitis herpetiformis, skin Dermatomyositis, eczema, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, Evans syndrome , exophthalmos, fibromyalgia, Goodpasture's syndrome, Graves' disease, hemophagocytic lymphoma Histiocytosis (HLH) (including type 1 hemophagocytic lymphohistiocytosis), histiocytosis / histiocytic disorders, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, immune Proliferative diseases or disorders, inflammatory bowel disease (IBD), interstitial lung disease, juvenile arthritis, juvenile idiopathic Arthritis (JIA), Kawasaki disease, Lambert-Eaton myasthenic syndrome, lichen planus, localized scleroderma, Lupus nephritis, Meniere's disease, microangiopathic hemolytic anemia, microscopic polyangiitis, Miller's disease Fisher syndrome / acute disseminated cerebrospinal radiculopathy, mixed connective tissue disease, multiple sclerosis ( MS), muscular rheumatism, myalgic encephalomyelitis (ME), myasthenia gravis, eye inflammation, pemphigus foliaceus, common pemphigus Pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome (Whitaker's syndrome) group), polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis / autoimmune cholangitis, primary glomerulonephritis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis Arthritis, true erythroid anemia, Raynaud's phenomenon, Reiter's syndrome / reactive arthritis, relapsing multiple Chondritis, restenosis, rheumatic fever, rheumatic diseases, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleroderma / systemic sclerosis, Sjögren's syndrome, stiff-man syndrome , Sweet's syndrome (febrile neutrophilic dermatosis), systemic lupus erythematosus (SLE), systemic sclerosing leukemia (SLE), skin disease, Takayasu arteritis, temporal arteritis / giant cell arteritis, thyroiditis, type 1 diabetes, type 2 diabetes, grape These include uveitis, vasculitis, vitiligo, Wegener's granulomatosis, and X-linked lymphoproliferative disorder.

[0188] Of particular importance are diseases and disorders that are primarily caused by T cell activation and proliferation. and includes: -Diseases and disorders not related to alloreactivity, including: Alopecia areata, atopic dermatitis, eczema, psoriasis, lichen planus, psoriatic arthritis, vitiligo; ·Uveitis; · Ankylosing spondylitis, Reiter's syndrome / reactive arthritis; · Aplastic anemia, autoimmune lymphoproliferative syndromes / disorders, hemophagocytic lymphohistiocytosis; Type 1 diabetes; and · Refractory celiac disease; - bone marrow cells or allogeneic cells of other origin, including hematopoietic precursor and / or stem cells acute rejection of transplanted tissues and organs after transplantation of any of the following: acute graft rejection; Host-versus-host disease (GVHD).

[0189] Equally important is the activation and proliferation of both T and B cells, resulting in the proliferation of B cells. Diseases and disorders in which the cell plays an important role, including: -Diseases and disorders in which the involvement of pathogenic autoantibodies is well characterized, including: What: ·allergy; Cicatricial pemphigoid, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus foliaceus, pemphigus vulgaris, Dermatitis herpetiformis; ANCA-associated vasculitis and microscopic polyangiitis, vasculitis, Wegener's granulomatosis; Churg-S Strauss syndrome (CSS), polyarteritis nodosa, cryoglobulinemia, and essential mixed cryoglobulinemia rioglobulinemia; Systemic lupus erythematosus (SLE), antiphospholipid syndrome (Hughes syndrome), cutaneous lupus, Lupus nephritis, mixed connective tissue disease; Thyroiditis, Hashimoto's thyroiditis, Graves' disease, exophthalmos; ·Autoimmune hemolytic anemia, autoimmune neutropenia, ITP, pernicious anemia, vericytic anemia , microangiopathic hemolytic anemia; Primary glomerulonephritis, Burger's disease, Goodpasture's syndrome, IgA nephropathy; and Chronic idiopathic polyneuropathy, chronic inflammatory demyelinating polyneuropathy (CIPD), chronic relapsing polyneuropathy Guillain-Barré syndrome, Miller Fisher syndrome, stiff-man syndrome, Bart-Eaton myasthenic syndrome, myasthenia gravis. - Characterization of B cell involvement in response (sometimes with anti-CD20 monoclonal antibodies or intravenous The effectiveness of intravenous immunoglobulin infusions is unclear, and the presence of pathogenic antibodies production is not responsive or limited (although non-pathogenic antibodies have sometimes been described, Diseases and disorders such as (and often exist and are used as diagnostic biomarkers) and includes: Addison's disease, autoimmune oophoritis and azoospermia, polyglandular syndrome (Whitaker's syndrome), Schmidt syndrome; Autoimmune myocarditis, cardiomyopathy, Kawasaki disease; Rheumatoid arthritis, Sjögren's syndrome, mixed connective tissue disease, polymyositis and dermatomyositis ;Polychondritis; Primary glomerulonephritis; Multiple sclerosis; ·Autoimmune hepatitis, primary biliary cirrhosis / autoimmune cholangopathy, Hyperacute rejection of transplanted organs; Chronic rejection of the graft or transplanted plant; Chronic graft-versus-host reaction / disease following transplantation of bone marrow cells or hematopoietic precursor cells.

[0190] Of additional importance is the activation / proliferation of T cells, as well as the activation of innate immune cells and other inflammatory Cell groups (subpopulations) (including myeloid cells such as macrophages or granulocytes) and resident cells (fibroblasts) Diseases and disorders that share a common mechanism for the activation / proliferation of myoblasts and endothelial cells, Including: COPD, idiopathic pulmonary fibrosis, interstitial lung disease, sarcoidosis; Adult-onset Still's disease, juvenile idiopathic arthritis, systemic sclerosis, CREST syndrome (except B cell Cells and pathogen antibodies may also play a role); Sweet's syndrome; Takayasu's arteritis, temporal artery inflammation / giant cell arteritis; Inflammatory bowel disease (IBD), including ulcerative cholangitis, Crohn's disease and ulcerative colitis, primary sclerosis Sexual cholangitis.

[0191] Equally important, mechanisms remain poorly understood, including T cell activation and proliferation. Diseases and disorders characterized by the development of: Alzheimer's disease, cardiovascular syndrome, type 2 diabetes, restenosis, chronic fatigue and immune dysfunction syndrome group (CFIDS). -Autoimmune lymphoproliferative disorders, including: ·Autoimmune lymphoproliferative syndrome and X-linked lymphoproliferative disease.

[0192] Preferably the disease or disorder is an inflammatory skin disease, such as psoriasis or lichen planus; acute and / or juvenile or chronic GVHD, such as steroid-resistant acute GVHD; acute lymphoproliferative syndrome; systemic erythropoietin or cutaneous lupus; or transplant. the disease or disorder is selected from myasthenia gravis, multiple sclerosis, and scleroderma / systemic sclerosis You can also do this.

[0193] The compounds of formula (I) can be used in the treatment of cancer. Thus, in one embodiment, there is provided a compound of formula (I) or a pharmaceutical composition thereof for use in the treatment of cancer. Pharmaceutically acceptable salts and / or solvates, and / or derivatives thereof are provided. do.

[0194] and administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof. and / or solvates and / or derivatives thereof in a subject. Methods for treating cancer in a subject are provided.

[0195] Additionally provided is a compound of formula (I) in the manufacture of a medicament for treating cancer in a subject. or a pharmaceutically acceptable salt and / or solvate thereof, and / or The use of these derivatives.

[0196] Preferably, the cancer is a hematological cancer, for example, acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, or the like. lymphoma, B-cell acute lymphoblastic leukemia, Sweet's syndrome, T-cell non-Hodgkin's lymphoma ( Natural killer / T-cell lymphoma, adult T-cell leukemia / lymphoma, enteropathic T-cell lymphoma , including hepatosplenic T-cell lymphoma and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia , B-cell non-Hodgkin's lymphoma (Burkitt lymphoma, diffuse large B-cell lymphoma, leukemia) follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma), hairy cell leukemia, Hodgkin lymphoma Lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue Lymphoma, multiple myeloma, myelodysplastic syndrome, plasma cell myeloma, primary mediastinal large B-cell myeloma lymphoma, chronic myeloproliferative disorders (e.g., chronic myelogenous leukemia, primary myelofibrosis, essential thrombocythemia, polycythemia vera, etc.) or chronic lymphocytic leukemia.

[0197] Alternatively, the cancer may be, for example, bladder cancer, breast cancer, melanoma, neuroblastoma, malignant pleural mesothelioma, and and non-hematological cancers such as selected from the group consisting of sarcomas and sarcomas.

[0198] Additionally, the compounds of formula (I) may promote recovery from vascular injury or surgery in a subject, It can be used to reduce morbidity and mortality associated with vitimitis and restenosis. The compounds of formula (I) can be used to prevent, reduce or inhibit neointima formation. prior to its insertion or implantation to prevent, reduce, or inhibit formation of Treating a medical device with a composition containing an effective amount of a compound of formula (I) before administering the device or implant The device may be inserted or implanted into the subject's body. In some embodiments, the device may be a surgically implanted or permanently implanted device. Examples of medical devices include, but are not limited to, needles, cannulas, catheters, etc. These include catheters, shunts, balloons, and implants such as stents and valves. Preferably, the subject is a mammal, and in particular the subject is a human.

[0199] (Pharmaceutical composition) For use in therapy, the compounds of the invention are typically administered as pharmaceutical compositions. The disclosure also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof (e.g., (e.g., salts), and / or derivatives thereof, and pharmaceutically acceptable carriers or excipients. A pharmaceutical composition comprising the agent is provided.

[0200] In one embodiment, for use in the treatment or prevention of a disease or disorder described herein. or a pharmaceutically acceptable salt and / or solvate thereof (e.g. , salts), and / or derivatives thereof, are provided.

[0201] In a further embodiment, a method for treating or preventing a disease or disorder described herein. Thus, a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof (e.g.,

[0033] An effective amount of a pharmaceutical composition containing the compound (e.g., a salt thereof) and / or a derivative thereof is administered to a patient in need thereof. administering to a subject.

[0202] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvent thereof. and pharmaceutical compositions comprising the compounds (e.g., salts) and / or derivatives thereof for the treatment of diseases described herein. and (c) the use of a compound of formula (I) or (II) in the manufacture of a medicament for the treatment or prevention of a disease or disorder.

[0203] A compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, and and / or derivatives thereof may be administered in any convenient manner, for example, orally, parenterally, intraoral buccal, lingual It can be administered intranasally, intranasally, rectally or transdermally using pharmaceutical compositions adapted accordingly.

[0204] A compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, and and / or their derivatives can be administered topically, for example to the eye, gastrointestinal tract or skin. Thus, in one embodiment, the compounds of the present invention are optionally administered in one or more topically acceptable diluents. Pharmaceutical compositions are provided that include the compounds in combination with a diluent or carrier.

[0205] The pharmaceutical compositions of the present invention can be delivered topically to the skin. Compositions suitable for transdermal administration include soft Such pharmaceutical compositions also preferably include creams, lotions, gels and patches. It may also be in the form of a sachet, foam, powder, paste or tincture.

[0206] The pharmaceutical composition preferably contains a vitamin D3 analogue (e.g., calcipotriol and maxazone). calcitol), steroids (e.g., fluticasone propionate, betamethasone valerate and clobetasol propionate), retinoids (e.g., Tazarol Topical medications may include cereals containing ... Products are often used in combination with each other (e.g., vitamin D3 and steroids) or as salicylic acid. It is used in combination with further reagents such as carboxylic acids.

[0207] The pharmaceutical compositions of the present invention can be delivered topically to the eye. Such pharmaceutical compositions preferably comprise: It can be formulated as eye drops or an ointment. The pharmaceutical compositions of the present invention can be delivered locally to the gastrointestinal tract. Such pharmaceutical compositions are preferably The compound can be delivered orally in tablet or capsule form, or rectally in suppository form. A preferred delayed release formulation is in capsule form.

[0208] A compound of formula (I) or a pharmaceutically acceptable salt thereof, which is active when administered orally, and / or or solvates, and / or derivatives thereof, may be formulated, for example, as syrups, suspensions, emulsions, tablets, The compositions can be formulated in liquid or solid form such as tablets, capsules or lozenges.

[0209] Liquid formulations generally contain the active ingredient (a compound of formula (I) or a pharmaceutically acceptable salt thereof) and / or solvates (e.g., salts, and / or derivatives thereof, etc.) with, for example, water, Aqueous solvents such as ethanol or glycerin, or polyethylene glycol or oil, etc. The formulation may also consist of a suspension or solution of the compound in a non-aqueous solvent with an appropriate liquid vehicle. , suspending agents, preservatives, flavoring and / or coloring agents.

[0210] The composition in tablet form is magnesium stearate, starch, lactose, sucrose Any suitable pharmaceutical carrier routinely used for preparing solid formulations, such as cellulose, It can be prepared using

[0211] A composition in capsule form can be prepared using routine encapsulation procedures, e.g., by adding an active ingredient such as hydroxybenzoates or hydroxybenzoates to a composition containing hydroxybenzoates. The component (a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, e.g. Pellets containing hydroxybenzoates (e.g., salts) and / or their derivatives are prepared using standard carriers. The dispersion or suspension may be prepared and then filled into a hard gelatin capsule, or the dispersion or suspension may be optionally prepared using any suitable pharmaceutical carrier, for example, aqueous gums, cellulose, silicates or oils, The dispersion or suspension may then be filled into a soft gelatin capsule.

[0212] Typical parenteral compositions comprise an active ingredient (a compound of formula (I) or a pharmaceutically acceptable salt thereof) in a dose of 100 mg / kg or more. and / or solvates (e.g., salts, and / or derivatives thereof) in a sterile aqueous solution. Carriers or parenterally acceptable oils, e.g., polyethylene glycol, polyvinylpyrrolidone It consists of a solution or suspension in peanut oil, lecithin, peanut oil, or sesame oil. Alternatively, the solution can be lyophilized and reconstituted with a suitable solvent immediately prior to administration. .

[0213] Compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. Aerosol formulations are typically prepared in pharmaceutically acceptable aqueous or non-aqueous solutions. It comprises a solution or fine suspension of the active ingredient in an aqueous solvent, usually packaged in a cartridge for use in a nebulizer. Single or multiple doses in a sterile, sealed container, which may be in the form of a cartridge or refill. Alternatively, the sealed container may be a single dose nasal inhaler or an inhaler equipped with a metering valve. The dosage form may be a disposable dispenser such as an aerosol dispenser. If it contains a penetrator, it may be a compressed gas, such as air, or a fluorochlorohydrocarbon or The aerosol may contain a propellant, which may be an organic propellant such as a hydrofluorocarbon. The dosage forms can also take the form of a pump-atomiser.

[0214] Compositions suitable for oral buccal or sublingual administration include tablets, lozenges and drops, These formulations contain active ingredients such as sugar and acacia, tragacanth, or gelatin and glycerin. It is formulated with a carrier. Compositions for rectal administration conveniently comprise a suppository containing a conventional suppository base such as cocoa butter. The dosage form of the drug. Preferably the composition is in the form of a predetermined unit dose such as a tablet, capsule or ampoule.

[0215] The composition may contain, for example, 0.1 to 100% by weight, for example, 10 to 60% by weight of active ingredient, depending on the method of administration. The composition may contain 0 to 99% by weight, for example 40 to 90% by weight, depending on the method of administration. The composition may contain a carrier in an amount of 0.05 mg to 2000 mg, depending on the method of administration. For example, the composition may contain from 1.0 mg to 500 mg of the active ingredient. It may also contain 50 mg to 1000 mg, for example 100 mg to 400 mg, of a carrier. The dose of the compound used for prophylaxis or prevention will depend on the severity of the disorder, the weight of the patient, and other similar factors. However, as a general guide, the appropriate units of The dosage may be from 0.05 mg to 1000 mg, more preferably from 1.0 mg to 500 mg, and such Such unit doses may also be administered more than once a day, for example, two or three times a day. Such therapy may continue for several weeks or months.

[0216] In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: The solvates and / or derivatives thereof may be further formulated with one or more pharmaceutically acceptable active ingredients. with a compound of formula (I), or a pharmaceutically acceptable derivative thereof (a combination including

[0217] The present invention further provides a method for the preparation of a pharmaceutical composition for use in combination with one or more pharmaceutically acceptable active ingredients. A compound of formula (I) is provided. When the compounds are used in combination with other therapeutic agents, the compounds may be administered by any convenient route. The compounds may be administered separately, sequentially, or simultaneously.

[0218] The optimal combination will vary depending on the disease or disorder. Possible combinations include: 5-aminosalicylic acid; Licylic acid or its prodrugs (sulfasalazine, olsalazine or bisalazide) lazide, etc.); corticosteroids (e.g., prednisolone, methylprednisolone, or budesonide); immunosuppressants (e.g., cyclosporine, tacrolimus, sirolimus, methotrexate, Rexate, azathioprine, mycophenolate mofetil, leflunomide, cyclophosph amide, 6-mercaptopurine, or antilymphocyte (or thymocyte) globulin); anti-TNFα antibodies (e.g. For example, infliximab, adalimumab, certolizumab pegol, or golimumab; anti-IL12 / IL23 antibodies (e.g., ustekinumab); anti-IL6 or anti-IL6R antibodies, anti-IL17 antibodies, or small molecule IL12 / IL23 inhibitors (e.g., apilimod); anti-α4β7 antibodies (e.g., vedolizumab); MAdC AM-1 blockers (e.g., PF-00547659); antibodies against the cell adhesion molecule α4-integrin (e.g., , natalizumab); antibodies against the IL2 receptor alpha subunit (e.g., daclizumab or basil); liximab; JAK inhibitors, including JAK1 and JAK3 inhibitors (e.g., tofacitinib, baricitinib) Syk inhibitors and their prodrugs (e.g., fostamatinib and and R-406); phosphodiesterase 4 inhibitors (e.g., tetomilast); HMPL-004; Probiotics; Dersalazine; Semapimod / CPSI-2364; and protein kinase C inhibitors (e.g., AEB-071). This includes combinations with one or more active agents that are

[0219] For cancer, further pharmaceutically acceptable active ingredients include antimitotic drugs, such as vincristine, thiazolinone ... alkylating agents such as cisplatin, carboplatin, Platinum, dacarbazine and cyclophosphamide; antimetabolites, such as 5-fluorouracil le, cytosine arabinoside and hydroxyurea; intercalating agents, e.g. Adriamycin and bleomycin; topoisomerase inhibitors such as etoposide, Potecan and irinotecan; thymidylate synthase inhibitors, such as raltitrexed; PI3 kinase inhibitors mTor inhibitors, such as everolimus and temsirolimus proteasome inhibitors, e.g., bortezomib; histone deacetylase inhibitors, e.g., and hedgehog pathway blockers, such as bis(methicone) and bis(methicone). You can choose from Modegib.

[0220] Further pharmaceutically acceptable active ingredients include tyrosine kinase inhibitors, e.g., axitinib dasatinib, erlotinib, imatinib, nilotinib, pazopanib, sunitinib, etc. You can choose from.

[0221] Anti-cancer antibodies may be included in the combination therapy, such as olaratumab, daratumumab, Necitumumab, dinutuximab, trastuzumab emtansine, pertuzumab, obinutuximab Ibuprofen, brentuximab, ofatumumab, panitumumab, catumax Mab, bevacizumab, cetuximab, tositumomab, trastuzumab, gemtuzumab ozo The anti-inflammatory drug may be selected from the group consisting of gamycin and rituximab. The compounds or pharmaceutical compositions of the present invention can also be used in combination with radiation therapy.

[0222] Some of the above-mentioned combinations are conveniently presented for use in the form of pharmaceutical preparations. Therefore, the above-defined combinations can be used in combination with a pharmaceutically acceptable carrier or excipient. The individual components of such combinations comprise: They may be administered either sequentially or simultaneously as separate or combined pharmaceutical formulations. The individual components of the combination can also be administered separately by the same or different routes.

[0223] The compounds of formula (I) or their pharmaceutically acceptable derivatives may be used in combination with other compounds active against the same disease conditions. When used in combination with a second therapeutic agent, the dose of each compound may be adjusted to The amount may vary depending on the case in which it is used, and appropriate amounts will be readily apparent to those skilled in the art.

[0224] (Medical Devices) In one embodiment, the compounds of the present invention or pharmaceutical compositions comprising the compounds are Applying the composition directly to the site to prevent or treat the conditions disclosed herein , can be formulated to allow incorporation into medical devices.

[0225] In one embodiment, the compounds of the present invention or pharmaceutical compositions thereof are used as coatings on medical devices. The compound can be formulated in a coating. The compound or pharmaceutical composition thereof may be prepared by coating with a polymer that allows release over a long period of time. In some embodiments, the compounds can be directly implanted into a medical device. The device within the vehicle, such as a microparticle or liposome, facilitates its release and delivery. In some embodiments, the compound or pharmaceutical composition is coated on the inside. It is miscible in coating.

[0226] In some embodiments, the medical device is a vascular implant, such as a stent. Tents are used in medicine to prevent or eliminate vascular stenosis. The catheter may be inserted into a narrowed vessel, and the narrowed vessel is then expanded. Overgrowth of adjacent cells after vascular implantation can lead to vascular narrowing, especially at the edges of the implant. This reduces the effectiveness of the implant, e.g., to eliminate arteriosclerotic stenosis. When a vascular implant is inserted into a human artery, intimal hyperplasia occurs at the end of the vascular implant within one year. Thickening may occur and new stenosis ("restenosis") may occur.

[0227] Thus, in some embodiments, the stent comprises a compound of the present invention or a pharmaceutical composition thereof, and and optionally a targeting signal, a delivery vehicle, or a combination thereof. Numerous stents are commercially available or known in the art. do.

[0228] In some embodiments, the stent is a drug-eluting stent. Various drug-eluting surfaces are available that provide support while simultaneously delivering therapeutic substances to the treatment site. Intraluminal devices, including stents, are sometimes coated on their exterior surfaces, e.g., For example, the stent may be coated with a drug-releasing agent, growth factor, or other substance. The device may be developed to have a hollow tubular structure with holes or ports therethrough, a central lumen However, the hollow nature of this stent allows for the release of drugs from the central lumen. This hollow space can carry a drug solution that is delivered through a port or hole in the side wall of the device. Tubular structures may not have adequate mechanical strength to provide adequate scaffolding within the vasculature. do.

[0229] In some embodiments, the device also comprises a compound of the invention or a pharmaceutical composition thereof, and one or more Coated or impregnated with the above additional therapeutic agents, including the following: These include, but are not limited to, antiplatelet agents, anticoagulants, anti-inflammatory agents, antibacterial agents, antimetabolites, additional Anti-neointima agents, additional anti-proliferative agents, immunomodulatory agents, anti-proliferative agents, migration and extracellular matrix Agents that affect platelet adhesion or thrombus formation, and agents that affect vascular healing and re-endothelialization. Agents that promote cell proliferation, such as those described in Sousa et al. (2003) and Salu et al. (2004) This includes things like:

[0230] Examples of antithrombin agents include, but are not limited to, heparin (low molecular weight heparin including R-hirudin, Hirulog, argatroban, efegatran ), tick anticoagulant peptide, and Ppack. Examples of antiproliferative agents include, but are not limited to, paclitaxel (taxol), QP-2 bilirubin, Methotrexate, Angiopeptin, Mycobacterium tuberculosis tomycin, BCP678, antisense c-myc, ABT 578, actinomycin D, restenase (R estenASE), 1-chloro-deoxyadenosine, PCNA ribozyme, and Contains celecoxib.

[0231] Examples of anti-restenotic agents include, but are not limited to, sirolimus (rapamycin), tacrolimus (anticoagulant), and thrombus (thrombus). Limus, Biorest, Mizoribine, Cyclosporine, Interf Elon-γlb, leflunomide, tranilast, corticosteroids, mitomycin Immunomodulators such as cophenolic acid and biphosphonates are included. Examples of anti-migratory agents and extracellular matrix modulating agents include, but are not limited to, halofen Zinone, propyl hydroxylase inhibitor, C-proteinase inhibitor, MMP inhibitor, bachi These include mastat and probucol.

[0232] Examples of antiplatelet agents include, but are not limited to, heparin. Examples of wound healing and endothelialization promoting agents include vascular epidermal growth factor ("VEGF"), 17-estradiol, ol, Tkase inhibitors, BCP671, statins, nitric oxide ("NO") donors, and endothelial progenitor cells Antibodies include endothelial cell ("EPC") antibodies.

[0233] In addition to coronary artery use, the drugs and active agents may also be used in stents or stent coatings for other indications. For example, in urinary applications, antibiotics can be incorporated into the skin to prevent infection. It can be incorporated into stents or stent coatings. The present invention relates to the incorporation of active agents into stents or stent coatings for the localized treatment of cancer. Contrast agents, radiopaque markers, or other additives may be placed in or on the stent. Incorporating imaging technology to image the stent in vivo can also be useful for tracking, positioning, and other purposes. Such additives may be advantageous for applications such as stents or stent coatings. It may be added to the absorbent composition used to manufacture or to the entire or part of the stent. It can also be absorbed, melted or sprayed onto the surface. Additives include silver, iodine and iodine-labeled compounds, barium sulfate, gadolinium oxide, bismuth, and Derivatives, zirconium dioxide, cadmium, tungsten, gold tantalum, bismuth, white These additives include gold, iridium, and rhodium. These additives are present in the form of micro- or nano-sized particles or The radiopacity may be, but is not limited to, nanoparticles. It can be determined by fluoroscopy or x-ray analysis.

[0234] The compound of the present invention and one or more additional agents or pharmaceutical compositions thereof may be added to an absorbent material prior to manufacture. The compound and one or more additional reagents or pharmaceutical compositions thereof are carried in the formulation, and The reagent is incorporated into the stent either by coating the surface of the stent with the reagent. The release rate of the agent can be controlled in a number of ways by varying the following factors: The factors that change include: the compound and one or more additional reagents or pharmaceutical compositions; The proportion of absorbent material, the molecular weight of the absorbent material, the composition of the compound and one or more additional reagents or drugs The composition of the drug composition, the composition of the absorbent polymer, the coating thickness, the number of coating layers and the like the relative thickness of these, and / or the composition of the compound and one or more additional reagents or pharmaceutical compositions. Topcoats of polymers and other materials, including absorbent polymers, may also be used. , can be applied to the active agent coating to control the release rate. For example, P4HB It was applied as a topcoat on a metallic stent coated with P4HB containing an active agent. , which allows for slow release of the active agent. The present invention is further illustrated by the following non-limiting examples. [Example]

[0235] (Example) Abbreviations used herein are defined below. Any abbreviations not defined shall remain the property of their respective owners. are intended to convey their generally accepted meanings.

[0236] (abbreviation) [Table 1] TIFF0007667225000060.tif244170TIFF0007667225000061.tif236170TIFF0007667225000062.tif241170TIFF0007667225000063.tif129170

[0237] (General Procedure) All starting materials and solvents were either commercially available or prepared according to the literature. All reactions were stirred unless otherwise noted. Organic solutions were routinely diluted with anhydrous The hydrogenation was carried out in a Thales H-cube flow reactor. The experiment was carried out under the specified conditions.

[0238] Column chromatography was performed using pre-packed silica (230-400 mesh, 40-63 μm) cartridges. SCX was purchased from Supelco and treated with 1 M hydrochloric acid before use. Unless otherwise stated, reaction mixtures for purification were first diluted with MeOH and a few drops of AcOEt. The solution was then acidified with 0.7M NH3 in MeOH. The target material was eluted by washing with the solution.

[0239] (Preparative reversed-phase high-performance liquid chromatography) (preparative HPLC) (acidic preparative) Waters X-Select CSH column C18, 5 um (19 x 50 mm), flow rate 28 mL / min, H containing 0.1% v / v formic acid A 2O-MeCN gradient was used for elution in 6.5 min with UV detection at 254 nm. (Basic fractionation) Waters X-Bridge Prep Column C18, 5um (19 x 50 mm), flow rate 28 mL / min, 10 mM NH4HCO3-M eCN gradient, eluted in 6.5 min, with UV detection at 254 nm.

[0240] (analytical method) (Reversed-phase HPLC conditions for LCMS analysis) (HPLC acidic: acidic LCMS 4 minutes (5~95%)) Analytical LCMS was performed using a Waters X-Select CSH C18, 2.5um, 4.6x30mm column with 0.1% Gradient elution of formic acid in MeCN was performed with 0.1% formic acid in water. A 5-95% gradient of the solution was run at 2.5 mL / min from 0.00 to 3.00 min and 4.5 mL / min from 3.01 to 3.5 min. The column was flushed with 5% MeCN. The column was equilibrated to 5% MeCN at 2.5 mL / min from 3:60 to 4:00 min. The elution peaks of the V spectrum were measured at 254 nm using an Agilent 1260 Infinity VWD. Mass spectra were acquired using an Agilent 6120 MSD with positive / negative switching. Measurements were taken while in use.

[0241] (HPLC basic: LCMS basic 4 min (5-95%)) Analytical LCMS was performed using a Waters X-Select BEH C18, 2.5 um, 4.6 x 30 mm column with MeCN. Gradient elution was performed with 10 mM ammonium bicarbonate solution. The agent was flushed at 2.5 mL / min from 0.00 to 3.00 min and at 4.5 mL / min from 3.01 to 3.5 min. The column was equilibrated with 5% MeCN at 2.5 mL / min from 3:60 to 4:00 min. Eluting peaks were measured at 254 nm using an Agilent 1260 Infinity VWD. Mass spectra was measured using an Agilent 6120 MSD with positive / negative switching. Ta.

[0242] (Reversed-phase HPLC conditions for UPLC analysis) (UPLC acidic: acidic UPLC 3 minutes) Analytical UPLC / MS was performed using a Waters Acquity CSH C18, 1.7 um, 2.1 x 30 mm column. The gradient elution was performed using a 0.1% formic acid solution in MeCN with 0.1% formic acid in water. The starting point was 5% MeCN, held for 0.0-0.11 min. The 5-95% gradient was 0.11-2.15 min. The column was equilibrated to 5% MeCN from 2.56 to 2.83 minutes, followed by flushing from 2.15 to 2.56 minutes. The elution peaks of the UV spectrum were measured using an Acquity PDA, and the mass spectrum was The spectra were recorded using an Acquity QDa detector with ESI pos / neg switching.

[0243] (UPLC2 acidic: acidic UPLC 1 minute) Analytical UPLC / MS was performed using a Waters Acquity CSH C18, 1.7 um, 2.1 x 30 mm column. A gradient of 0.1% formic acid in MeCN was run with 0.1% formic acid in water. The starting point was 5% MeCN, held for 0.0-0.08 minutes. The 5-95% gradient was 0.08-0.70 minutes. The column was equilibrated to 5% MeCN for 0.8-0.9 minutes. The elution peaks of the UV spectra were measured using an Acquity PDA, and the mass spectra were analyzed by A Recordings were made using a cquity QDa detector with ESI pos / neg switching.

[0244] (UPLC basic: basic UPLC 3 min) Analytical UPLC / MS was performed using a Waters Acquity BEH C18, 1.7 um, 2.1 x 30 mm column with MeCN The column was eluted with a gradient of 10 mM ammonium bicarbonate. The starting point was 5% MeCN, held for 0.0-0.11 minutes. The 5-95% gradient was 0.11-2.1 minutes. The column was equilibrated to 5% MeCN from 2.56 to 2.83 minutes. The elution peaks of the UV spectrum were measured using an Acquity PDA, and the mass spectrum was The spectra were recorded using an Acquity QDa detector with ESI pos / neg switching.

[0245] (UPLC 2 basic: basic UPLC 1 min) Analytical UPLC / MS was performed using a Waters Acquity BEH C18, 1.7 um, 2.1 x 30 mm column with MeCN The column was eluted with a gradient of 10 mM ammonium bicarbonate. The starting point was 5% MeCN, held for 0.0-0.08 minutes. The 5-95% gradient was 0.08-0.7 The column was equilibrated to 5% MeCN for 0.8-0.9 minutes. The elution peaks of the UV spectrum were measured using an Acquity PDA, and the mass spectrum was , recorded using an Acquity QDa detector with ESI pos / neg switching. The column temperature was 40°C for all runs. The injection volume was 3 uL and the flow rate was 0.77 mL / min. A-scans were taken from 210 to 400 nm in all runs.

[0246] (Normal Phase HPLC Conditions for Chiral Analysis) Chiral IC3 method: Chiral HPLC (Diacel Chiralpak IC, 5 μm, 4.6 × 250 mm, 1.0 mL / min, 25- A solution of 70% EtOH (0.2% TFA) in isohexane (0.2% TFA) was used. Chiral IC4 method: Chiral HPLC (Diacel Chiralpak IC, 5 μm, 4.6 × 250 mm, 1.0 mL / min, 40% EtOH (0.2% TFA) in a 4:1 heptane / chloroform (0.2% TFA) mixture was used. Chiral IC5 method: Chiral HPLC (Diacel Chiralpak IC, 5µm, 4.6 x 250 mm, 1.0 mL / min, 20% A solution of isohexane (0.2% TFA) in EtOH (0.2% TFA) was used.

[0247] (Reversed-phase HPLC conditions for chiral analysis) Chiral IC6 method: Chiral HPLC (Diacel Chiralpak IC, 5 μm, 4.6 × 250 mm, 1.0 mL / min, 50% MeCN (0.1% formic acid) in water (0.1% formic acid). Chiral IC7 method: Chiral HPLC (Diacel Chiralpak IC, 5µm, 4.6 x 250 mm, 1.0 mL / min, 5-9 5% MeCN (0.1% formic acid) in water (0.1% formic acid).

[0248] ( 1 H NMR spectroscopy) 1 H NMR spectra were obtained on a Bruker Avance III spectrometer at 400 MHz or a Bruker Avance IIIH D spectrometer at 500 MHz using residual non-deuterated solvent as reference, unless otherwise stated. The experiment was carried out in DMSO-d6.

[0249] (Preparation of intermediates) Known synthetic intermediates were either commercially available or obtained using published literature procedures. Additional intermediates were prepared by the representative synthetic processes described herein. Any of Methods 1 to 10 (described later in this specification) or A to N may be used to synthesize compounds of formula (I). For example, a scheme showing the use of a compound where X=N, Y=CR2 and Z=CR3 can also be used. and Z can be used to synthesize compounds in which Z is as defined in the claims.

[0250] (Preparation of diester intermediates) 1-(tert-butyl) 3-methyl 2-(2-chloropyrimidin-4-yl)malonate INTC1 [ka] NaH (60 wt % in mineral oil, 5.10 g, 128 mmol) was added to ice-cooled, stirred tert-butyl methyl malonate ( To a solution of 20.5 mL of HCl (121 mmol) in 160 mL of THF was added portionwise. The reaction was stirred at 0° C. for 20 min, then The mixture was stirred at room temperature for 60 minutes until hydrogen evolution ceased. , 67.1 mmol) was added and the resulting mixture was stirred at 70 °C for 3 h. The reaction was allowed to cool and NH4Cl Partition between (saturated aqueous solution, 500 mL) and EtOAc (500 mL), separate the two phases, and phase separate the organic phase. The crude product was separated by filtration on silica gel (220 g column, 0-30% EtOAc / isohexane). Purified by chromatography to give 1-tert-butyl 3-methyl 2-(2-chloropyrimidin-4-yl)malonate. The ester (13.1 g, 44.3 mmol, 66% yield) was obtained as a clear, pale yellow oil. Rt 2.09 min (HPLC acid ); m / z 230 (M+H-tBu) + (ES + ) and 287(M+H) + (ES + ); [ka]

[0251] 1-(tert-butyl) 3-methyl 2-(2-chloro-5-fluoropyrimidin-4-yl)malonate INTC2 [ka] NaH (60 wt% in mineral oil, 0.575 g, 14.4 mmol) was added to stirring tert-butyl methyl malonate (2. The reaction mixture was stirred at room temperature under a N2 atmosphere for 1 hour. The reaction was allowed to cool to 0°C and 2,4-dichloro-5- Fluoropyrimidine (2.0 g, 12.0 mmol) was added. The resulting mixture was slowly heated to room temperature. The mixture was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo (reduced pressure). The crude product was separated by precipitation onto silica gel (40 g). Purification by chromatography (0-50% EtOAc / isohexane) gave 1-tert-butyl 3-methylpropional. ethyl 2-(2-chloro-5-fluoropyrimidin-4-yl)malonate (1.96 g, 5.47 mmol, 46% yield) (yield: 1.001) was obtained as a clear, colorless oil. Rt 1.42 min (HPLC acidic); m / z 305 (M+H) + (ES + ); [ka]

[0252] 1-(tert-butyl) 3-methyl 2-(2-chloro-5-methylpyrimidin-4-yl)malonate INTC3 [ka] NaH (60 wt % dispersion in mineral oil, 0.466 g, 11.7 mmol) was added to ice-cooled, stirred tert-butylmethyl methyl methacrylate. To a solution of 1.97 mL (11.7 mmol) of thiazolinone in 10 mL of THF was added portionwise. The reaction was allowed to stand at room temperature. Stirred for 10 minutes, then added 2,4-dichloro-5-methylpyrimidine (1.0 g, 6.13 mmol), The resulting mixture was stirred at 70 °C for 2 h. The reaction was allowed to cool and then saturated aqueous NH4Cl (10 mL) and The mixture was partitioned between 10 mL of ethyl acetate and 10 mL of EtOAc, the two phases were separated, and the organic phase was passed through a phase separator. The residue was purified by chromatography on silica gel (12 g column, 0-30% EtOAc / isohexane). , 1-tert-butyl 3-methyl 2-(2-chloro-5-methylpyrimidin-4-yl)malonate (1.40 g, 4 (0.41 mmol, 72% yield) as a colorless oil. Rt 1.39 min (HPLC acidic); m / z 201 (M-Boc+H) + (ES + ); [ka]

[0253] 1-tert-butyl 3-methyl 2-(2-chloro-6-methylpyrimidin-4-yl)malonate INTC54 [ka] As with INTC1, commercially available 2,4-dichloro-6-methylpyrimidine and tert-butylmethylmalonate were used. 1-tert-butyl 3-methyl 2-(2-chloro-6-methylpyrimidin-4-yl)pyrimidinate The methyl malonate (61% yield) was obtained as a clear oil. Rt 1.39 (UPLC basic); m / z 301 ( 35 Cl M+H ) + (ES + ); [ka]

[0254] 1-tert-butyl 3-methyl 2-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)malonate Nate INTC55 [ka] As with INTC1, commercially available 2,4-dichloro-6-(trifluoromethyl)pyrimidine and tert-butylpyrimidine were used. Prepared using ethyl methyl malonate and 1-tert-butyl 3-methyl 2-(2-chloro-6-(trifluoromethyl)methyl)propanol. (Fluoromethyl)pyrimidin-4-yl)malonate (67% yield) was obtained as a clear oil. Rt 1.34 ( UPLC basic); m / z not observed. [ka]

[0255] Dimethyl 2-(2-chloropyrimidin-4-yl)-2-methoxymalonate INTC56 [ka] As with INTC1, 2,4-dichloropyrimidine and dimethyl 2-methoxymalonate were used. Dimethyl 2-(2-chloropyrimidin-4-yl)-2-methoxymalonate (79% yield) was prepared by Obtained as a clear, colorless oil. Rt 1.55 (HPLC acidic); m / z 275( 35 Cl M+H) + (ES + ); 1 H NMR was not recorded. The material was used directly in the next step without further characterization.

[0256] Dimethyl 2-(2-chloropyrimidin-4-yl)-2-isopropylmalonate INTC57 [ka] As with INTC1, 2,4-dichloropyrimidine and dimethyl 2-isopropyl malonate were used. Dimethyl 2-(2-chloropyrimidin-4-yl)-2-isopropyl malonate (98 % yield) was obtained as a red gum. Rt 0.64 (UPLC, acid 2); m / z 286 ( 35 Cl M+H) + (ES + ) ; 1 1 H NMR was not recorded. The material was used directly in the next step without further characterization.

[0257] (Decarboxylation of chloropyrimidines) Methyl 2-(2-chloropyrimidin-4-yl)acetate INTC4 [ka] TFA (55.3 mL, 717 mmol) was added to ice-cold, stirring 1-tert-butyl 3-methyl 2-(2-chloropyrimidine) The reaction mixture was added dropwise to a solution of di-(4-yl)malonate INTC1 (12.1 g, 42.2 mmol) in DCM (50 mL). The mixture was stirred at 25° C. for 1 h and then concentrated in vacuo. The residue was dissolved in EtOAc (200 mL). The mixture was basified with NaHCO3 (200 mL), and the organic phase was isolated and passed through a phase separator, and the solvent was removed in vacuo ( The crude product was removed under reduced pressure. Purify by chromatography on methyl 2-(2-chloropyrimidin-4-yl)acetate (7.12 g, 37.8 mmol, 90% yield) was obtained as a pale yellow oil. Rt 1.16 min (HPLC acidic); m / z 187 (M+ H) + (ES + ); [ka]

[0258] Method A: Decarboxylation of chloroheterocycles such as chloropyrimidines [ka] TFA (10 equiv.) was added dropwise to an ice-cold, stirring solution of the malonate derivative (1 equiv.) in DCM (15 vol.). The reaction vessel was stirred at room temperature for 18 hours and then concentrated. The crude product was purified by normal phase chromatography. The product was purified by filtration.

[0259] (Table 1: The following intermediates were prepared according to Method A.) [Table 2]

[0260] (Alkylation) Methyl 2-(2-chloropyrimidin-4-yl)-2-methylpropanoate INTC7 [ka] MeI (0.24 mL, 3.89 mmol) was added to stirring methyl 2-(2-chloropyrimidin-4-yl)acetate. To a suspension of INTC4 (0.29 g, 1.55 mmol) and K2CO3 (0.644 g, 4.66 mmol) in acetone (5 mL), The reaction vessel was sealed and stirred at 60° C. for 18 hours. The reaction mixture was concentrated in vacuo (reduced pressure). Water (40 mL) was added and then extracted with DCM (2 x 40 mL). The organic phase was dried (phase separator) and vacuum The crude product was purified by silica gel (24 g column, 0-50% EtOAc / isohexane). The product was purified by chromatography to give methyl 2-(2-chloropyrimidin-4-yl)-2-methylpropionate. The benzoate (0.25 g, 1.11 mmol, 71% yield) was obtained as a clear pale yellow liquid. Rt 1.70 min (HP LC acidic);m / z 215(M+H) + (ES + ); [ka]

[0261] Methyl 2-(2-chloropyrimidin-4-yl)propanoate INTC8 [ka] MeI (14.1 mL, 225 mmol) was added to stirring methyl 2-(2-chloropyrimidin-4-yl)acetate. To a suspension of INTC4 (10.37 g, 45.0 mmol) and K2CO3 (31.1 g, 225 mmol) in acetone (150 mL), The reaction mixture was stirred at 60°C for 40 hours under N2 atmosphere. The reaction mixture was concentrated in vacuo (reduced pressure). The resulting mixture was diluted with 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 (220 g column, 0-30% EtOAc / isohexane). and purified by chromatography to obtain methyl 2-(2-chloropyrimidin-4-yl)propanoate ( 1.27 g, 5.00 mmol, 11% yield) was obtained as a by-product. Rt 0.89 min (UPLC acidic); m / z 201 (M+H ) + (ES + ). 1 H-NMR data was not recorded.

[0262] (Method B: Alkylation) [ka] A base (2.5-5 equivalents) is added to methyl 2-(2-chloropyrimidin-4-yl)acetate in an ice-cold, stirred solution. to a mixture of 1 equivalent of acetone and a suitable aprotic polar solvent such as DMF or acetone (10 volumes). After 20 minutes, an alkyl halide (1-5 equivalents) was added. The reaction vessel was then heated at 0°C for 30 minutes. The reaction was then stirred at room temperature for 2 hours. The reaction was quenched with NH4Cl (aq) or 1 M HCl (aq). The mixture was stirred for 20 minutes and then extracted with EtOAc. The organic phase was dried (phase separator) and concentrated. The product was purified by normal phase chromatography.

[0263] (Table 2: The following intermediates were prepared according to Method B.) [Table 3] TIFF0007667225000085.tif230170

[0264] (2,6-dichloropyrimidines N Ar) Methyl 2-(2-chloro-6-methoxypyrimidin-4-yl)-2-methylpropanoate INTC65 [ka] Methyl 2-(2,6-dichloropyrimidin-4-yl)-2-methylpropane was stirred at 0°C under N2 atmosphere. To a solution of panoate INTC64 (0.77 g, 2.78 mmol) in MeOH (10 mL) was added 5.4 M sodium methoxychloride. MeOH (0.6 mL, 3.24 mmol) was added. The mixture was stirred at 0° C. for 30 min and then at room temperature for another 30 min. The reaction was then concentrated in vacuo (reduced pressure). The crude product was separated by silica gel (40 g column, 0 Purification by chromatography in 50% EtOAc / isohexane to give methyl 2-(2-chloro-6-methyl- (4-hydroxypyrimidin-4-yl)-2-methylpropanoate (0.54 g, 1.72 mmol, 62% yield) was Obtained as a colored solid. Rt 1.35 min (UPLC acid); m / z 245 ( 35 Cl M+H) + (ES + ); [ka]

[0265] (Heterocycle formation via alkylation) Methyl 4-(2-chloropyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylate IN TC52 [ka] Methyl 2-(2-chloropyrimidin-4-yl)acetate INTC4 (2.0 g, 10.7 mmol) in DMF ( To a solution of 10 mL of NaOH (10.7 mmol) was added NaOH (0.986 g, 24.6 mmol). The reaction mixture was stirred at 0° C. for 20 The mixture was stirred for 1 minute, and then 1-bromo-2-(2-bromoethoxy)ethane (1.8 mL, 12.9 mmol) was added. The reaction was stirred at room temperature for 23 hours. The reaction mixture was diluted with 1M HCl (aq, 53.6 mL, 53.6 mmol) The mixture was acidified with HCl and extracted with DCM (70 mL). The two phases were separated using a phase separator cartridge. The separated aqueous phase was further extracted with DCM (2 x 50 mL). The combined organic phases were concentrated in vacuo. The crude product was chromatographed on silica gel (80 g column, 0-50% EtOAc / isohexane). Purified by HPLC and purified to give methyl 4-(2-chloropyrimidin-4-yl)tetrahydro-2H-pyran-4-carbohydrate. The xylate (1.83 g, 5.57 mmol, 52% yield) was obtained as a yellow oil. Rt 1.56 min (HPLC acidic); m / z 257( 35 Cl M+H) + (ES + ); [ka]

[0266] (Enolate S N Heterocycle formation via Ar) 1-tert-butyl 4-methyl 4-(2-chloropyrimidin-4-yl)piperidine-1,4-dicarboxylate Rate INTC66 [ka] LiHMDS (1.61 mL, 1.61 mmol) was added to ice-cooled, stirred 1-tert-butyl-4-methylpiperidine-1,4- dicarboxylate (340 mg, 1.40 mmol) and 2,4-dichloropyrimidine (200 mg, 1.34 mmol) To a solution of HCl (10 mL) in THF was added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by the addition of NaH2PO4 (aq, 1M, 3 mL). The product was extracted with DCM (2 x 10 mL). The combined organic extracts were dried in a hydrophobic phase separator and concentrated in vacuo. The crude product was chromatographed on silica gel (24 g column, 0-50% EtOAc / isohexane). Purification by HPLC gave 1-tert-butyl 4-methyl-4-(2-chloropyrimidin-4-yl)piperidine-1,4- The dicarboxylate (315 mg, 0.66 mmol, 49% yield) was obtained as a colorless oil. Rt 2.29 min (H PLC acidic);m / z 255( 35 Cl M-Boc+H) + (ES + ); [ka]

[0267] 1-tert-butyl 3-methyl 3-(2-chloropyrimidin-4-yl)azetidine-1,3-dicarboxylate Rate INTC67 [ka] Similar to INTC66, 1-tert-butyl 3-methylazetidine-1,3-dicarboxylate and 2,4- Prepared using dichloropyrimidine in toluene and 1-tert-butyl 3-methyl 3-(2-chloropyrimidine) (pyrimidin-4-yl)azetidine-1,3-dicarboxylate (7% yield) was obtained as a pale yellow oil. Rt 2.12 min (basic HPLC); m / z 272 ( 35 Cl M-tBu+H) + (ES + ); [ka]

[0268] (Hydrolysis of chloropyrimidines) Lithium 2-(2-chloropyrimidin-4-yl)-4-methoxybutanoate INTC68 [ka] Methyl 2-(2-chloropyrimidin-4-yl)-4-methoxybutanoate INTC60 (479 mg, 1.96 To a solution of LiOH (56 mg, 2.35 mmol) in THF (5 mL) and MeOH (2.5 mL) was added a solution of LiOH (56 mg, 2.35 mmol) in water (3 mL). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo to give 2-(2 Lithium (-chloropyrimidin-4-yl)-4-methoxybutanoate (441 mg, 1.49 mmol, 76% yield) ) was obtained as a colorless solid. Rt 1.34 min (HPLC acidic); m / z 231 (as free acid) 35 Cl M+H) + (ES+ ) ; [ka]

[0269] (Coupling (sulfonamidation)) 1-(tert-butyl)3-methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)methyl Ronate INTC17 [ka] In a 20 mL container, add cyclopropanesulfonamide (0.254 g, 2.09 mmol), Cs2CO3 (1.14 g, 3. 49 mmol), 1-tert-butyl 3-methyl 2-(2-chloropyrimidin-4-yl) malonate INTC1 (0.50 g, 1.74 mmol) and dioxane (2 mL) were added. The mixture was degassed (N2, 5 min). In a 20 mL vessel, [Pd(allyl)Cl]2 (16 mg, 0.044 mmol), tBuXPhos (74 mg, 0.174 mmol) and dioxane (1 mL) were stirred under N2 atmosphere for 5 minutes and then added to the first vessel. The reaction mixture was heated at 60 °C under a N atmosphere for 2.5 h. The mixture was allowed to cool to room temperature and diluted with H2O (2 The residue was diluted with 1M HCl (aq, 5 mL) and then carefully acidified to pH 4 with 1M HCl (aq, 5 mL). Extract with HCl (2 x 20 mL), filter the organic phase through a phase separator, and remove the solvent in vacuo. The yellow residue was triturated with TBME (10 mL) and filtered. Wash with E (10 mL) and 1-tert-butyl 3-methyl 2-(2-(cyclopropanesulfonamido)pyrimidinone). Zin-4-yl)malonate (0.394 g, 1.05 mmol, 60% yield) was obtained as a white solid. Rt 1.87 min(HPLC acidic);m / z 372(M+H) + (ES + ); [ka] 8:2 mixture of tautomers.

[0270] Method C: Formation of sulfonamides from aromatic halides [ka] The 2-chloropyrimidine intermediate (1 equivalent), sulfonamide (1.2 equivalents) and base (2 equivalents) were reacted with dichloromethane. The mixture was degassed (N2, 5 min) and then the catalyst (5 mol%) was added. The resulting mixture was heated at 90°C under a nitrogen atmosphere for 2 hours. The mixture was filtered and The crude product was purified by normal phase chromatography or The product was purified by trituration using an appropriate solvent (fine crystallization with the addition of an antisolvent).

[0271] (Table 3: The following intermediates were prepared according to Method C.) [Table 4] TIFF0007667225000100.tif242170TIFF0007667225000101.tif241170TIFF0007667225 000102.tif205170TIFF0007667225000103.tif217170TIFF0007667225000104.tif39170

[0272] (decarboxylation) Methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)acetate 2,2,2-trimethylpyrimidin-4-yl Trifluoroacetate INTC33 [ka] TFA (1 mL, 13.0 mmol) was added to ice-cooled, stirring 1-tert-butyl 3-methyl 2-(2-cyclopropanediol). (Sulfonamido)pyrimidin-4-yl)malonate INTC17 (0.27 g, 0.73 mmol) in DCM (2 mL) The reaction vessel was stirred at room temperature for 2 hours, concentrated in vacuo (reduced pressure), and methyl 2-(2-( Cyclopropanesulfonamido)pyrimidin-4-yl)acetate 2,2,2-trifluoroacetate Tate (0.29 g, 0.68 mmol, 93% yield) was obtained as a yellow solid. Rt 0.79 min (HPLC basic); m / z 272(M+H) + (ES + ); [ka] 1:1 mixture of tautomers.

[0273] Method D: Decarboxylation of pyrimidines bearing sulfonamide groups [ka] TFA (10 equiv.) was added dropwise to an ice-cold, stirring solution of the malonate derivative (1 equiv.) in DCM (15 vol.). The reaction vessel was stirred at room temperature for 18 hours and then concentrated in vacuo (reduced pressure). Purified by chromatography.

[0274] Table 4: The following intermediates were prepared according to Method D. [Table 5]

[0275] (hydrolysis) Potassium 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanoate INTC37 [ka] Methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanoate INTC35( A solution of 2.4 g (7.22 mmol) in THF (80 mL) was treated with TMSOK (2.26 g, 15.9 mmol). The mixture was stirred at room temperature for 18 hours. The resulting suspension was concentrated in vacuo to give 2-(2-cyclopropanediol). Potassium (phenylsulfonamido)pyrimidin-4-yl)butanoate (3 g, 6.49 mmol, 90% yield) Obtained as a pale yellow solid. Rt 0.19 min (UPLC basic); m / z 286 (M+H) + (ES + ), io as the free acid ngization; [ka] No NH protons were observed.

[0276] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-methoxybutanoic acid potassium salt MINTC38 [ka] Methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-methoxybutanoate A solution of INTC36 (0.23 g, 0.69 mmol) in THF (5 mL) was treated with TMSOK (0.22 g, 1.54 mmol). The reaction mixture was stirred at room temperature for 18 hours. The resulting suspension was quenched with MeOH (2 mL) and then Concentrate in vacuo to give 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-4-methanone. Potassium tetrahydrofuranate (0.33 g, 0.65 mmol, 94% yield) was obtained as a pale red solid. Rt 0.14 min(UPLC basic); m / z 316(M+H) + (ES + ), ionized as the free acid; [ka] A mixture of tautomers.

[0277] Potassium 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)acetate INTC39 [ka] Methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)acetate (600 mg, A solution of INTC33 (2.212 mmol) in THF (12 mL) was treated with TMSOK (624 mg, 4.87 mmol). The mixture was stirred at room temperature for 18 hours. The resulting suspension was concentrated in vacuo to give 2-(2-(cyclopropyl)- ... (P-sulfonamido)pyrimidin-4-yl) potassium acetate (1.069 g, 2.208 mmol, quantitative yield) (yield: 1.0%) was obtained as a pale yellow solid. Rt 0.14 min (UPLC acidic); m / z 258 (M+H) + (ES + ), as the free acid ionization; [ka] No CH2 or NH signals were observed.

[0278] 2-(2-(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)acetic acid INTC40 [ka] Methyl 2-(2-(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)acetate To a solution of thiamin (0.49 g, 1.457 mmol) INTC34 in MeOH (5 mL) and water (2 mL) was added LiOH (0.105 g, 4.37 mmol). l) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo (reduced pressure) and the crude product was extracted with RP Purification by Flash C18 (40 g column, 0–50% MeCN / water 0.1% formic acid) chromatography was performed to obtain 2-( 2-(Cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)acetic acid (0.44 g, 0.991 m mol, 68% yield) as a yellow solid. Rt 0.65 min (UPLC acidic); m / z 276 (M+H) + (ES + ); [ka] No CO2H was observed.

[0279] 4-(6-ethoxypyrazin-2-yl)-N-(4-methoxybenzyl)aniline INTC41 [ka] 4-(6-ethoxypyrazin-2-yl)aniline INTD18 (0.1 g, 0.465 mmol) and 4-methoxybenzyl To a solution of benzoxaldehyde (0.085 mL, 0.697 mmol) in DCM (3 mL) was added sodium triacetate. Borohydride (0.148 g, 0.697 mmol) was added and the reaction was stirred at room temperature for 16 hours. To the mixture was added saturated aqueous NaHCO3 (20 mL), the aqueous phase was extracted with DCM (3 x 20 mL), and the combined organic phase The crude product was purified by silica gel (24 g cartridge, 0-50% EtOAc / Isopropyl alcohol). The product was purified by chromatography on hexane (isohexane) and 4-(6-ethoxypyrazin-2-yl)-N-(4-methan-2-yl)- (Oxybenzyl)aniline (0.174 g, 0.467 mmol, quantitative yield) was obtained as a white solid. 1.68 min (UPLC basic); m / z 336 (M+H) + (ES + ). [ka]

[0280] tert-Butyl 3-((4-(6-ethoxypyrazin-2-yl)phenyl)(4-methoxybenzyl)amine (o)-3-oxopropanoate INTC42 [ka] HATU (0.289 g, 0.760 mmol) was added to stirring 4-(6-ethoxypyrazin-2-yl)-N-(4-methoxypyrazin-2-yl)- (Dibenzyl)aniline INTC41 (0.17 g, 0.507 mmol), 3-(tert-butoxy)-3-oxopropionyl To a solution of carboxylic acid (0.1 mL, 0.649 mmol) and TEA (0.21 mL, 1.507 mmol) in DCM (5 mL) was added. The resulting reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and diluted with DCM (3×20 The combined organic extracts were dried (phase separator) and the solvent was removed under reduced pressure. The crude product was chromatographed on silica gel (24 g column, 0-100% EtOAc / isohexane). Purify by filtration and tert-butyl 3-((4-(6-ethoxypyrazin-2-yl)phenyl)(4-methoxyphenyl)- (benzyl)amino)-3-oxopropanoate (0.2 g, 0.377 mmol, 74% yield) was Obtained as a thick gum. Rt 1.74 min (UPLC basic); m / z 478 (M+H) + (ES + ); [ka]

[0281] tert-Butyl 2-(2-chloropyrimidin-4-yl)-3-((4-(6-ethoxypyrazin-2-yl)phenyl)- (4-Methoxybenzyl)amino)-3-oxopropanoate INTC43 [ka] NaH (60% mineral oil dispersion) (0.034 g, 0.838 mmol) was added to a stirring tert-butyl 3-((4-(6-ethoxy)- Cipirazin-2-yl)phenyl)(4-methoxybenzyl)amino)-3-oxopropanoate INT To a solution of C42 (0.2 g, 0.419 mmol) in THF (4 mL, 0.419 mmol) was added. The reaction was stirred at room temperature for 10 min. The mixture was stirred for 1 minute, and then 2,4-dichloropyrimidine (0.087 g, 0.586 mmol) was added. The mixture was stirred at 70°C under N2 atmosphere for 2 hours. The reaction mixture was quenched with brine (20 mL). The phase was extracted with DCM (3 x 50 mL), dried (phase separator) and concentrated in vacuo (reduced pressure). The residue was purified by chromatography on silica gel (24 g column, 0-100% EtOAc / isohexane). , tert-butyl 2-(2-chloropyrimidin-4-yl)-3-((4-(6-ethoxypyrazin-2-yl)phenyl)- (4-methoxybenzyl)amino)-3-oxopropanoate (0.13 g, 0.189 mmol, 45% Yield: 1.86 min (UPLC basic); m / z 591 (M+H) + (ES+ ); [ka]

[0282] 2-(2-chloropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-(4- (Methoxybenzyl)acetamide INTC44 [ka] TFA (0.234 mL, 3.03 mmol) was added to ice-cold, stirring tert-butyl 2-(2-chloropyrimidine-4- yl)-3-((4-(6-ethoxypyrazin-2-yl)phenyl)(4-methoxybenzyl)amino)-3-o The reaction mixture was added dropwise to a solution of 20 mL of dibenzofuran-1-propanoate INTC43 (0.13 g, 0.189 mmol) in DCM. The mixture was stirred at 25 °C for 7 h and then carefully basified with NaHCO (20 mL). The aqueous phase was diluted with DCM (2 × 20 mL). ), dried (phase separator) and the solvent was removed under reduced pressure. Purification by chromatography on a 100% EtOAc / isohexane column (0-100% EtOAc / isohexane) gave 2-(2-chloropyridinyl) rimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-(4-methoxybenzyl ) Acetamide (0.05 g, 0.092 mmol, 49% yield) was obtained as a clear, colorless gum. 1.62 min (UPLC acidic); m / z 490 (M+H) + (ES + ); [ka]

[0283] 2-(2-chloropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-N-(4- (Methoxybenzyl)butanamide INTC45 [ka] Ethyl iodide (0.410 mL, 5.10 mmol) was added to the stirring 2-(2-chloropyrimidin-4-yl)-N-( 4-(6-ethoxypyrazin-2-yl)phenyl)-N-(4-methoxybenzyl)acetamide INTC44( To a mixture of potassium carbonate (0.705g, 5.10 mmol) and acetone (5 mL) The reaction vessel was heated to 60°C and stirred under a N2 atmosphere for 18 hours. The reaction mixture was concentrated and Diluted with water (40 mL) and extracted with DCM (3 x 40 mL). The combined organic phases were dried (phase separator). The crude product was purified by silica gel (40 g column, 0-100% EtOAc / isohexane) Purification by chromatography on hexane and 2-(2-chloropyrimidin-4-yl)-N-(4-(6-ethoxy)- (xypyrazin-2-yl)phenyl)-N-(4-methoxybenzyl)butanamide (0.31 g, 0.539 mm ol, 53% yield) was obtained as a clear, pale yellow gum. Rt 2.73 min (HPLC acidic); m / z 519 (M +H) + (ES + ); [ka]

[0284] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine) -2-yl)phenyl)-N-(4-methoxybenzyl)butanamide INTC46 [ka] In a 20 mL container, add cyclopropanesulfonamide (0.078 g, 0.646 mmol), Cs2CO3 (0.351 g, 1.08 mmol), 2-(2-chloropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl) (4-Methoxybenzyl)-N-(4-methoxybenzyl)butanamide INTC45 (0.31 g, 0.539 mmol) and dioxane (10 The mixture was degassed with N2 for 5 minutes. Pd-174 (0.012 g, 0.016 mmol) was added, followed by The mixture was then heated at 80°C for 1 hour and then at 100°C for 7 hours. Pd-174 (0.012 g, 0.016 mmol) was added, and the mixture was further heated at 100 °C. The reaction mixture was quenched with saturated aqueous NH4Cl (40 mL) and diluted with DCM (3 x 40 mL). The crude product was extracted with HCl, dried (phase separator) and concentrated in vacuo (reduced pressure). Purification by chromatography on a 0-100% EtOAc / isohexane cartridge gave 2-(2-(cyclohexane) -N-(4-(6-ethoxypyrazin-2-yl)phenyl)-4-pyrimidin-4-yl)- N-(4-methoxybenzyl)butanamide (0.18 g, 0.269 mmol, 50% yield) was obtained as a dark yellow solid. Obtained as a gum. Rt 1.65 min (UPLC acidic); 603.6 (M+H) + (ES + ); [ka]

[0285] tert-Butyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-3-((4-(6-ethoxy)methyl)- ... (4-Methoxybenzyl)amino)-3-oxopropanoate I NTC47 [ka] In a 20 mL container, add cyclopropanesulfonamide (0.074 g, 0.610 mmol), Cs2CO3 (0.331 g, 1.017 mmol), tert-butyl 2-(2-chloropyrimidin-4-yl)-3-((4-(6-ethoxypyrazine- 2-yl)phenyl)(4-methoxybenzyl)amino)-3-oxopropanoate INTC43 (0.3g, 0 The mixture was stirred and gassed (N2, 5 min). In a separate 20 mL container, add [Pd(allyl)Cl]2 (4.68 mg, 0.013 mmol), tBuXPhos (0.022 g, 0.05 mmol), The mixture was stirred under N2 atmosphere for 5 minutes, then the first The resulting mixture was heated at 60°C for 4 hours under a N2 atmosphere. Isopropanesulfonamide (0.074 g, 0.610 mmol), followed by Pd-174 (11.00 mg, 0.015 mmol). The mixture was then heated at 80° C. for 1 hour. The reaction mixture was diluted with saturated aqueous NH4Cl. (40 mL), extracted with DCM (3 x 20 mL), dried (phase separator) and concentrated in vacuo (reduced pressure). The crude product was chromatographed on silica gel (40 g column, 0-100% EtOAc / isohexane). Purified by column chromatography to obtain tert-butyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl) -3-((4-(6-ethoxypyrazin-2-yl)phenyl)(4-methoxybenzyl)amino)-3-oxo Isopropanoate (0.1 g, 0.130 mmol, 26% yield) was obtained as a white solid. Rt 2.51 min (HP LC basic);m / z 675(M+H) + (ES + ).

[0286] (PMB protection) Methyl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl Butanoate INTC48 [ka] 1-(bromomethyl)-4-methoxybenzene (0.470 mL, 3.34 mmol) was added to a stirring flask containing methyl 2-(2 -(Cyclopropanesulfonamido)pyrimidin-4-yl)butanoate (1g, 3.34 mmol) INTC To a heterogeneous mixture of 35 and K2CO3 (0.46 g, 3.34 mmol) in DMF (20 mL) was added. The reaction mixture was stirred at room temperature for 18 h, then poured into water (200 mL) and extracted with EtOAc (3 x 50 mL). The organic extract was washed with water (100 mL) and brine (100 mL), dried over MgSO4, and the solvent was evaporated. The crude product was removed in vacuo (reduced pressure). The product was purified by chromatography on methyl 2-(2-(N-(4-methoxybenzyl)cyclopropane) (4-amino-2-phenylsulfonamido)pyrimidin-4-yl)butanoate (844 mg, 1.95 mmol, 58% yield) Obtained as a colorless oil. Rt 2.43 min (HPLC acidic); m / z 420 (M+H) + (ES + ); [ka]

[0287] 1-tert-butyl 3-methyl 2-(2-(N-(4-methoxybenzyl)methylsulfonamido)pyrimidin (4-methyl-2-(2-methoxyethyl) malonate INTC79 [ka] As with INTC48, 1-tert-butyl 3-methyl 2-(2-methoxyethyl)-2-(2-methylsulfone Amido)pyrimidin-4-yl)malonate INTC73 and 1-(chloromethyl)-4-methoxybenzene Prepared using 1-tert-butyl 3-methyl 2-(2-(N-(4-methoxybenzyl)methyl)sulfonyl) (2-Methoxyethyl)-2-(2-amino-4-pyrimidin-4-yl)-malonate (65% yield) was obtained as a colorless oil. Obtained by: Rt 2.55 min (HPLC acidic); m / z 524 (M+H) + (ES + ); [ka]

[0288] Dimethyl 2-isopropyl-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamide) (d)pyrimidin-4-yl)malonate INTC80 [ka] Similar to INTC48, dimethyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)- Using 2-isopropyl malonate INTC78 and 1-(chloromethyl)-4-methoxybenzene Prepare dimethyl 2-isopropyl-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonate) (Cyclohexyl)pyrimidin-4-yl)malonate (28% yield) was obtained as a colorless oil. Rt 0.72 min (UPL C, acidic 2); m / z 492(M+H) + (ES + ); 1 1 H NMR not recorded.

[0289] (Decarboxylation of PMB-protected sulfonamides) Methyl 4-methoxy-2-(2-(N-(4-methoxybenzyl)methylsulfonamido)pyrimidine-4 -yl)butanoate INTC81 [ka] HCl (4 M in dioxane) (0.44 mL, 14.51 mmol) was added to stirring 1-tert-butyl 3-methyl 2-( 2-(N-(4-Methoxybenzyl)methylsulfonamido)pyrimidin-4-yl)-2-(2-methoxybenzyl)methylsulfonamido To a solution of ethyl)-malonate INTC79 (8.0 g, 14.5 mmol) in DCM (100 mL), the resulting reaction mixture was added. The mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated in vacuo (reduced pressure) and the crude product was purified by silica gel column chromatography. Purification was performed by chromatography on gel (220 g column, 0-100% EtOAc / isohexane) and methyl 4-Methoxy-2-(2-(N-(4-methoxybenzyl)methylsulfonamido)pyrimidin-4-yl) The butanoate (2.47 g, 5.54 mmol, 38% yield) was obtained as a colorless oil. Rt 2.13 min (HPLC acid ); m / z 424(M+H) + (ES + ); [ka]

[0290] Methyl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl (I)-3-methylbutanoate INTC82 [ka] Dimethyl 2-isopropyl-2-(2-(N-(4-methoxybenzyl)methyl)) in water (0.11 mL, 6.11 mmol) Cyclopropanesulfonamido)pyrimidin-4-yl)malonate INTC80 (2.79 g, 5.68 mmol To a solution of 140 mg of 1,4-dichloromethane in DMSO (7 mL) was added lithium chloride (0.29 g, 6.81 mmol). The reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL) and water (100 mL). The two phases were separated and the organic phase was further diluted with water (100 mL), water / brine (1:1, 50 mL) and saturated brine (50 mL). The organic phase was dried over MgSO4, filtered and concentrated onto silica (10 g). chromatographed on silica gel (40 g cartridge, 0-30% EtOAc / isohexane) Purified by methyl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidinium (4-methyl-3-methylbutanoate) (2.00 g, 3.69 mmol, 65% yield) was obtained as a colorless gum. Obtained as a pure product. Rt 0.70 min (UPLC, acid 2); m / z 434 (M+H) + (ES + ); 1 1 H NMR not recorded.

[0291] (Alkylation of PMB-protected sulfonamides) Methyl 4-methoxy-2-(2-(N-(4-methoxybenzyl)methylsulfonamido)pyrimidine-4 -yl)-2-methylbutanoate INTC83 [ka] Method B was used to obtain methyl 4-methoxy-2-(2-(N-(4-methoxybenzyl)methylsulfonamide) (Iodo)pyrimidin-4-yl)butanoate INTC81 was prepared from methyl 4-methyl- 2-(2-(N-(4-methoxybenzyl)methylsulfonamido)pyrimidin-4-yl)-2-methyl- Tilbutanoate (89% yield) was obtained as a colorless oil. Rt 2.20 min (HPLC acidic); m / z 438 (M+H) + (ES + ); [ka]

[0292] Methyl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl (I)-2-methylbutanoate INTC84 [ka] Method B was used to prepare methyl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamide) pyrimidin-4-yl)butanoate INTC48 was synthesized using K2CO3 and MeI in DMF to give methyl 2-(2- (N-(4-Methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl The butanoate (39% yield) was obtained as a colorless gum. Rt 2.57 min (HPLC acidic); m / z 43 4(M+H) + (ES + ); [ka] (1H was unclear in DMSO.)

[0293] (fluorinated) Methyl 2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridine (4-(4-methyl-4-methyl-2-pyridin-4-yl)butanoate INTC49 [ka] Methyl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidinyl) To a solution of 1.19 g of dimethyldimethacrylate (DIMETHYL-4-YL)butanoate INTC48 (400 mg, 0.95 mmol) in 10 mL of THF, LHMDS (1.19 mL, 1.19 mmol, 1M THF solution) was added dropwise over 5 min. The resulting mixture was allowed to warm to room temperature and 1 The solution was cooled again to -78°C and N-fluoro-N-(phenylsulfonyl)benzyl A solution of benzenesulfonamide (376 mg, 1.19 mmol) in THF (3 mL) was added dropwise over 5 minutes. The resulting mixture was warmed to room temperature and stirred for 1 h. The solution was diluted with saturated aqueous NaHCO3 (100 mL) and EtOAc. (100 mL) and the two phases were separated. The aqueous phase was extracted with EtOAc (2 x 50 mL). The organic phase was dried over Na2SO4, filtered and the solvent removed in vacuo. The crude product was purified by silica gel chromatography. Purification by chromatography (24 g column, 0-50% EtOAc / isohexane) gave methyl 2-fluorenone. Fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl) The methylbutanoate (390 mg, 0.865 mmol, 91% yield) was obtained as a clear oil. Rt 2.48 min (HPL C acidic);m / z 438(M+H) + (ES + ); [ka]

[0294] (Enantioenriched INTC49 can be prepared using the method described below.) -40°C methyl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin To a solution of methyl-4-methylbutanoate INTC48 (0.066 g, 0.157 mmol) in THF (2.5 mL), LHMDS (0.189 mL, 0.189 mmol) was added dropwise over 5 min. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. (-)-Cinchonidine (0.069 g, 0.236 mmol) and Selectfluor (0.072 g, 0.205 mmol) in MeCN ( A second solution (2.5 mL) was prepared and stirred at room temperature for 30 minutes. This solution of fluorinating reagent was then diluted to -40 The reaction mixture was cooled to -40°C and the deprotonated ester solution was added dropwise over 5 minutes. The reaction mixture was stirred at rt for 1 h and then allowed to warm to room temperature over 2 h until the cooling bath effect expired. The mixture was stirred at room temperature for 20 hours, and the reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and EtOAc (20 mL). The two phases were separated and the organic phase was further washed with saturated aqueous NaHCO3 (10 mL) and then with 1M HCl (aq., 1 0 mL) The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo (reduced pressure). The crude product was chromatographed on silica gel (4 g cartridge, 0-50% EtOAc / isohexane). Purify by filtration and use as methyl 2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonyl)methyl)cyclopropanesulfonate. (Hydroxy)pyrimidin-4-yl)butanoate (0.024 g, 0.052 mmol, 33% yield) was added to the colorless Obtained as an oil. Rt 0.70 min (UPLC2 acidic); m / z 438 (M+H) + (ES + ); [ka]

[0295] Methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-fluorobutanoate INTC177 [ka] Methyl 2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridine To a solution of 24 mg (0.055 mmol) of methylparaben-4-ylbutanoate INTC49 in 5 mL of DCM, was added 0.5 mL of TFA. , 6.49 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then subjected to vacuum (reduced pressure ) and the resulting brown residue was loaded onto silica gel (4 g cartridge, 0-50% EtOAc / isohexane The product was purified by chromatography on hexane and methyl 2-(2-(cyclopropanesulfonamido)piperidin) (Irimidin-4-yl)-2-fluorobutanoate (18 mg, 0.053 mmol, 97% yield) as a colorless oil Obtained by: Rt 0.55 min (UPLC2 acid); m / z 318 (M+H) + . [ka] The product as a mixture of enantiomers was analyzed by HPLC using Chiral IC7 method; Rt 29.08 minutes (10%) and 29.75 minutes (90%).

[0296] (lithium salt formation) 2-Fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidine (4-yl)butanoic acid lithium INTC50 [ka] Methyl 2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridine (4-amino-4-yl)butanoate INTC49 (1.45 g, 3.31 mmol) in THF (15 mL) and MeOH (7.5 mL). To the solution was added a solution of LiOH (0.091 g, 3.81 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo (reduced pressure) and the resulting yellow oil was taken up in MeCN (10 mL) and Concentrate in vacuo to obtain 2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonyl) Lithium (4-amino)pyrimidin-4-yl)butanoate (1.46 g, 3.30 mmol, quantitative yield) was added to a 100 mL flask. Obtained as a yellow foam and used without further purification. Rt 0.95 min (UPLC basic); m / z 424 (CO Ionized as OH, M+H) + (ES + ); [ka]

[0297] (Method H: Benzylic Fluorination of Heteroaromatic Esters) [ka] A solution of the heteroaromatic ester (1 equiv.) in THF (10 vol.) was cooled to -78 °C and treated with LiHMDS (1.25 equiv.). A small amount of 1M THF solution was added. The reaction mixture was then warmed to room temperature for 1 hour. The solution was then cooled to -78°C. The mixture was cooled to rt, and NSFI (1.25 eq) in THF or as a solid was added dropwise, followed by warming to room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCO3 and the product was extracted with EtOAc. The crude product was purified by normal phase chromatography. It was refined by filtration.

[0298] Table 5: The following intermediates were prepared according to Method H. [Table 6]

[0299] Methyl 2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridine (4-amino-3-methylbutanoate) INTC86 [ka] Methyl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidinyl) To a solution of (4-methyl-3-methylbutanoate) INTC82 (1.50 g, 3.46 mmol) in anhydrous THF (30 mL) LiHMDS (1 M in THF) (4.15 mL, 4.15 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 5 minutes. It was then warmed to room temperature and stirred for 1 hour, then cooled again to -78°C. Selectfluor (1.90g, A solution of 5.10 mmol) in MeCN (30 mL) was added dropwise to the reaction mixture over 5 minutes. The mixture was warmed to rt and stirred for 1 h, then saturated aqueous NaHCO3 (5 mL) was added. Partially concentrate (to approximately 10 mL) in vacuo, then add EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). mL) was added. The two phases were separated and the organic phase was washed with saturated brine (50 mL). The crude product was dried over O4, filtered, and concentrated onto silica (15 g). Purification by chromatography (0-60% EtOAc / isohexane) of methyl 2-fluoro- 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl)-3-methyl Tilbutanoate (680 mg, 1.48 mmol, 43% yield) was obtained as a yellow gum. Rt 0. 72 minutes (UPLC, acidic 2); m / z 452 (M+H) + (ES + ); [ka]

[0300] (Potassium salt formation) 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl)-3- Potassium methylbutanoate INTC87 [ka] Similar to INTC37, methyl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamide) )pyrimidin-4-yl)-3-methylbutanoate INTC82 and potassium trimethylsilanolate Prepared using 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridine Potassium 3-methylbutanoate (4-amidin-4-yl) (99% yield) was obtained as a pale yellow solid. Rt 1.59 min(HPLC basic);m / z 420(M+H) + (ES + ); 1 1 H NMR not recorded.

[0301] (Difluoro derivatives via thioethers) Ethyl 2,2-difluoro-2-(2-(methylsulfonyl)pyrimidin-4-yl)acetate INTC10 0 [ka] Ethyl 2,2-difluoro-2-(2-(methylthio)pyrimidin-4-yl)acetate (240 mg, 0.9 A suspension of 1.7 mmol) in MeOH (8 mL) and water (5 mL) was treated with Oxone (1.19 g, 1.93 mmol). The mixture was stirred vigorously for 3 hours. DCM (10 mL) was added, and the two phases were separated using a phase separator. The combined organic phases were concentrated onto silica (1 g) and the crude product was separated by silica gel ( Purify by chromatography on a 12g column (0-50% EtOAc / isohexane) to obtain ethyl 2,2-dihydrobenzoate. Fluoro-2-(2-(methylsulfonyl)pyrimidin-4-yl)acetate (80 mg, 0.28 mmol, 2 9% yield) was obtained as a colorless gum and was left as is. Rt 0.52 (UPLC acidic); m / z 281 ( M+H) + (ES + ); [ka]

[0302] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,2-difluoroacetic acid INTC10 1 [ka] Cyclopropanesulfonamide (40 mg, 0.33 mmol) and ethyl 2,2-difluoro-2-(2-( Methylsulfonyl)pyrimidin-4-yl)acetate INTC100 (80 mg, 0.29 mmol) in DMF (1 mL The solution was treated with NaH (60 wt % in mineral oil) (14 mg, 0.35 mmol) and stirred at room temperature for 5 min, then heated at 60 °C for 6 1M HCl (10 mL) was added and the reaction mixture was extracted with EtOAc (4×10 mL). The phases were combined, dried over Na2SO4, filtered and concentrated onto silica (500 mg). Purification by chromatography on silica gel (4 g column, 0-5% MeOH / DCM) was performed to obtain 2-(2-(cyclopropyl)- ... (4,4-difluoro-2,2-difluoro-4-methyl-2,2-propanesulfonamido)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 acquisition Without.

[0303] (Amide formation of selected building blocks) Table 6: The following intermediates were prepared according to methods 1 to 4 described below for the synthesis of compounds of formula (I): did.) [Table 7] TIFF0007667225000158.tif219170TIFF0007667225000159.tif209170TIFF0007667225000160.tif63170

[0304] (lithium salt formation) Lithium (4-(carboxylato(methoxy)methyl)pyrimidin-2-yl)(cyclopropyl) Sulfonyl)amide INTC99 [ka] Dimethyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methoxamate with stirring A mixture of cimarronate (0.50 g, 1.25 mmol) INTC75 in MeOH (15 mL) was dissolved in LiOH (0.10 g, 4.18 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then reduced in vacuo ( Concentrated under reduced pressure, and lithium (4-(carboxylate(methoxy)methyl)pyrimidin-2-yl)( (chloropropylsulfonyl)amide (0.4 g, 1.19 mmol, 95% yield) was obtained as a brown solid. 0.18 min (UPLC basic); m / z 288 as free acid (M+H) + (ES + ); 1 H NMR not obtained.

[0305] (pyridine core portion) (Sulfonation via sulfonyl chlorides) Ethyl 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)acetate INTC102 [ka] Ethyl 2-(6-aminopyridin-2-yl)acetate (2 g, 11.10 mmol) and DMAP (0.136 g, 1. A solution of 11 mmol) in pyridine (9.0 mL) was cooled to 0°C. The solution was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with MeOH (10 mL) and concentrated in vacuo. The crude product was purified by C18-RP Purify by chromatography on silica gel (80 g column, 0-50% MeCN / water 0.1% formic acid) and ethyl 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)acetate (1.35g, 4.70mm ol, 42% yield) was obtained as a pale brown oil. Rt 0.95 min (UPLC acidic); m / z 285 (M+H) + (ES + NMR No data obtained.

[0306] (Alkylation) Ethyl 2-(6-bromopyridin-2-yl)-2-methylpropanoate INTC103 [ka] t-BuOK (0.115 g, 1.02 mmol) was added to ice-cooled, stirred ethyl 2-(6-bromopyridin-2-yl)acetate. A solution of acetate (0.100 g, 0.41 mmol) in THF (1.5 mL) was added. After 30 min, MeI (2 M in TBME) was added. , 0.82 mL, 1.64 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was quenched with MeOH (1 mL) and concentrated in vacuo. The crude product was transferred to silica gel (24 g). Purification by chromatography (0-50% EtOAc / isohexane) of ethyl 2-(6-bromo Pyridin-2-yl)-2-methylpropanoate (0.06 g, 0.21 mmol, 51% yield) was obtained by Obtained as a liquid. Rt 1.54 min (UPLC acidic); m / z 273 ( 79 BrM+H) + (ES + ); [ka]

[0307] Ethyl 2-(6-bromopyridin-2-yl)butanoate INTC104 [ka] LiHMDS (1 M in THF) (2.25 mL, 2.25 mmol) was added to ethyl 2-(6-bromopyridin-1-yl)propanol at -78 °C while stirring. To a solution of lysin-2-yl)acetate (0.5 g, 2.05 mmol) in THF (10 mL) was added. After 1 h, Et I (0.182 mL, 2.25 mmol) was added dropwise at the same temperature and the reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was partitioned between EtOAc (20 mL) and saturated aqueous NH4Cl (20 mL) and the organic phase was transferred to a phase separator. The crude product was purified by silica gel (40 g cartridge, 0-50% E Purification by chromatography in hexane (tOAc / isohexane) and ethyl 2-(6-bromopyridin-2-yl) (H) butanoate (0.35 g, 1.27 mmol, 62% yield) was obtained as a pale yellow liquid. Rt 2.30 min (H PLC acidic);m / z 272( 79 BrM+H) + (ES + ); [ka]

[0308] (Heterocycle formation via alkylation) Ethyl 4-(6-bromopyridin-2-yl)tetrahydro-2H-pyran-4-carboxylate INTC 105 [ka]

[0309] Commercially available ethyl 2-(6-bromopyridin-2-yl)acetate (2.51 g, 10.28 g) was used in the same manner as INTC52. ethyl 4-(6-bromo)ethane was prepared using 1-bromo-2-(2-bromoethoxy)ethane. (pyridin-2-yl)tetrahydro-2H-pyran-4-carboxylate (52% yield) as a clear oil. Rt 1.42 min (UPLC basic); m / z 314 ( 79 BrM+H) + (ES + ); [ka]

[0310] (Method I: Buchwald Coupling: Sulfonylation) [ka]

[0311] The 2-bromopyridine intermediate (1 equivalent), sulfonamide (1.2 equivalents) and base (2 equivalents) were reacted with the di The mixture was degassed (N2, 5 min) and then the catalyst (5 mol%) was added. The resulting mixture was heated at 90°C under a nitrogen atmosphere for 2 hours. The mixture was filtered and diluted with EtOAc or The residue was washed with DCM, and the resulting filtrate was concentrated. The crude product was purified by normal phase chromatography. Ta.

[0312] Table 7: The following intermediates were prepared according to Method I. [Table 8]

[0313] (Method J: Hydrolysis) [ka] 2M LiOH (aqueous, 2 eq) was added to a solution of the ester (1 eq) in MeOH (3 vol) and THF (3 vol). The resulting reaction mixture was stirred at 50° C. for 2 hours. The solvent was removed under reduced pressure, followed by 1M HCl. The solution was acidified with (aqueous) to pH 3. The solution was extracted with EtOAc and the organic phase was passed through a phase separator. The compound was used in crude form or purified by reverse phase chromatography. Used.

[0314] Table 8: The following intermediates were prepared according to Method J. [Table 9]

[0315] (pyrazine nucleus) (ester formation) Methyl 2-(6-chloropyrazin-2-yl)acetate INTC112 [ka] Thionyl chloride (1.15 mL, 15.65 mmol) was added to 2-(6-chloropyrazine-2- The mixture was added dropwise to a solution of (methyl)-2-hydroxybenzoylacetic acid (2.70 g, 15.65 mmol) in MeOH (50 mL). The reaction mixture was concentrated in vacuo and the crude residue was diluted with DCM (100 mL). The organic extract was washed successively with saturated aqueous NaHCO3 (2 x 100 mL), and brine (100 mL). was dried (MgSO4), filtered, and the solvent removed in vacuo to give methyl 2-(6-chloropyrazine-2- (2.63 g, 13.67 mmol, 87% yield) of methylamino)acetate was obtained as a brown oil. Rt 1.25 min (HPLC acid gender);m / z 187( 35 Cl M+H) + (ES + ); [ka]

[0316] Methyl 2-(6-chloropyrazin-2-yl)-2-methoxyacetate INTC121 [ka] Similar to INTC112, 2-(6-chloropyrazin-2-yl)-2-methoxyacetic acid INTC120 was used. Methyl 2-(6-chloropyrazin-2-yl)-2-methoxyacetate (3.35 g, 15.31 mmol, (96% yield) was obtained as a clear yellow oil. Rt 1.33 min (HPLC basic); m / z 217 ( 35 Cl M+H) + (ES + ) , NMR data not recorded.

[0317] (Preparation of diester intermediates) 1-tert-Butyl 3-methyl 2-(6-chloropyrazin-2-yl)malonate INTC113 [ka] As with INTC1, this was prepared using commercially available 2,6-dichloropyrazine and 1-tert-butyl-3-methylpyrazine. 2-(6-chloropyrazin-2-yl)malonate (78% yield) was obtained as a clear, colorless oil. Rt 2.18 min(HPLC acidic);m / z 286( 35 Cl M+H) + (ES + ); [ka]

[0318] Dimethyl 2-(6-chloropyrazin-2-yl)-2-methoxymalonate INTC114 [ka] As with INTC1, dimethyl 2-methoxymalonate and 2,6-dichloropyrazine were used. Prepare and prepare colorless dimethyl 2-(6-chloropyrazin-2-yl)-2-methoxymalonate (33% yield) Obtained as a clear oil. Rt 1.65 min (HPLC acidic); m / z 275 ( 35 Cl M+H) + (ES + ); [ka]

[0319] (Alkylation of pyrazine intermediates) (Table 9: The following intermediates were prepared according to Method B above.) [Table 10]

[0320] (TFA decarboxylation) Ethyl 2-(6-chloropyrazin-2-yl)-4-methoxybutanoate INTC118 [ka] As in Method A, 1-tert-butyl 3-ethyl 2-(6-chloropyrazin-2-yl)-2-(2-methoxyphenyl)-2-methylpropional was prepared. Ethyl 2-(6-chloropyrazin-2-yl)-4-methylpropional (ethyl) malonate INTC115 was used to prepare Toxoxybutanoate (2.49 g, 8.65 mmol, 71% yield) was obtained as a pale purple oil. Rt 0.59 min (UP LC, basic 2); m / z 259( 35 Cl M+H) + (ES + ); [ka]

[0321] (hydrolysis) 2-(6-chloropyrazin-2-yl)-2-methoxyacetic acid INTC120 [ka] Dimethyl 2-(6-chloropyrazin-2-yl)-2-methoxymalonate INTC114 (4.54 g) A mixture of 16.53 mmol) in THF (40 mL) and water (10 mL) was dissolved in 2 M aqueous NaOH (4 mL, 8.00 mmol). The reaction mixture was stirred at room temperature for 66 hours. An additional 2M aqueous NaOH solution (5 equivalents) was added. The mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo (reduced pressure) and the crude product was purified by RP Flash C18 ( Purify by chromatography on an 80g column (5-50% MeCN / 10 mM ammonium bicarbonate). 2-(6-chloropyrazin-2-yl)-2-methoxyacetic acid (3.67 g, 16.30 mmol, 99% yield) was dissolved in water. Obtained as a solid. Rt 1.06 min (HPLC acidic); m / z 203 ( 35 Cl M+H) + (ES + ); [ka] No exchangeable protons in 1 were observed.

[0322] 2-(6-chloropyrazin-2-yl)-4-methoxy-2-methylbutyric acid INTC131 [ka] Ethyl 2-(6-chloropyrazin-2-yl)-4-methoxy-2-methylbutanoate INTC119 (1.93g To a solution of LiOH (0.203 g, 8.49 mmol) in EtOH (2 mL) and THF (15 mL), The solution was added. The reaction was stirred at room temperature for 18 hours. Further LiOH (0.068 g, 2.83 mmol) in water ( 5 mL) solution was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo (reduced pressure). The resulting residue was acidified using 1 M HCl (50 mL). The product was extracted with EtOAc (3 x 50 mL). ), and the combined organic liquids were dried (MgSO4) and concentrated in vacuo to give 2-(6 (-chloropyrazin-2-yl)-4-methoxy-2-methylbutyric acid (1.92 g, 5.98 mmol, 84% yield) Obtained as a light brown oil and used without further purification. Rt 0.95 min (UPLC acidic); m / z 245 ( 35 Cl M +H) + (ES + ); [ka]

[0323] 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)butyric acid INTC132 [ka] Similar to INTC131, methyl 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)butadiene Prepared using 2-(6-(cyclopropanesulfonamido)pyrazine-2-yl)-2-methylpropanol INTC126 (I)-butyric acid (59% yield) was obtained as a colorless gum. Rt 1.35 min (HPLC acidic); m / z 286 (M+H ) + (ES + ); [ka]

[0324] 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-2-fluorobutyric acid INTC133 [ka] Similar to INTC131, methyl 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-2- Prepared using fluorobutanoate INTC130 and 2-(6-(cyclopropanesulfonamide) Pyrazin-2-yl)-2-fluorobutyric acid (95% yield) was obtained as a dark red paste. Rt 0. 89 minutes (UPLC acidic); m / z 304 (M+H) + (ES + ); [ka]

[0325] 2-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-2-methoxyacetic acid INTC134 [ka] Similar to INTC131, methyl 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-2- Prepared using methoxyacetate INTC128, 2-(6-(cyclopropanesulfonamide)piperidinone) (Hexane-2-yl)-2-methoxyacetic acid (24% yield) was obtained as a pale tan solid. Rt 1.06 min (HPL C acidic);m / z 288(M+H) + (ES + ); [ka]

[0326] (Heterocycle formation via alkylation) Methyl 4-(6-chloropyrazin-2-yl)tetrahydro-2H-pyran-4-carboxylate INTC one two three [ka] Similar to INTC52, methyl 2-(6-chloropyrazin-2-yl)acetate INTC112 was used. Methyl 4-(6-chloropyrazin-2-yl)tetrahydro-2H-pyran-4-carboxylate (12% yield) was obtained as a yellow oil. Rt 1.05 min (UPLC acidic); m / z 257 ( 35 Cl M+H) + (ES + ); [ka]

[0327] (Fluorination of pyrazine intermediates) Table 10: The following intermediates were prepared according to Method H above. [Table 11]

[0328] (Amide formation of selected building blocks) Table 11: The following intermediates can be prepared by analogy to methods 1-10 previously described for the synthesis of compounds of formula (I): It was prepared.) [Table 12]

[0329] (2,6-pyrimidine nucleus) N-(2-chloropyrimidin-4-yl)cyclopropanesulfonamide INTC138 [ka] To a suspension of 2,4-dichloropyrimidine (15 g, 101 mmol) in acetonitrile (250 mL) was added cyclohexylpyrimidine. Propanesulfonamide (14.64 g, 121 mmol) and K2CO3 (27.8 g, 201 mmol) were added. The resulting mixture was refluxed with stirring for 18 hours. The mixture was slowly added to ice-cold 6M HCl (aqueous The biphasic mixture was poured into 100 mL of ethyl acetate (100 mL) with vigorous stirring and then diluted with EtOAc (100 mL). After filtration, the two phases were separated and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with NaSO 4, filtered and concentrated onto silica gel, then loaded onto silica gel (330 g column, 50-100% EtOAc / This was purified by chromatography in hexane (250 ml) to give a white solid. triturated with MeCN (30 mL) and then azeotroped under vacuum to give N-(2-chloropyrimidinyl) (4-phenyl-4-yl)cyclopropanesulfonamide (11.68 g, 49.5 mmol, 49% yield) as a white solid. Rt 0.79 min (UPLC acid); m / z 234 ( 35 Cl M+H) + (ES + ); [ka]

[0330] N-(2-chloropyrimidin-4-yl)-N-(4-methoxybenzyl)cyclopropanesulfonamide Do INTC139 [ka] N-(2-chloropyrimidin-4-yl)cyclopropanesulfonamide INTC138 (11.68%) g, 50.0 mmol) in DMF (50 mL) was treated with K2CO3 (13.82 g, 100 mmol) and 1-(chloromethyl)-4- Methoxybenzene (8.13 mL, 60.0 mmol) was added stepwise at room temperature. The mixture was stirred at room temperature for 3 hours, then heated at 40°C for 18 hours. Benzenes (2.03 mL, 15.0 mmol) were added and the resulting mixture was stirred at 40° C. for 18 hours. The mixture was cooled to room temperature, poured into water (200 mL), and diluted with EtOAc (100 mL). The two phases were separated, and the aqueous phase The mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na2SO4, filtered, and the solvent was evaporated. The crude product was purified by silica gel (330 g column, 0-50% EtOAc / isohexane). The solid was purified by trituration with MeCN (20 mL) to give a white solid. N-(2-chloropyrimidin-4-yl)-N-(4-methoxybenzyl)cyclopropanesulfone The amide (8.4 g, 23.50 mmol, 47% yield) was obtained as a white powder. Rt 1.41 min (UPLC basic); m / z 354( 35 Cl M+H) + (ES + ); [ka]

[0331] 1-tert-butyl 3-ethyl 2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamide) Pyrimidin-2-yl)malonate INTC140 [ka] To a solution of tert-butyl ethyl malonate (1.41 mL, 7.46 mmol) in DME (25 mL), Cs2CO3 (4.86 g, 14.92 mmol) and N-(2-chloropyrimidin-4-yl)-N-(4-methoxybenzyl)cyclopropyl Pansulfonamide INTC139 (2.4 g, 6.78 mmol) was added sequentially and the resulting mixture was heated to 90°C. The reaction mixture was cooled to room temperature and poured into saturated aqueous NH4Cl (100 mL) and diluted with EtO The mixture was diluted with HCl (50 mL). The two phases were separated and the aqueous phase was extracted with EtOAc (3×30 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The crude product was purified by silica gel (2 Purification by chromatography on a 20 g column (0-70% EtOAc / isohexane) was performed to obtain 1-tert-butyl 2- 3-ethyl 2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidine-2- (I)yl malonate (1.67 g, 3.14 mmol, 46% yield) was obtained as a yellow oil. Rt 1.67 min (UPLC acid m / z 507(M+H) + (ES+ ); [ka]

[0332] 1-tert-butyl 3-ethyl 2-ethyl-2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonyl) Amido)pyrimidin-2-yl)malonate INTC141 [ka] 1-tert-butyl 3-ethyl 2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamide) To a solution of pyrimidin-2-yl malonate INTC140 (2.96 g, 5.85 mmol) in DMF (40 mL) was added K2CO3 (1 To the resulting mixture were added EtI (0.780 g, 12.88 mmol) and EtI (0.52 mL, 6.44 mmol). The mixture was vigorously stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and added with saturated aqueous NH4Cl (150 mL). The mixture was poured into a 50 mL flask and diluted with EtOAc (50 mL). The two phases were separated and the aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phase was washed with half-saturated brine (50 mL), dried over Na2SO4, filtered, and the solvent was removed. The crude product was purified by vacuum stripping. The crude product was purified by silica gel (120 g column, 0-50% EtOAc / isohexyl) Purification by chromatography on 1-tert-butyl 3-ethyl 2-ethyl-2-(4-(N-(4-methoxyphenyl)-2-methyl-2-propanol) Dibenzyl)cyclopropanesulfonamido)pyrimidin-2-yl)malonate (2.63g, 4.39 (mmol, 75% yield) was obtained as a light yellow oil. Rt 1.82 min (UPLC acidic); m / z 534 (M+H) + (ES + ); [ka]

[0333] Ethyl 2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-2-yl Butanoate INTC142 [ka] 1-tert-butyl 3-ethyl 2-ethyl-2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonyl) To a solution of (amino)pyrimidin-2-yl)malonate INTC141 (3.0 g, 5.06 mmol) in DCM (40 mL) Then, TFA (15.59 mL, 202 mmol) was added. The resulting solution was stirred at room temperature for 18 hours. The solution was poured into saturated aqueous NaHCO3 (200 mL) and diluted with DCM (50 mL). The two phases were separated and the aqueous phase was The solution was readjusted to pH 4 with 12M HCl and the aqueous phase was extracted with DCM (3 x 50 mL). The combined organic phases were dried over Na2SO4, filtered and the solvent was removed in vacuo (reduced pressure). The crude product was purified by chromatography on silica gel (120 g column, 0-100% EtOAc / isohexane). Purified by ethyl 2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyridine Rt 1 .56 min (UPLC acidic); m / z 434 (M+H) + (ES + ); [ka] The CH protons of 1 were obscured by the DMSO peak.

[0334] N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-(4-(N-(4-methoxybenzyl) Cyclopropanesulfonamido)pyrimidin-2-yl)butanamide INTC143 [ka] Method 2 was employed to obtain 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine INTD33 (449 mg, 2.08 mmol) and ethyl 2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamide)pi Prepared using N-(5-(6-ethoxypyrazine-2-yl)-butanoate INTC142 yl)pyridin-2-yl)-2-(4-(N-(4-methoxybenzyl)cyclopropanesulfonamide) (pyrimidin-2-yl)butanamide (11% yield) was obtained as a colorless oil. Rt 1.70 min (UPLC acidic); m / z 604(M+H) + (ES + ); [ka]

[0335] (Benzamidopyrimidine intermediate) (sulfonylation) N-(4-cyanopyrimidin-2-yl)cyclopropanesulfonamide INTC144 [ka] 2-chloropyrimidine-4-carbonitrile, cyclopropanesulfonyl ether, and cyclopropanesulfonyl ether were prepared by the following method C. The amide was prepared using Cs2CO3, tBuXPhos, and [Pd(allyl)Cl]2 in dioxane. N-(4-cyanopyrimidin-2-yl)cyclopropanesulfonamide (88% yield) was obtained as a pale orange solid. Rt 0.70 min (UPLC acid); m / z 225 (M) + (ES + ); [ka]

[0336] (nitrile reduction) tert-Butyl((2-(cyclopropanesulfonamido)pyrimidin-4-yl)methyl)carbamate INTC145 [ka] N-(4-cyanopyrimidin-2-yl)cyclopropanesulfonamide INTC144 (0.5 g, 2. To a suspension of 23 mmol) in MeOH (20 mL) was added di-tert-butyl dicarbonate (0.973 g, 4.46 mmol), followed by the salt. Nickel(II) chloride hexahydrate (0.029 g, 0.223 mmol) was added, followed by NaBH4 (0.675 g, 17.8 mmol). ) was added in small increments over 30 minutes, with each increment being added after the foaming from the previous addition had subsided. The reaction mixture was stirred at room temperature for 18 hours. It was quenched by the addition of ethanediamine (0.5 mL, 4.50 mmol) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness and the resulting orange residue was dissolved in EtOAc (50 mL) and water (50 mL). The two phases were separated, and the aqueous phase (pH 8) was neutralized with saturated aqueous NH4Cl (50 mL), and the product was The aqueous phase was extracted with EtOAc (50 mL). 1M HCl (aq) was added in small portions to further Acidified to H4. The product was extracted using EtOAc (50 mL). The combined organic liquid The crude product was concentrated onto silica gel and evaporated. Purification by chromatography on a 24 g column (0-100% EtOAc / isohexane) was performed to obtain tert-butyl ether. ethyl((2-(cyclopropanesulfonamido)pyrimidin-4-yl)methyl)carbamate (85 m g, 0.207 mmol, 9% yield) as a clear, colorless glass. Rt 0.98 min (UPLC acidic); m / z 350(M+Na)+(ES + ); [ka]

[0337] (Alkylation) Methyl 1-(2-chloropyrimidin-4-yl)cyclopropanecarboxylate INTC146 [ka] Methyl 2-(2-chloropyrimidin-4-yl)acetate (3 g, 16.08 mmol) in DMF (40 mL) To the resulting mixture was added NaOH (1.93 g, 48.2 mmol). The resulting mixture was stirred at room temperature for 15 minutes, and then 1, 2-Dibromoethane (2.77 mL, 32.2 mmol) was added dropwise and the mixture was stirred at room temperature for 3 hours. Poured into saturated aqueous solution (100 mL) and diluted with EtOAc (40 mL). The two phases were separated and the aqueous phase was diluted with EtOAc (2×4 The combined organic phases were dried (Na2SO4), filtered, and the solvent was removed in vacuo (reduced pressure). The crude product was chromatographed on silica gel (120 g column, 0-50% EtOAc / isohexane). Purified by column chromatography to obtain methyl 1-(2-chloropyrimidin-4-yl)cyclopropanecarboxylate. The ester (1.78 g, 8.12 mmol, 51% yield) was obtained as a colorless oil. Rt 1.05 min (UPLC basic); m / z 213(M+H) +(ES + ); [ka]

[0338] (hydrolysis) 1-(2-chloropyrimidin-4-yl)cyclopropanecarboxylic acid INTC147 [ka] As in Method J, methyl 1-(2-chloropyrimidin-4-yl)cyclopropanecarboxylate was used. Prepared using INTC146, 1-(2-chloropyrimidin-4-yl)cyclopropanecarboxylic acid (quantitative yield) was obtained as a colorless solid. Rt 0.83 min (UPLC acidic); m / z 199 (M+H) + (ES + NMR Day No data was recorded.

[0339] (Curtius) tert-Butyl (1-(2-chloropyrimidin-4-yl)cyclopropyl)carbamate INTC148 [ka] 1-(2-chloropyrimidin-4-yl)cyclopropanecarboxylic acid INTC147 (1.85 g, 9.31 mmol) To a solution of tert-butanol (15 mL) and toluene (15 mL), EtN (1.49 mL, 10.3 mmol) and D PPA (2.23 mL, 9.78 mmol) was added portionwise, and the resulting mixture was stirred at 90° C. for 4 hours. The mixture was cooled to room temperature and diluted with saturated aqueous NaHCO3 (50 mL) and EtOAc (30 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried (Na2SO4) and filtered. The crude product was purified by silica gel chromatography (120 g column, 0-50% EtOAc) and purified by filtration. / isohexane and purified by chromatography to obtain tert-butyl (1-(2-chloropyrimidine-4 -yl)cyclopropyl)carbamate (1.02 g, 3.33 mmol, 36% yield) as a colorless solid Got it. Rt 1.26 min (UPLC acidic); m / z 270 (M+H) + (ES + ). [ka]

[0340] 1-(2-Bromopyrimidin-4-yl)propan-1-one INTC149 [ka] A solution of 2-bromopyrimidine (17.91 g, 113 mmol) in anhydrous THF (150 mL) was cooled to -60°C. 1M Lithium magnesium 2,2,6,6-tetramethylpiperidin-1-ide dichloride (THF / Trimethylpiperidin-1-ide) A solution of 180 mL of toluene (169 mmol) was added dropwise over 1 hour. The resulting solution was heated at -55°C for 3 hours. Stir, then dissolve N-methoxy-N-methylpropionamide (11 g, 94 mmol) in anhydrous THF (20 mL). The reaction mixture was warmed to -40°C and after 30 minutes slowly cooled to -40°C. The reaction mixture was cooled in an ice bath and then diluted with 5% citric acid (aqueous The mixture was quenched by careful dropwise addition of brine (150 mL) and the organic phase was The aqueous phase was further extracted with DCM (3 x 100 mL) and the combined organic phases were dried (MgSO4) and filtered. The crude product was purified by silica gel (330 g column, 0-10% EtOAc / isohexane) and purified by chromatography to obtain 1-(2-bromopyrimidin-4-yl)propane 1-(2 ... ); m / z 215( 79 BrM+H) + (ES + ). [ka]

[0341] N-(1-(2-bromopyrimidin-4-yl)propylidene)-2-methylpropane-2-sulfina Mido INTC150 [ka] Ti(Oi-Pr)4 (30.1 ml, 103 mmol) was dissolved in (R)-2-methylpropane-2-sulfinamide (7.3 g , 60.2 mmol), (S)-2-methylpropane-2-sulfinamide (5.9 g, 48.7 mmol) and 1-(2- bromopyrimidin-4-yl)propan-1-one INTC149 (11.5 g, 51.3 mmol) was added to the mixture. The reaction mixture was then heated at 70°C for 10 hours. The reaction mixture was cooled in an ice bath and THF (200 mL) was added. The mixture was stirred for 15 minutes and then added to celite (50 mL). The mixture was filtered through 80 g of toluene and eluted with 1 L of THF. The filtrate was concentrated in vacuo. Purify by chromatography on silica gel (330 g column, 0-100% EtOAc / isohexane) and N-(1-(2-bromopyrimidin-4-yl)propylidene)-2-methylpropane-2-sulfine The amide (12.87 g, 39.6 mmol, 77% yield) (mixture of E and Z isomers) was obtained as a pale yellow solid. Rt 1.79 and 2.12 min (HPLC basic); m / z 318 ( 79 BrM+H) + (ES + ).NMR data not obtained.

[0342] (reduction of sulfoximine) N-(1-(2-bromopyrimidin-4-yl)propyl)-2-methylpropane-2-sulfinamide I NTC151 [ka] N-(1-(2-bromopyrimidin-4-yl)propylidene)-2-methylpropane-2-sulfina A solution of the amide INTC150 (10 g, 30.8 mmol) in THF (200 mL) and water (2 mL) was cooled to -50 °C (external bath temperature). The reaction mixture was cooled and then treated with sodium borohydride (1.2 g, 31.7 mmol). After 1 h, saturated aqueous NaHCO3 (20 mL) was added and the reaction mixture The mixture was stirred for 20 minutes. The mixture was acidified to pH 5 with 1N HCl (aq) and then reduced in vacuo. The aqueous phase was extracted with DCM (3 x 80 mL) and the combined organic phases were dried (phase separator). , concentrated in vacuo (reduced pressure) to give N-(1-(2-bromopyrimidin-4-yl)propyl)-2-methylpropional Benzene-2-sulfinamide (7.2 g, 20.9 mmol, 68% yield) was treated with HCl to give an orange gum, diastereoisomer. Obtained as a 1:3 mixture of mers. Rt 1.63 and 1.77 min (HPLC basic); m / z 320 (M+H) + (ES + ).NM No R data was obtained.

[0343] (Grignard-type introduction into the second R4 / R5 group) N-(2-(2-bromopyrimidin-4-yl)butan-2-yl)-2-methylpropane-2-sulfina Mid INTC152 [ka] N-(1-(2-bromopyrimidin-4-yl)propylidene)-2-methylpropane-2-sulfina A solution of the amide INTC150 (100 mg, 0.314 mmol) in THF (100 mL) was added to MeMgBr (0.13 mL, 0.38 mmol) at -78 °C. The resulting mixture was allowed to warm to room temperature and stirred for 1 hour, then NH4Cl The reaction mixture was quenched by the addition of saturated aqueous solution (50 mL). The product was extracted with EtOAc (2×100 mL) and dried. It was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by silica gel (40 g column) , 0-100% EtOAc / isohexane) and purified by chromatography to give N-(2-(2-bromopyrimidine) (4-in-4-yl)butan-2-yl)-2-methylpropane-2-sulfinamide (0.107 g, 0.321 mmO 1, quantitative yield) was obtained as a clear, colorless gum, a single diastereomer. Rt 1.9 5 minutes (HPLC acidic); m / z 332 ( 79 BrM+H) + (ES + ). [ka]

[0344] (Sulfonamide formation from aromatic halides) Table 12: The following intermediates were prepared according to Method C above. [Table 13] TIFF0007667225000225.tif242170TIFF0007667225000226.tif63170

[0345] (Deprotection: Boc) N-(4-(1-aminocyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide salt Acid acid INTC156 [ka] tert-Butyl(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)cyclopropane) To a solution of the hydroxycarbamate INTC153 (200 mg, 0.564 mmol) in dioxane (2 mL), HCl (4 M dioxane) was added. A solution of 1.41 mL of hexane (5.64 mmol) was added, and the resulting solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo and N-(4-(1-aminocyclopropyl)pyrimidin-2-yl)cyclopropyl Propanesulfonamide hydrochloride (164 mg, 0.564 mmol, quantitative yield) was obtained as a slightly yellow solid and used without further purification. Rt 0.39 min (UPLC acidic); m / z 255 (M+H) + (ES + NMR data No data obtained.

[0346] N-(4-(aminomethyl)pyrimidin-2-yl)cyclopropanesulfonamide hydrochloride INTC157 [ka] Similar to INTC156, tert-butyl ((2-(cyclopropanesulfonamido)pyrimidin-4-yl) Prepared using N-(4-(aminomethyl)pyrimidine-2-yl)methyl)carbamate INTC145 (I)cyclopropanesulfonamide hydrochloride (70 mg, 0.225 mmol, 88% yield) was obtained as a pale yellow solid Rt 0.13 min (UPLC acid); m / z 229 (M+H) + (ES + ).NMR data not obtained.

[0347] (Deprotection of sulfoximines) 1-(2-chloropyrimidin-4-yl)propan-1-amine INTC158 [ka] N-(1-(2-bromopyrimidin-4-yl)propyl)-2-methylpropane-2-sulfinamide I A solution of NTC151 (7.2 g, 22.48 mmol) in THF (30 mL) was dissolved in 4 N HCl in dioxane (2.9 mL, 95 mmol). The reaction mixture was treated with HCl and MeOH (1.0 mL) and then stirred at room temperature for 3 hours. The mixture was concentrated and then made basic with saturated aqueous NaHCO3 (100 mL). The product was extracted with DCM (3 x 80 mL). The combined organic phases were dried (phase separator) and concentrated in vacuo (reduced pressure). Purification was performed by chromatography (80 g column, 0-10% (0.7 M ammonia / MeOH) / DCM). , 1-(2-chloropyrimidin-4-yl)propan-1-amine (1.34 g, 6.01 mmol, 27% yield), Obtained as a clear brown oil. Rt 0.75 min (UPLC basic); m / z 172 ( 35 Cl M+H) + (ES + ). [ka] Br-Cl exchange was observed during the reaction.

[0348] N-(4-(2-aminobutan-2-yl)pyrimidin-2-yl)cyclopropanesulfonamide hydrochloride Salt INTC159 [ka] Similar to INTC158, N-(4-(2-(1,1-dimethylethylsulfinamido)butan-2-yl)pyridinone Prepared using N-(4-(2-aminoimidomethyl)cyclopropanesulfonamide INTC154 (Minobutan-2-yl)pyrimidin-2-yl)cyclopropanesulfonamide hydrochloride (92% yield) was obtained as a yellow solid. Rt 0.41 min (UPLC basic); m / z 271 (M+H) + (ES + ). [ka]

[0349] (reductive amination) 1-(2-Bromopyrimidin-4-yl)propan-1-amine INTC160 [ka] 2,2,2-Trifluoroacetic acid, ammonium salt (6.09 g, 46.5 mmol) and 1-(2-bromopyrimidine) (Diazin-4-yl)propan-1-one INTC149 (500 mg, 2.32 mmol) suspended in THF (20 mL, 244 mmol) The mixture was stirred at 45°C for 15 minutes to give a clear yellow solution, which was then cooled to room temperature. Ammonium trifluoroacetate (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 room temperature for 3 hours. The reaction mixture was evaporated in vacuo (reduced pressure) to about 10 The volume was reduced to mL, diluted with EtOAc (50 mL), and washed with 2M aqueous Na2CO3 (2 x 50 mL). The organic phase was stirred with Si-tosylate (10 g), filtered, and diluted with EtOAc (2 x 50 mL) and MeOH (2 x 50 mL). Washing and elution with 0.7 M NH3 in MeOH gave 1-(2-bromopyrimidin-4-yl)propan-1- The amine (227 mg, 0.99 mmol, 43% yield) was obtained as an orange oil. Rt 0.69 min (UPLC basic) ; m / z 216( 79 BrM+H) + (ES + ). [ka] No NH2 was observed.

[0350] (oxime formation) N-(4-(1-(methoxyimino)propyl)pyrimidin-2-yl)cyclopropanesulfonamido Do INTC161 [ka] O-Methylhydroxylamine hydrochloride (170 mg, 2.04 mmol), N-(4-propionylpyrimidinyl) A mixture of (2-methyl-2-phenyl)cyclopropanesulfonamide INTC155 (500 mg, 1.96 mmol) and pyridine (0.3 A suspension of 5 mL of HCl (4.33 mmol) in 4 mL of EtOH was heated to reflux for 18 h. The reaction mixture was concentrated and then The organic phase was taken up in EtOAc (20 mL) and washed with 1M HCl (15 mL) and brine (15 mL). Na2SO4), filtered, and concentrated onto silica (3 g). The crude product was purified by silica gel (12 g column, 0-100 Purification by chromatography in 100% EtOAc / isohexane gave N-(4-(1-(methoxyimino)propyl)propanol). (pyr)pyrimidin-2-yl)cyclopropanesulfonamide (428 mg, 1.43 mmol, 70% yield) was obtained as a yellow gum. Rt 0.60 min (UPLC, basic 2); m / z 285 (M+H) + (ES + ). [ka]

[0351] N-(4-(1-aminopropyl)pyrimidin-2-yl)cyclopropanesulfonamide INTC162 [ka] N-(4-(1-(methoxyimino)propyl)pyrimidin-2-yl)cyclopropanesulfonamido A solution of INTC161 (428 mg, 1.51 mmol) in 7 M NH3 in MeOH (4 mL) was added to Pd-C 10% activated carbon (char The reaction mixture was treated with 10 mg of HCl and hydrogenated at 5 bar for 1 hour. The mixture was filtered and eluted with DCM (30 mL), then concentrated in vacuo to give N-(4-(1-aminopropyl) pyrimidin-2-yl)cyclopropanesulfonamide (380 mg, 1.19 mmol, 79% yield), Obtained as an off-white solid. Rt 0.44 min (HPLC basic); m / z 257 (M+H) + (ES + NMR data collection No gain.

[0352] (HATU amide coupling) Table 13: The following intermediates were prepared according to Method 1 described below for the synthesis of compounds of formula (I): Ta.) [Table 14] TIFF0007667225000239.tif91170

[0353] (Benzamidopyrazines) (Curtius) tert-Butyl (1-(6-chloropyrazin-2-yl)propyl)carbamate INTC169 [ka] Similar to INTC148, commercially available 2-(6-chloropyrazin-2-yl)butyric acid was used to prepare tert- Butyl (1-(6-chloropyrazin-2-yl)propyl)carbamate (6% yield) as a colorless solid Obtained. Rt 2.15 min (HPLC acidic); m / z 272 ( 35 Cl M+H) + (ES + ). [ka]

[0354] (Grignard) N-(6-(2-hydroxypropan-2-yl)pyrazin-2-yl)cyclopropanesulfonamide INTC172 [ka] Methyl 6-(cyclopropanesulfonamido)pyrazine-2-carboxylate INTC170 (3.00g A solution of MeMgBr (3.0 M in EtO) (18 mL, 5 4.0 mmol) was added dropwise over 15 minutes and the reaction mixture was then allowed to warm to room temperature. The mixture was stirred at 40° C. for 18 hours. The reaction mixture was further heated at 40° C. for 24 hours. The reaction mixture was cooled in an ice bath. 1M HCl (aq, 60 mL) was added carefully, and the aqueous phase was extracted with EtOAc (4×500 mL). The organic phases were combined, dried (Na2SO4), filtered and concentrated onto silica (10 g). Purify by chromatography on silica gel (40 g column, 0–100% EtOAc / isohexane) and N- (6-(2-hydroxypropan-2-yl)pyrazin-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 + ). [ka]

[0355] (liters) 2-chloro-N-(2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl ) Acetamide INTC173 [ka] N-(6-(2-hydroxypropan-2-yl)pyrazin-2-yl)cyclopropanesulfonamide INTC172 (330 mg, 1.28 mmol) and 2-chloroacetonitrile (0.65 mL, 10.3 mmol) in AcOH (0 The mixture (0.75 mL, 13.1 mmol) was cooled in an ice bath, and then H2SO4 (0.82 mL, 15.4 mmol) was added dropwise. The reaction was then warmed to 50° C. and stirred for 18 h. The solution was poured into ice water (30 mL) and EtOAc (3× 30 mL), and the organic phases were combined, dried (Na2SO4), filtered, and concentrated onto silica (2 g). The crude product was purified by chromatography on silica gel (12 g column, 0-100% EtOAc / isohexane). Purified by HPLC and purified with 2-chloro-N-(2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propanol. (2-phenyl-2-yl)acetamide (100 mg, 0.294 mmol, 19% yield) was obtained as a yellow gum. Rt 0.98 min (HPLC acidic); m / z 333 ( 35 Cl M+H) + (ES + ). [ka]

[0356] (Boc removed) N-(6-(1-aminopropyl)pyrazin-2-yl)cyclopropanesulfonamide hydrochloride INTC1 74 [ka] Similar to INTC156, tert-butyl(1-(6-cyclopropanesulfonamido)pyrazine-2-yl) Prepared using N-(6-(1-aminopropyl)pyrazine)carbamate INTC171 (2-yl)cyclopropanesulfonamide hydrochloride (85 mg, 0.276 mmol, 42% yield) was added to a colorless Obtained as a solid. Rt 0.58 min (HPLC basic); m / z 257 (M+H) + (ES + ). [ka]

[0357] (Deprotection of thioureas) N-(6-(2-aminopropan-2-yl)pyrazin-2-yl)cyclopropanesulfonamide INTC 175 [ka] 2-chloro-N-(2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl ) Acetamide (100 mg, 0.30 mmol) INTC173 in EtOH (1.3 mL) was added to thiourea (23 mg, 0 The mixture was treated with AcOH (0.35 mL, 6.11 mmol) and then heated to reflux for 1 h. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. It was then carefully diluted with 0.7M NH The crude product was treated with a solution of 3 in MeOH (5 mL) and concentrated. The crude product was purified by RP Flash C18 (12 g column, 0-25% MeOH). Purification by chromatography on CN / 10 mM ammonium bicarbonate gave N-(6-(2-aminopropanediol) (pyrazin-2-yl)cyclopropanesulfonamide (63 mg, 0.23 mmol, 78% yield) (yield: 100%) was obtained as a colorless solid. Rt 0.37 min (HPLC basic); m / z 257 (M+H) + (ES + ). [ka] 3× exchangeable H was not observed.

[0358] (Preparation of Amine Intermediates) Method E: Suzuki Coupling of Haloanilines with Heteroaromatic Boronates [ka] A solution of Ar1-X (1 equivalent) and Ar2-Z (1 equivalent) in solvent (3 volumes) and base (2.5 equivalents) was degassed (N2, 5 min) and heated to 40°C, whereupon Pd catalyst (3 mol%) was added and the reaction mixture was further degassed. (N2, 5 min), then heated at 90°C for 90 min. The reaction mixture was allowed to cool to room temperature. The desired compound was purified by column chromatography.

[0359] (Method F: Suzuki Coupling of Heteroaromatic Halides with Aniline Boronates) [ka] Pd catalyst (5 mol%) was added to a degassed (N, 5 min) solution of Ar1-X (1 equiv.), Ar2-Z (1 equiv.) and base (3 equiv. To a solution of 1,2-dimethyl-2,4-dichloro-1,4-dichloro-2 ... The mixture was heated at 2°C for 2 hours and then allowed to cool to room temperature. It was purified by chromatography.

[0360] (Method G: Sequential boronate formation and Suzuki coupling) [ka] Bispin (1.1 eq) and KOAc (4 eq) were added to a solution of Ar1-Hal (1 eq) in dioxane (5 volumes). The reaction was heated to 60 °C and degassed (N2, 5 min). PdCl2(dppf) (5 mol%) was added to the reaction mixture. The mixture was then added to the mixture, and the temperature was raised to 90°C for 1 hour. The reaction mixture was then allowed to cool to room temperature. Cool and add a solution of Ar2-Hal (1 eq) in dioxane (3 vol) followed by K2CO3 (4 eq) in water (2 vol) The reaction mixture was then heated to 90°C for 18 hours. After cooling, an aqueous workup was performed and the crude compound was purified by normal phase chromatography.

[0361] (aniline) Table 14: The following intermediates were prepared according to Methods E, F or G. [Table 15] TIFF0007667225000254.tif231170TIFF0007667225000255.tif216170TIFF000 7667225000256.tif224170TIFF0007667225000257.tif225170TIFF0007667225 000258.tif217170TIFF0007667225000259.tif220170TIFF0007667225000260. tif224170TIFF0007667225000261.tif230170TIFF0007667225000262.tif75170

[0362] 2-chloro-6-(prop-1-en-2-yl)pyrazine INTD60 [ka] 2,6-Dichloropyrazine (1.0 g, 6.71 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-ene) A solution of (2-yl)-1,3,2-dioxaborolane (1.13 g, 6.72 mmol) in dioxane (60 mL) was added to a 2 M Treat with K2CO3 (aq, 8.4 mL, 16.8 mmol), then degas (N2, 5 min) and heat to 40 °C. PdCl2(dppf)-DCM adduct (274 mg, 0.336 mmol) was added and the mixture was further degassed (N2, 5 min), then the reaction was heated at 70° C. for 1 h. The reaction was allowed to cool to room temperature and then diluted with 1 M HCl (aqueous This was treated with ethyl acetate (40 mL) and EtOAc (40 mL). This was passed through celite and the two phases were separated. The aqueous phase was extracted with more EtOAc (2 x 20 mL). The organic phases were combined, dried (MgSO4), and filtered. The crude product was purified by silica gel (24 g column, 0-15% EtOAc / isohexane). The product was purified by chromatography on a 1000-well plate (Sun Microsystems) and purified with 2-chloro-6-(prop-1-en-2-yl)pyrazine (1.0 g, 3.75 mmol, 56% yield) as a brown gum. Rt 1.96 min (HPLC acidic); m / z Not observed. [ka]

[0363] 5-(6-(prop-1-en-2-yl)pyrazin-2-yl)pyridin-2-amine INTD61 [ka] 2-chloro-6-(prop-1-en-2-yl)pyrazine INTD60 (1 g, 3.75 mmol) and 5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.65 g, 7.50 mmol) The dioxane (60 mL) solution was treated with 2 M K2CO3 (aq, 7.5 mL, 15.00 mmol) and then degassed. (N2, 5 min) and heated to 40 °C. PdCl2(dppf)-DCM adduct (0.306 g, 0.375 mmol) was added. The mixture was further degassed (N2, 5 min) and the reaction was heated at 70 °C for 1 h. The reaction was allowed to warm to room temperature. It was cooled and then concentrated (to about 10 mL). This was then diluted with 1M HCl (aq, 37.5 mL) and EtOAc (40 The mixture was treated with 10 mL of ethyl acetate, filtered through celite, and eluted with EtOAc (50 mL). The two phases were separated. The organic phase was discarded. The aqueous phase was then adjusted to pH 10 by adding solid Na2CO3, followed by EtOAc (3 x 50 mL). The organic phases were combined, dried (MgSO4), filtered, and concentrated onto silica (5 g) to give the crude product. The product was chromatographed on silica gel (24 g column, 30-100% EtOAc / isohexane). Purified and purified to give 5-(6-(prop-1-en-2-yl)pyrazin-2-yl)pyridin-2-amine (320 mg, 1.4 3 mmol, 38% yield) as an off-white solid. Rt 0.98 min (HPLC acidic); m / z 213 (M+H ) + (ES + ); [ka]

[0364] 4-(6-Isopropylpyrazin-2-yl)aniline INTD62 [ka] 4-(6-(prop-1-en-2-yl)pyrazin-2-yl)aniline INTD52 (380 mg, 1.44 mmol) The MeOH (10 mL) solution was dissolved in an H-Cube flow hydrogenator (10% Pd / C, 30 × 4 mm, full hydrogen, 25 °C, 1 m The reaction mixture was concentrated and 4-(6-isopropylpyrazin-2-yl) ) Aniline (296 mg, 1.37 mmol, 95% yield) was obtained as an orange oil. Rt 1.74 min (HPLC basic ); m / z 214(M+H) + (ES + ); [ka]

[0365] 2-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine INTD6 3 [ka] To a solution of 2-bromo-6-methoxypyrazine (500 mg, 2.65 mmol) in 1,4-dioxane (15 mL), Ispin (739 mg, 2.91 mmol) and KOAc (1.04 g, 10.58 mmol) were added successively. The mixture was degassed (N) and PdCl(dppf)-CHCl adduct (108 mg, 0.132 mmol) was added. The resulting mixture was heated at 110° C. for 2.5 hours. The mixture was cooled to room temperature and celite was added. The crude product was filtered through a 24 g cartridge and the solvent was removed in vacuo. The residue was purified by chromatography in 0-50% EtOAc / isohexane. and washed with water (3 x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo (reduced pressure). and 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (28 1 mg, 0.845 mmol, 32% yield) as a pale tan solid. [ka]

[0366] (Method K: Suzuki coupling) [ka] Boronic acid (1 equiv.), aryl halide (1.05 equiv.), and Cs2CO3 (3 equiv.) in dioxane (4 A mixture of PdCl2(dppf)-CH2Cl2 (5 mol%) was degassed (N2, 5 min) and water (6 vol). The reaction mixture was further degassed (N) and then heated at 90° C. for 18 hours. Filtration through celite followed by aqueous workup and subsequent purification by normal phase chromatography did.

[0367] Table 15: The following intermediates were prepared according to Method K. All aryl-halides were commercially available. It is possible to obtain it.) [Table 16] TIFF0007667225000273.tif240170TIFF0007667225000274.tif69170

[0368] (Method L: Ester deprotection with TFA) [ka] A solution of the ester (1 equiv) in DCM (20 vol) was treated with TFA (10 equiv) and stirred at room temperature for 3 h. The reaction mixture was then concentrated and azeotroped with MeOH and MeCN without further purification.

[0369] Method M: Ester Deprotection with Base [ka] A solution of the ester (1 equiv.) in THF / MeOH (4 / 1 by volume) was treated with LiOH (2.2–6 equiv.) and heated at room temperature and 50 The mixture was stirred for 3 to 18 hours at a temperature ranging from 100°C. The organic solvent was removed in vacuo (reduced pressure), and then 1M The mixture was acidified with HCl and extracted with EtOAc. The organic phases were combined, dried (Na2SO4), filtered and concentrated. The product was used directly in the next step without further purification.

[0370] (Method N: Potassium Salt Formation) [ka] A solution of the ester (1 equiv) in THF (4 vol) was treated with TMSOK (1 equiv) and stirred at room temperature for 2 h, then The reaction mixture was filtered and washed with isohexane and the product was directly used without further purification. It was used in the next step.

[0371] (Table 16: The following intermediates were prepared according to methods L to N.) [Table 17] TIFF0007667225000279.tif203170

[0372] (5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methanol INTD84 [ka] (5-Bromopyridin-2-yl)methanol (1.00 g, 5.32 mmol), Bispin (1.5 g, 5.91 mmol) A suspension of KOAc (1.6 g, 16.0 mmol) in dioxane (20 mL) was heated to 30° C. and then degassed. (N2). PdCl2(dppf)-CH2Cl2 (0.217 g, 0.266 mmol) was added and the reaction mixture was heated at 90 °C for 2 h. The reaction mixture was cooled to 40° C., and 2-chloro-6-ethoxypyrazine (900 mg, 5.68%) was obtained. Cs2CO3 (3.47 g, 10.6 mmol), Cs2CO3 (3.47 g, 10.6 mmol) and water (5 mL) were added. The mixture was degassed (N2) and then PdCl(dppf)-CHCl (0.217 g, 0.266 mmol) was added and the mixture was degassed again (N). The reaction mixture was heated at 90° C. for up to 18 hours. The reaction mixture was partially concentrated (to approximately 5 mL) and then The mixture was taken up in water (20 mL) and EtOAc (50 mL), passed through celite, and eluted with EtOAc (20 mL). The two phases were then diluted with water (20 mL) and separated. The organic phase was washed with brine (30 mL) and dried. (Na2SO4), filtered, and concentrated onto silica (5 g). The crude product was purified by silica (40 g cartridge, 0-1 Purification by chromatography in 0.00% EtOAc / isohexane gave (5-(6-ethoxypyrazine-2- (2-(2-yl)pyridin-2-yl)methanol (675 mg, 2.86 mmol, 54% yield) was obtained as a brown solid. Rt 1.24 min (HPLC acidic); m / z 232 (M+H) + (ES + ); [ka]

[0373] 5-(6-ethoxypyrazin-2-yl)picolinaldehyde INTD85 [ka] (5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)methanol INTD84 (375 mg, 3.18 mm A solution of 100 ml of HCl (15 mL) was treated with manganese dioxide (3 g, 34.5 mmol). The reaction was stirred at room temperature for 4 h. Stirred warm, then filtered through celite and concentrated onto silica (4 g). The material was purified by chromatography on silica (24 g cartridge, 0-100% EtOAc / isohexane). 5-(6-ethoxypyrazin-2-yl)picolinaldehyde (309 mg, 1.32 mmol, 42% yield) was obtained. (yield: 1.001) was obtained as a colorless solid. Rt 1.85 min (HPLC acidic); m / z 230 (M+H) + (ES + ); [ka]

[0374] 5-(6-ethoxypyrazin-2-yl)picolinic acid INTD86 [ka] 5-(6-ethoxypyrazin-2-yl)picolinaldehyde INTD85 (302 mg, 1.32 mmol) in DMF ( The solution (5 mL) was treated with oxone (1.02 g, 1.66 mmol). The reaction mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with water (10 mL) and filtered. The filtrate was then taken up in EtOAc (10 mL). The mixture was then heated to 40°C to give a free-flowing suspension, to which was then added isohexane (10 mL) dropwise. The mixture was treated, cooled to room temperature, and filtered to give 5-(6-ethoxypyrazin-2-yl)picolinic acid (240 mg, 0.93 mmol, 71% yield) as a colorless solid. Rt 1.45 min (HPLC acidic); m / z 246 (M+H) + (ES + ); [ka]

[0375] Preparation of Examples (amide formation) (Method 1: Amide coupling using HATU) [ka] A stirring suspension of acid or potassium salt (1 equiv., X = H or K) and DIPEA (6 equiv.) in DMF (15 vol.) To the reaction mixture was added aniline (1 eq.) and HATU (1.5 eq.). The reaction was stirred at room temperature for 18 hours, then Concentrated in vacuo (reduced pressure). MeOH and 2M NaOH (aq) were added. The mixture was stirred for 30 minutes. It was then concentrated in vacuo (reduced pressure). The aqueous phase was acidified to pH 6 with 1M HCl (aq) and the product was extracted with DCM. The organic phases were combined, dried (phase separator) and concentrated in vacuo (reduced pressure). The crude product was purified by reversed-phase or normal-phase chromatography, or a combination of both. Purified.

[0376] N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2-cyclopropanesulfonamido)pi Rimidin-4-yl)butanamide P1 [ka] 4-(5-chloropyridin-3-yl)aniline INTD8 (0.117 g, 0.573 mmol) and HATU (0.327 g, 0 0.859 mmol) to a stirring 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanol solution. A suspension of potassium phosphate INTC37 (0.265 g, 0.573 mmol) and DIPEA (0.60 mL, 3.44 mmol) in DMF (6 mL) The reaction was stirred at room temperature for 18 hours and then concentrated in vacuo. OH (20 mL) and 2M NaOH (aq) (20 mL) was added. The mixture was stirred for 30 min, then The aqueous phase was acidified to pH 6 with 1M HCl (aq) (40 mL) and the product was extracted with DCM (3× The organic phases were combined, dried (phase separator) and concentrated in vacuo (reduced pressure). The product was purified by silica gel (12 g column, 0-100% EtOAc / isohexane) followed by RP Flash C18 (5 Purification by chromatography in 75% MeCN / water with 0.1% formic acid gave N-(4-(5-chloropyridine-3- yl)phenyl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide ( 0.158 g, 0.318 mmol, 56% yield) as a white solid. Rt 1.36 min; m / z 472 (M+H) + (ES + ); [ka]

[0377] (Method 2: Ester to AlMe3-mediated amide coupling) [ka] To an ice-cold solution of aniline (2 equiv.) in toluene (40 vol.) was added AlMe3 (2.0 M in heptane, 2 equiv.). The mixture was stirred at this temperature for 5 minutes and then at room temperature for 10 minutes. The ester (1 equivalent) was added in one portion and the resulting mixture was heated and stirred at 80° C. for 2 hours. The mixture was cooled in an ice bath and carefully quenched with MeOH (10 vol). After stirring for 20 min, the mixture was Diluted with M / MeOH mixture (10 vol), filtered through celite and concentrated the filtrate. The crude product was purified by reverse or normal phase chromatography.

[0378] 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine) -2-yl)phenyl)cyclopentanecarboxamide P2 [ka] Dissolve 4-(6-ethoxypyrazin-2-yl)aniline INTD18 (0.099 g, 0.461 mmol) in toluene on ice. To the toluene (4 mL) solution was added AlMe3 (2.0 M in toluene) (0.307 mL, 0.615 mmol). The mixture was stirred at this temperature for 5 minutes, then at room temperature for 20 minutes. To this solution was added methyl 1-(2-(cyclohexanediol)-2-methyl-2-(cyclohexanediol). Propanesulfonamido)pyrimidin-4-yl)cyclopentanecarboxylate INTC29(0. 1 g, 0.307 mmol) was added in one portion and the resulting mixture was heated at 100 °C for 3 h under N2 atmosphere. The reaction mixture was carefully quenched with MeOH (2 mL). After stirring for 20 min, the mixture Dilute with MeOH (50 mL), filter through celite (5 g), and concentrate the filtrate in vacuo. The crude product was purified by chromatography on RP Flash C18 (25-75% MeCN / water 0.1% formic acid). 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyridine) (Zin-2-yl)phenyl)cyclopentanecarboxamide (0.053 g, 0.099 mmol, 32% yield) was obtained as a white solid. Rt 1.59 min (UPLC acidic); m / z 509 (M+H) + (ES + ); [ka]

[0379] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyrazine) -2-yl)phenyl)-2-methylpropanamide P3 [ka] 4-(6-Methoxypyrazin-2-yl)aniline INTD1 (101 mg, 0.501 mmol) was added to ice-cold AlMe To a solution of 3 (2M in heptane) (0.33 mL, 0.668 mmol) in toluene (4 mL) was added the mixture. The mixture was stirred at this temperature for 5 minutes, and then at room temperature for 10 minutes. (4-methyl-2-methylpropanoate) INTC21 (100 mg, 0.334 mmol) was added in one portion. The resulting mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled in an ice bath and carefully After stirring for 20 min, the mixture was quenched with MeOH (10 mL). The crude product was diluted with HCl, filtered through celite, and the solvent removed to give an orange oil. The product was purified by chromatography on silica gel (24 g column, 0-100% EtOAc / isohexane). 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-methoxypyridine)- (Diazin-2-yl)phenyl)-2-methylpropanamide (37 mg, 0.077 mmol, 23% yield) was added to a 100 ml solution of 100 ml ... Obtained as a pale beige solid. Rt 2.03 min (HPLC acidic); m / z 469 (M+H) + (ES + ); [ka]

[0380] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(5-(trifluoromethyl)-2-pyrimidin-4-yl)-2-methyl-N-(4-(5- ... (fluoromethyl)pyridin-3-yl)phenyl)propanamide P4 [ka] Ice-cold 4-(5-(trifluoromethyl)pyridin-3-yl)aniline INTD7 (0.119 g, 0.501 m To a solution of AlMe3 (2.0 M in heptane) (0.334 mL, 0.668 mol) in toluene (4 mL) and THF (2 mL), The mixture was stirred at this temperature for 5 minutes and then at room temperature for 10 minutes. , methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methylpropanoate The salt INTC21 (0.1 g, 0.334 mmol) was added in one portion, and the resulting mixture was heated at 80 °C for 2 h in a sealed vessel. The reaction mixture was heated and stirred in a vessel. The reaction mixture was cooled in an ice bath and carefully quenched with MeOH. 20 min After stirring for a while, the mixture was diluted with a mixture of DCM / MeOH and filtered through celite. The liquid was concentrated in vacuo (reduced pressure). The crude product was purified by RP Flash C18 chromatography (5-75% MeCN / water 0.1% formic acid). The product was purified by chromatography to give 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2- Methyl-N-(4-(5-(trifluoromethyl)-pyridin-3-yl)phenyl)propanamide (0.10 9g, 0.205 mmol, 61% yield) was obtained as a white solid. Rt 2.17 (HPLC acidic); m / z 506 (M+H) + (ES + ); [ka]

[0381] 2-Methyl-N-(2-methyl-4-(6-methylpyrazin-2-yl)phenyl)-2-(2-methylsulfone Amido)pyrimidin-4-yl)propanamide P5 [ka] Ice-cold 4-(6-chloropyrazin-2-yl)-2-methylaniline INTD26 (0.549 mmol, 121 mg) To a solution of in toluene (2 mL) was added AlMe3 (0.55 mL, 1.098 mmol, 2.0 M solution in heptane). The mixture was stirred at this temperature for 5 minutes, then at room temperature for 10 minutes. (2-(methylsulfonamido)pyrimidin-4-yl)propanoate INTC19 (100 mg, 0.366 mm ol) was added in one portion and the resulting mixture was heated and stirred at 90°C for 2 hours. The mixture was cooled to room temperature, 1M HCl (5 mL) was added, and the residue was extracted with EtOAc (2×20 mL). The organic extract was passed through a phase separator and the solvent was removed under reduced pressure. The crude product was purified by RP Flash C18 (0- Purification by chromatography in 100% MeCN / water (0.1% formic acid) gave 2-methyl-N-(2-methyl-4-(6- Methylpyrazin-2-yl)phenyl)-2-(2-(methylsulfonamido)pyrimidin-4-yl)pyrimidin-4-yl) Lopanamide (78.9 mg, 0.170 mmol, 47% yield) was obtained as an off-white solid. Rt 1. 74 (HPLC acidic); m / z 441 (M+H) + (ES + ); [ka]

[0382] 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine) -2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide P115 [ka] 5-(6-ethoxypyrazin-2-yl)pyridin-2-amine INTD33 (0.14 g, 0.66 mmol) in toluene To a solution of 1,2-dimethyl-3,4-dichloro-2 ... ) was added. The reaction mixture was stirred at 0°C for 5 minutes and then at room temperature for 10 minutes. (Isopropanesulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylate The salt INTC53 (0.15 g, 0.44 mmol) was added in one portion and the reaction mixture was heated at 95° C. for 1 h, then 0 The reaction mixture was cooled to ° C. The reaction mixture was quenched with 1M HCl (5 mL) and diluted with EtOAc (10 mL). The two phases were separated and the aqueous phase was further extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with MgS The crude product was dried over O, filtered, and concentrated in vacuo. The crude product was purified by silica gel (12 g column, 0-100 Purification by chromatography in 10% EtOAc / isohexane gave 4-(2-cyclopropanesulfone). Amido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)tetra Hydro-2H-pyran-4-carboxamide (0.022 g, 0.040 mmol, 9% yield) as a white solid Got it. Rt 1.31 min (UPLC acidic); m / z 526 (M+H) + (ES + ); [ka]

[0383] (Method 2b: Ester to amide coupling via DABAL-Me3) [ka] To a solution of the ester (1 equiv.) and aniline (1.5 equiv.) in toluene (30 vol.) was added DABAL-Me3 (1.5 equiv.). Amount of HCl was added and the resulting mixture was heated at 100°C for 4 hours. The reaction mixture was cooled to 0°C and 1M The reaction was quenched by careful addition of HCl (aq, 20 vol). The aqueous phase was extracted with EtOAc (3 x 20 vol). The combined organic phases were washed with 1 M HCl (aq, 2 x 10 vol), dried over Na2SO4 and filtered. The crude product was purified by reverse or normal phase chromatography.

[0384] Method 3: Amide coupling from potassium salts using T3P [ka] Pyridine (10 equiv.) followed by T3P (50 wt.% in DMF, 2 equiv.) was added to the amine (1.1 equiv.) and and potassium 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanoate (1 equivalent) The resulting reaction mixture was stirred at room temperature for 24 hours. The extract was concentrated in vacuo (reduced pressure), then diluted with NH4Cl (saturated aqueous solution) and extracted with DCM. The organic extract was dried (phase separator) and the solvent was removed. The crude product was purified by reversed or normal phase chromatography. It was refined by roughy.

[0385] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4-(pyridinyl) (2-phenyl)butanamide P6 [ka] T3P (50 wt% DMF solution) (1.120 mL, 1.546 mmol) was added to 2-fluoro-4-(pyrazine-2- 2-(2-(cyclopropanesulfonamido)pyridine)aniline INTD23 (154 mg, 0.773 mmol), A mixture of potassium tetrahydrofuran (4-amino-4-yl)butanoate INTC37 (250 mg, 0.773 mmol) and pyridine (0.313 mL, 3 To a suspension of 1.87 mmol of HCl in DMF (1 mL) was added the resulting reaction mixture, which was stirred at room temperature for 18 hours. The product was dissolved in DCM (10 mL) and filtered off. The crude product was purified by preparative HPLC (20-50% MeCN / water 0.1% formic acid). and purified to give 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro-4- (Pyrazin-2-yl)phenyl)butanamide (32 mg, 0.069 mmol, 9% yield) was obtained as a colorless powder. Rt 1.15 min (UPLC acid); m / z 457 (M+H) + (ES + ); [ka]

[0386] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5-(trifluoromethyl)- (ethyl)pyridin-3-yl)phenyl)butanamide P7 [ka] T3P (50 wt% DMF solution) (0.78 mL, 1.082 mmol) was added to 2-(2-cyclopropanesulfonyl) Potassium 4-(5-( ... (trifluoromethyl)pyridin-3-yl)aniline INTD7 (129 mg, 0.541 mmol) in pyridine (0 To a suspension of 1,2-dimethyl-3-(2,4-dimethyl-2,6-dimethyl-1,3-dimethyl-2,4 ... The reaction mixture was diluted with saturated aqueous NH4Cl (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were dried (phase separator) and the solvent was removed under reduced pressure. Purification was performed by chromatography on silica gel (0–10% MeOH / DCM) followed by RP Flash C18 (15–7 Purification by chromatography in 5% MeCN / water 0.1% formic acid gave 2-(2-cyclopropanesulfone). Amido)pyrimidin-4-yl)-N-(4-(5-(trifluoromethyl)pyridin-3-yl)phenyl) Butanamide (19 mg; 0.036 mmol; 7% yield) was obtained. Rt 1.44 (UPLC acid); m / z 506 (M+H). + (ES + ); [ka]

[0387] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-(trifluoromethyl)-2- ... (2-ethyl)pyrazin-2-yl)phenyl)acetamide P8 [ka] T3P (50 wt% DMF solution) (0.343 mL, 0.474 mmol) was added to 2-(2-cyclopropanesulfonyl) Potassium (4-(trifluoromethyl)pyrimidin-4-yl)acetate INTC39 (100 mg, 0.237 mmol), 4-(6-(trifluoromethyl)pyrimidin-4-yl)- (fluoromethyl)pyrazin-2-yl)aniline INTD19 (56.7 mg, 0.237 mmol) and pyridine (0.0 To a suspension of 1 mL of HCl (96 mL, 1.185 mmol) in DMF (1 mL) was added the resulting reaction mixture, which was stirred at room temperature for 18 hours. Water (5 mL) was added and the newly formed precipitate was filtered to give the crude product. was purified by chromatography on silica gel (0-10% MeOH / DCM) followed by preparative HPLC (5-95%). Purification by chromatography in 0.1% MeCN / water (0.1% formic acid) gave 2-(2-cyclopropanesulfonic acid). (6-(trifluoromethyl)pyrazin-2-yl)phenyl)-N-(4-(6-(trifluoromethyl)pyrazin-4-yl)phenyl)- Cetoamide (10 mg, 0.021 mmol, 9% yield) was obtained as a yellow powder. Rt 1.31 min (UPLC acidic); m / z 479(M+H) + (ES + ); [ka]

[0388] Method 4: Amide coupling from lithium salts using T3P N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2-(N-(4-methoxy) Dibenzyl)cyclopropanesulfonamido)pyrimidin-4-yl)butanamide INTC51 [ka] 2-Fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidine To a solution of lithium 5-(6-ethyl-4-yl)butanoate INTC50 (0.50 g, 1.17 mmol) in DMF (5 mL) was added 5-(6-ethyl-4-yl)butanoate at 0 °C. (2-thiazin-2-yl)pyridin-2-amine INTD33 (0.30 g, 1.40 mmol), followed by pyridine ( To the reaction mixture were added T3P (50 wt% solution in DMF) (1.69 mL, 2.34 mmol). The mixture was stirred at 0° C. for 2 hours, then warmed to room temperature and stirred for 20 hours. The reaction mixture was cooled to 0° C. Further, T3P (50 wt% solution in DMF) (0.5 mL, 0.69 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour, then The reaction mixture was diluted with saturated aqueous NH4Cl (45 mL) and the resulting precipitate was The product was isolated by filtration and washed with water (2 x 20 mL). The resulting yellow precipitate was dissolved in DCM (30 mL) and MeOH (4 mL). (30 mL) and concentrated onto silica gel. The crude product was purified by silica gel (24 g column, 0-60% EtOAc). C / isohexane) and purified by chromatography to give N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)pyridin-2-yl. Lysin-2-yl)-2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido) (d)pyrimidin-4-yl)butanamide (0.274 g, 0.433 mmol, 37% yield) as a colorless oil Got it. Rt 1.84 min (UPLC acidic); m / z 622 (M+H) + (ES + ); [ka]

[0389] Method 5: NH-amide formation via amide deprotection and / or decarboxylation [ka] To a solution of the protected amide in DCM, a mixture of TFA (88 equiv.) and triflic acid (1-6 equiv.) was added. The mixture was stirred at room temperature for 18-36 hours, then concentrated in vacuo. Purification was carried out by gel column chromatography or RP chromatography.

[0390] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine) -2-yl)phenyl)butanamide P105 [ka] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine) (4-methoxybenzyl)-N-(2-yl)phenyl)-N-(4-methoxybenzyl)butanamide INTC46 (0.18 g, 0.299 mmol) A solution of the resulting mixture in TFA (2 mL, 26.0 mmol) and DCM (2 mL) was stirred at 25° C. for 18 hours. The mixture was heated at 50°C for 2 hours. Triflic acid (0.027 mL, 0.299 mmol) was added to the reaction mixture and mixed. The mixture was stirred for 2 h at 25° C. The reaction mixture was concentrated and then diluted with 1 N HCl (aq) (20 mL). The aqueous phase was extracted with DCM (3 x 20 mL), dried (phase separator) and the solvent was removed under reduced pressure. The crude product was purified by RP Flash C18 (24 g column, 5–75% MeCN / water 0.1% formic acid) chromatography. Purified with 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxy)- (Pyrazin-2-yl)phenyl)butanamide (0.02 g, 0.041 mmol, 14% yield) was obtained as a white solid. Rt 2.23 min (HPLC acidic); 483 (M+H) + (ES + ).

[0391] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6-ethoxypyrazine) -2-yl)phenyl)acetamide P18 [ka] tert-Butyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-3-((4-(6-ethoxy)methyl)- ... (4-Methoxybenzyl)amino)-3-oxopropanoate I To a solution of NTC47 (0.1 g, 0.148 mmol) in a mixed solvent of TFA (1 mL, 12.98 mmol) and DCM (20 mL) Then, triflic acid (0.039 mL, 0.445 mmol) was added. The mixture was stirred at 25°C for 18 hours. To this was added triflic acid (0.039 mL, 0.445 mmol) and the mixture was stirred at 25° C. for a further 18 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (12 g column, 0-10% MeOH / DCM). The compound was purified by chromatography to give 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)- (6-ethoxypyrazin-2-yl)phenyl)acetamide (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 + ).

[0392] (Method 6: Deprotection of sulfonamides) [ka]

[0393] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine) -2-yl)pyridin-2-yl)-2-fluorobutanamide P112 [ka] TFA (0.28 mL, 3.70 mmol) was added to a stirring solution of N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)pyridin-2-yl 2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidinyl)-2-fluoro-2-(2-(N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidinyl) The resulting mixture was added to a solution of (diazin-4-yl)butanamide INTC51 (115 mg, 0.185 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give the crude product. Purify by chromatography on silica gel (12 g column, 0-100% EtOAc / isohexane) 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine-2 (-yl)pyridin-2-yl)-2-fluorobutanamide (77 mg, 0.15 mmol, 81% yield) was added to white Obtained as a colored solid. Rt 2.28 min (HPLC acidic); m / z 502 (M+H) + (ES + ); [ka]

[0394] Racemic P112 was purified by HPLC on a Diacel Chiralpak IC column (20% EtOH in [4:1 heptane:chloroform]). The resulting mixture was separated by chiral preparative HPLC using HCl (0.2% TFA) to give the following: (P112 Enantiomer 1: The stereochemistry of the product is not specified (P113).) 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine) (2-yl)pyridin-2-yl)-2-fluorobutanamide; Rt 2.28 min (HPLC acidic); m / z 502 (M+H) + (ES + ); [ka] The product was analyzed by chiral IC3 HPLC; Rt = 10.47 min, enantiomers measured at 254 nm -Excess rate 100%. (P112 Enantiomer 2: The stereochemistry of the product is not specified (P114).) 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-ethoxypyrazine) (2-yl)pyridin-2-yl)-2-fluorobutanamide; Rt 2.28 min (HPLC acidic); m / z 502 (M+H) + (ES+ ); [ka] The product was analyzed by chiral IC3 HPLC; Rt = 14.24 min, enantiomers measured at 254 nm -Excess rate 100%.

[0395] (Method 7: Sulfonylation from aromatic chlorides) [ka] 2-chloro-heteroaromatic intermediate (1 equivalent), sulfonamide (1.2 equivalents) and base (2 equivalents), The mixture was degassed (evacuated and filled with N2 three times) and then the catalyst (10 ml vol%) was added. The resulting mixture was heated at 90°C for 2 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature. The mixture was cooled to rt and diluted with saturated aqueous NH4Cl (80 vol) and DCM (80 vol). The two phases were separated and the aqueous phase The extract was further extracted with DCM (2 x 80 vol). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo (reduced The crude product was purified by normal phase chromatography or trituration with an appropriate solvent. It was purified by filtration.

[0396] Method 8: Amide coupling using 1-chloro-N,N,2-trimethylprop-1-en-1-amine ng) [ka] 1-Chloro-N,N,2-trimethylprop-1-en-1-amine (2 equivalents) was added to the carboxylic acid (1 equivalent) of D CM (20 vol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then vacuumed (reduced pressure ), and the residue was redissolved in DCM (20 vol) and pyridine (2 mL) was added, followed by the appropriate Methylamine (1.1 equiv.) was added. The reaction mixture was stirred at room temperature for 2 hours. An aqueous workup afforded the crude product. The material is purified by normal phase chromatography, reverse phase chromatography, or tritium ion chromatography from a suitable solvent. The product was purified by filtration.

[0397] (Method 9: Suzuki ArBr) [ka] To a suspension of Ar1-Br (1 equivalent) in dioxane (10 volumes) was added arylboronic acid or ester (1 equivalent). A solution of K2CO3 (2 equiv.) in water (5 vol.) was added. The resulting suspension was degassed (N2, 5 min). Cl2(dppf)-CH2Cl2 adduct or other suitable catalyst (10 mol%) was added and the reaction mixture was heated at 80 °C for 2 The reaction mixture was then cooled to room temperature. An aqueous workup was performed and the crude product was purified by normal phase chromatography. chromatography, reverse phase chromatography or trituration from a suitable solvent Purified by.

[0398] (Method 10: Free Acid and T3P) [ka] Pyridine (10 eq.) followed by T3P (50 wt% in DMF, 2 eq.) was added to the amine (1.1 eq.) and To a solution of 1 equivalent of carboxylic acid in 16 volumes of DMF was added the resulting reaction mixture, which was stirred at room temperature for 24 hours. The crude reaction mixture was concentrated in vacuo (reduced pressure), then diluted with NH4Cl (sat. aq.) and extracted with DCM. The combined organic extracts were dried (phase separator), the solvent was removed, and the crude product was purified by reverse phase or was purified by normal phase chromatography.

[0399] Table 17: Preparation methods and property data for Examples P9 to P115, P117 to P225 Table 18 TIFF0007667225000323.tif198170TIFF0007667225000324.tif229170TIFF0007667225000325.tif167170TIFF0007667225000326.tif186170TIFF0007667225000327.tif198170TIFF0007667225000328.tif203170TIFF0007667225000329.tif243170TIFF0007667225000330.tif249170TIFF0007667225000331.tif232170TIFF0007667225000332.tif246170TIFF0007667225000333.tif238170TIFF0007667225000334.tif249170TIFF0007667225000335.tif247170TIFF0007667225000336.tif237170TIFF0007667225000337.tif221170TIFF0007667225000338.tif223170TIFF0007667225000339.tif223170TIFF0007667225000340.tif224170TIFF0007667225000341.tif220170TIFF0007667225000342.tif238170TIFF0007667225000343.tif220170TIFF0007667225000344.tif214170TIFF0007667225000345.tif202170TIFF0007667225000346.tif214170TIFF0007667225000347.tif192170TIFF0007667225000348.tif244170TIFF0007667225000349.tif246170TIFF0007667225000350.tif248170TIFF0007667225000351.tif246170TIFF0007667225000352.tif240170TIFF0007667225000353.tif238170TIFF0007667225000354.tif247170TIFF0007667225000355.tif244170TIFF0007667225000356.tif247170TIFF0007667225000357.tif242170TIFF0007667225000358.tif248170TIFF0007667225000359.ti f235170TIFF0007667225000360.tif235170TIFF0007667225000361.tif248170TIFF0007667225000362.tif236170TIFF0007667225000363.tif2 47170TIFF0007667225000364.tif244170TIFF0007667225000365.tif247170TIFF0007667225000366.tif249170TIFF0007667225000367.tif242 170TIFF0007667225000368.tif247170TIFF0007667225000369.tif249170TIFF0007667225000370.tif249170TIFF0007667225000371.tif35170.

[0400] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropylpyrrolidin-4-yl)- (Pyridin-2-yl)pyridin-2-yl)-2-methylpropanamide P116 [ka] 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(5-(6-(propanesulfonamido)pyrimidin-4-yl) (1-en-2-yl)pyrazin-2-yl)pyridin-2-yl)propanamide P122 (77 mg, 0.161 m A solution of 100 mol of HCl in MeOH / DCM (4:1, 10 mL) was added to an H-Cube flow hydrogenator (10% Pd / C, 30 × 4 mm, The crude product was purified by hydrogenation using full hydrogen at 25°C, 1 mL / min. The crude product was purified by silica gel (12 g column, 50 Purify by chromatography in 100% EtOAc / isohexane to obtain 2-(2-cyclopropanediol). sulfonamido)pyrimidin-4-yl)-N-(5-(6-isopropylpyrazin-2-yl)pyridine-2- (yl)-2-methylpropanamide (21 mg, 0.043 mmol, 27% yield) was obtained as a white solid. . Rt 2.22 min (HPLC acidic); m / z 482 (M+H) + (ES + ); [ka]

[0401] Biological Examples Biological Example 1 - Human CTPS1 Enzyme Inhibition The enzyme inhibitory activity of the invented compounds against targets of interest was assessed using the ADP-Glo™ Max assay (P The assay for human CTPS1 was performed using a 50 mM Tris, 10 mM Mg The assay was performed as appropriate in 1x assay buffer containing Cl2, 0.01% Tween-20, and pH 8.0. Immediately before use, L-cysteine ​​was added to the 1x assay buffer to a final concentration of 2 mM. All reagents were from Sigma-Aldrich unless otherwise stated. Human full-length active C-terminal FLAG -His8-tagged CTPS1 [ka] was obtained from Proteros biostructures GmbH.

[0402] Assay Procedure 3x human CTPS1 protein was prepared in 1x assay buffer to obtain the final concentration required for the reaction. A volume of 2 uL per well of 3x human CTPS1 protein was added to the wells to form a working protein concentration. 2 uL of 3x test compound per tube (prepared in 1x assay buffer for the appropriate final 3x compound) The compound concentrations measured correspond to the concentration-response curve designed for that compound in the experiment) and The enzyme reaction was then started with 2 uL of premixed substrate mix per well volume. ADP-Glo™ Maxkit UltraPure ATP (0.31 mM), GTP (0.034 mM), UTP (0.48 mM) and L The mixture was incubated at 25°C in a sealed plate at 500 rpm, starting with the addition of glutamine (0.186 mM). Under steady stirring at rpm, the reaction is carried out in the linear phase specified for the reaction. ADP-Glo™ Max reagent was added (1000 mg / well) over a 60 minute period. 6 μL per well), then ADP-Glo™ Max development was added over 60 minutes (1 μL per well). 2 uL), and then a microplate reader (EnVision® Multilabel Reader, Perkin The signal was detected by a chromatograph (Elmer). Following the addition of each reagent during the assay, the assay The plates were pulse centrifuged for 30 seconds at 500 rpm.

[0403] In all cases, the enzyme converts ATP to ADP, after which the ADP-Glo™ Max Reagent remains in the reaction. The ADP-Glo™ Max detection reagent was then enzymatically generated to deplete all endogenous ATP. The ADP is converted back to ATP, and ATP serves as a substrate along with luciferin for the enzyme luciferase. The luminescence signal measured is generated by the enzyme reaction. The signal is directly proportional to the amount of ADP produced, and the reduction of this signal by compound treatment indicates the activity of the enzyme. The percentage of inhibition caused by each compound concentration was calculated using the following equation: It was calculated using:

number

[0404] The percentage of inhibition was then plotted against compound concentration, and the concentration-response curve was used to determine the percentage of inhibition at 50%. Harmful concentration (IC 50 ) was decided. Data for all compounds of formula (I) tested are provided below.

[0405] Table 18: Human CTPS1 enzyme inhibition data grouped by effective range (± IC 50 >10-20 microphones indicates the range of the lomol, and + indicates the IC 50 indicates IC in the range of >1–10 micromolar, and ++ indicates IC 50 is >0.1 ~1 micromolar range, +++ indicates IC 50 indicates ≦0.1 micromolar. [Table 19] TIFF0007667225000377.tif127170

[0406] All compounds of the present invention that were tested were found to exhibit inhibition of the CTPS1 enzyme in this assay. Consequently, these compounds would be expected to be useful in inhibiting CTPS1. The compounds of the present invention are also expected to be useful as research tools, for example for use in CTPS assays. It will be.

[0407] Biological Example 2 - RapidFire / MS-based Enzyme Selectivity Assay (Evaluation of human CTPS1 vs. CTPS2 selectivity by rapid fire / MS analysis) The key objective was to optimize the enzyme inhibitory activity against each target isoform. A hot-fire high-throughput mass spectrometry (RF / MS) assay format was used to RF / MS assays for both human CTPS1 and CTPS2 can be performed at 50 The solution consisted of 20 mM HEPES (Merck), 20 mM MgCl2, 5 mM KCl, 1 mM DTT, and 0.01% Tween-20. The assay can be conveniently performed in an assay buffer at pH 8.0. -His-tagged CTPS1 [ka] is available from Proteros biostructures GmbH. Human full-length active C-terminal FLAG-His-Avi tagged CTPS2 [ka] can be obtained from HarkerBio.

[0408] Assay Procedure Human CTPS (1 or 2) protein was prepared in 1x assay buffer and used for the minimum reaction time. This can be used as the final working protein concentration. Add 2 uL of 2x CTPS (1 or 2) tank per well. Proteins were mixed with 40 nL of compound using acoustic (ECHO) dispensing and incubated for 10 min at 25°C. Each isoform enzyme reaction is then performed using 2 uL of 2 Add the substrate mix in assay buffer to start the assay. For hCTPS1: ATP (0.3 mM), UTP (0.2 mM), GTP (0.07 mM) and L-glutamine (0.1 mM). For hCTPS2: ATP (0.1 mM), UTP (0.0 4 mM), GTP (0.03 mM) and L-glutamine (0.1 mM). Each mixture was used for the reaction at 25°C. Incubate for the appropriate amount of time per isoform within the specified linear phase. Add 60uL of stop solution (1% formic acid and 0.5uM 13 C9- 15 N3-CTP (H2O solution) was added, and Immediately after, the plate can be heat sealed and centrifuged at 4,000 rpm for 10 minutes. Following separation, the plate was connected to an API 4000 triple quadrupole mass spectrometer (RF / MS) for analysis. The samples can be subjected to an Agilent RapidFire Microfluidic Solid Phase Extraction System.

[0409] In all cases, the enzyme converts UTP to CTP. Highly specific and sensitive multiple reaction detection (MRM) The MS method involves the analysis of enzyme reaction products, CTP, and stable isotope-labeled product standards. 13 C9- 15 N3-CTP The data analysis readouts can be optimized for the detection of the product CTP and the internal standard 13 C9- 15 For the recorded data, the following equation can be used: Available:

number

Claims

1. A compound of formula (I): 【Chemistry 1】 (In the formula, A is an amide linker having the structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2; Z is N or CR 3 ; However, if at least one of X or Z is N, then Y is not N; R 1 is C 1-5 alkyl 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; R3 is H, halo, CH3, OCH3, CF3 or OCF3; wherein at least one of R 2 and R 3 is H; R 4 and R 5 are each independently H, C 1-6 alkyl, C 1-6 alkylOH, C 1-6 haloalkyl, C 0-2 alkyleneC 3-6 cycloalkyl, C 0-2 alkyleneC 3-6 heterocycloalkyl, C 1-3 alkyleneOC 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 a C 3-6 heterocycloalkyl; and When A is -NHC(=O)-: R 4 and R 5 may additionally be selected from halo, OC 1-6 haloalkyl, OC 0-2 alkyleneC 3-6 cycloalkyl, OC 0-2 alkyleneC 3-6 heterocycloalkyl, OC 1-6 alkyl, and NR 21 R 22 ; Ar1 is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl ring attached to Ar1 in the para position relative to the amide; 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 at the ortho or meta position relative to Ar1 and R 12 is H, halo, C 1-4 alkyl, C 2-4 alkenyl, C 0-2 alkyleneC 3-5 cycloalkyl, OC 1-4 alkyl, OC 0-2 alkyleneC 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 additionally be selected from CN, OCH 2 CH 2 N(CH 3 ) 2 , and C 3-6 heterocycloalkyl containing one nitrogen atom located at the point of attachment to Ar2, or R 12 together with the nitrogen atom to which it is attached forms an N-oxide (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; R22 is H or CH3; R 23 is H or C 1-2 alkyl; and R 24 is H or C 1-2 alkyl. or a salt and / or solvate thereof, wherein the compound of formula (I) or a salt and / or solvate thereof is N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2-(ethylsulfonamido)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxamide: 【Chemistry 2】 or a salt and / or solvate thereof, which is not a compound of formula (I) or a salt and / or solvate thereof.

2. The compound, salt, and / or solvate thereof according to claim 1, wherein A is -C(=O)NH-.

3. The compound, salt, and / or solvate thereof according to claim 1, wherein A is -NHC(=O)-.

4. The compound according to claim 1, wherein X is N, Y is CR 2 , and Z is CR 3 , or a salt and / or solvate thereof.

5. The compound according to claim 1, wherein X is CH, Y is N, and Z is CR 3 , or a salt and / or solvate thereof.

6. The compound according to claim 1, wherein X is CH, Y is CR 2 , and Z is N, or a salt and / or solvate thereof.

7. The compound, salt, and / or solvate thereof according to any one of claims 1 to 6, wherein R 1 is C 1-5 alkyl.

8. The compound, salt, and / or solvate thereof according to any one of claims 1 to 7, wherein R 2 is H.

9. The compound, salt, and / or solvate thereof according to any one of claims 1 to 8, wherein R 3 is H.

10. The compound according to claim 1, wherein R 4 is selected from halo, C 1-6 alkyl, C 1-3 alkylene OC 1-3 alkyl, or OC 1-6 alkyl, or a salt and / or solvate thereof.

11. The compound, salt, and / or solvate thereof according to any one of claims 1 to 10, wherein R 5 is H, fluoro, methyl, or ethyl.

12. The compound according to claim 1, wherein R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclopentyl ring, or a salt thereof, and / or a solvate thereof.

13. 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 tetrahydropyranyl ring, a salt thereof, and / or a solvate thereof.

14. The compound, salt, and / or solvate thereof according to any one of claims 1 to 13, wherein Ar1 is phenyl or 2-pyridyl.

15. The compound, salt, and / or solvate thereof according to any one of claims 1 to 14, wherein Ar2 is 3-pyridyl or 2,5-pyrazinyl.

16. The compound, salt, and / or solvate thereof according to any one of claims 1 to 15, wherein R 10 is H, F, Cl, CH 3 , OCH 3 , OCF 3 , or CN.

17. The compound according to any one of claims 1 to 16, wherein R 11 is H or F, or a salt and / or solvate thereof.

18. A compound, salt, and / or solvate thereof according to any one of claims 1 to 17, wherein R 12 is H, F, Cl, CH 3 , methoxy, ethoxy, isopropoxy, OC 0 alkylene C 3 cycloalkyl, CN, CF 3 , OCHF 2 , or OCH 2 CF 3 , OC 0 alkylene C 3 cycloalkyl, CF 3 , OCHF 2 , or OCH 2 CF 3 .

19. The compound, salt, and / or solvate thereof according to any one of claims 1 to 18, wherein R 13 is H.

20. The compound, its salt, and / or solvate according to any one of claims 1 to 19, which is the compound or a pharma- ceutical acceptable salt and / or solvate thereof.

21. A medicamentally acceptable solvate according to claim 20.

22. A pharma- ceutical acceptable salt according to claim 20.

23. A compound described in any one of claims 1 to 20.

24. Use of a compound according to any one of claims 20 to 23, a pharma- ceutical acceptable salt, and / or a solvate thereof in the manufacture of a medicament.

25. Use of a compound according to any one of claims 20 to 23, a pharma- ceutical acceptable salt thereof, and / or a solvate thereof in the manufacture of a medicament for reducing T cell and / or B cell proliferation in a subject.

26. Use of a compound according to any one of claims 20 to 23, a pharma- ceutical acceptable salt thereof, and / or a solvate thereof in the manufacture of a medicament for the treatment or prevention of inflammatory skin diseases; acute and / or chronic GVHD; acute lymphoproliferative syndrome (ALPS); systemic lupus erythematosus, lupus nephritis or cutaneous lupus; transplantation, myasthenia gravis, multiple sclerosis, scleroderma / systemic sclerosis, or for promoting recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject.

27. Use of a compound according to any one of claims 20 to 23, a pharma- ceutical acceptable salt, and / or a solvate thereof, in the manufacture of a medicament for the treatment of cancer.

28. The use of claim 27, wherein the cancer is a blood cancer selected from the group consisting of acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet's syndrome, T-cell non-Hodgkin's lymphoma, T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma, hairy cell leukemia, Hodgkin's lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, myelodysplastic syndromes, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorder, and chronic lymphocytic leukemia.

29. The use of claim 27, wherein the cancer is a non-hematological cancer selected from the group consisting of bladder cancer, breast cancer, melanoma, neuroblastoma, malignant pleural mesothelioma, and sarcoma.

30. The use of any one of claims 24 to 29, wherein the pharmaceutical is for use in human subjects.

31. A pharmaceutical composition comprising a compound, a salt thereof, and / or a solvate thereof according to any one of claims 1 to 23.

32. The pharmaceutical composition of claim 31 for reducing T cell and / or B cell proliferation in a subject.

33. The pharmaceutical composition of claim 31 for the treatment or prevention of inflammatory skin diseases; acute and / or chronic GVHD; acute lymphoproliferative syndrome (ALPS); systemic lupus erythematosus, lupus nephritis or cutaneous lupus; transplantation, myasthenia gravis, multiple sclerosis, scleroderma / systemic sclerosis, or for promoting recovery from vascular injury or surgery in a subject and reducing morbidity and mortality associated with neointima and restenosis.

34. The pharmaceutical composition of claim 31 for the treatment of cancer.

35. The pharmaceutical composition of claim 34, wherein the cancer is a blood cancer selected from the group consisting of acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet's syndrome, T-cell non-Hodgkin's lymphoma, T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma, hairy cell leukemia, Hodgkin's lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, myelodysplastic syndromes, plasma cell myeloma, primary mediastinal large B-cell lymphoma, chronic myeloproliferative disorder, and chronic lymphocytic leukemia.

36. The pharmaceutical composition of claim 34, wherein the cancer is a non-hematological cancer selected from the group consisting of bladder cancer, breast cancer, melanoma, neuroblastoma, malignant pleural mesothelioma, and sarcoma.

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