Combination therapy for treating MPS1

Abstract

The present application relates to compounds of formula (I), and salts and solvates thereof, 1 , R 2 , R 3 , R 3’ , R 4 , R 4’ and R 5 as described herein), as well as methods for their preparation, pharmaceutical compositions containing them, and their use, optionally in combination with α-L-iduronidase, or an analog or variant thereof, e.g., laronidase, for treating and / or preventing MPS1. TIFF2023512281000349.tif3364

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to European Patent Application No. EP20382071.7, filed on 3 February 2020, which is incorporated herein by reference in its entirety.

[0002] Areas of disclosure This disclosure relates to the compounds of formulas (I) and (I'), and to the use of such compounds in combination with laronidase as appropriate in the treatment and / or prevention of conditions in patients that are related to the alteration of α-L-iduronidase (IDUA) activity, such as mucopolysaccharidosis 1 (MPS1), heart valve disease, polyostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), disease conditions related to lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders and developmental disorders. [Background technology]

[0003] Background of the Invention Lysosomal storage disease Each of the more than 70 known lysosomal storage disorders (LSDs) is characterized by a similar etiology: damage to lysosomal hydrolases. Generally, the activity of a single lysosomal hydrolase is reduced or completely lost, usually due to inheritance through autosomal recessive mutations. As a result, substrates of the damaged enzyme accumulate undigested within lysosomes, leading to severe disruption of cellular architecture and a variety of disease symptoms. Mucopolysaccharidosis

[0004] Mucopolysaccharidosis (MPS) is a group of rare genetic disorders classified as lysosomal storage disorders (LSD). MPS is characterized by a deficiency of lysosomal enzymes responsible for the normal breakdown of glycosaminoglycans (GAGs) or mucopolysaccharides. This enzyme deficiency leads to the progressive accumulation of GAGs in lysosomes and their excretion in urine, followed by the development of various physical and neurological symptoms (Noh, H. et al., J. Clin. Pharm. Ther. 39:215-224 (2014)). GAGs are long-chain, unbranched polysaccharides characterized by disaccharide repeat units, and in the body, they have been found to link to core proteins to form proteoglycans. Proteoglycans are primarily located in the extracellular matrix and on the cell surface, where they lubricate joints and contribute to structural integrity (generally, see Neufeld et al., 1995, *The Mucopolysaccharidoses*, *In: The Metabolic and Molecular Bases of Inherited Diseases*, Scriver et al., eds., McGraw-Hill, New York, 7). th See ed., pages 2465-2494). Dermatan sulfate and heparan sulfate are the two most common GAGs associated with MPS. Recently, heparan sulfate proteoglycans have been suggested to be involved in Alzheimer's disease and other amyloid-related disorders (van Horssen, J. et al., Lancet Neurology 2:482-492 (2003); Spillantini, MG et al., Acta Neuropathol. 97:585-594 (1999)).

[0005] Mucopolysaccharidosis is classified into seven types (I, II, III, IV, VI, VII, and IX) based on the enzymes affected. These types vary in their prevalence, clinical manifestations, and severity. Significant physical involvement affecting the heart, lungs, bones, joints, and gastrointestinal tract is seen in most types of MPS, and CNS dysfunction is present in MPS I, II, III, and VII. Noh, H. et al., J. Clin. Pharm. Ther. 39:215-224 (2014); Morishita, K. et al., Rheumatology 50:v19-v25 (2011).

[0006] MPS I (also known as MPS1) is caused by a deficiency of α-L-idulonidase (IDUA), which is necessary for the breakdown of GAGs, mainly heparan sulfate and dermatan sulfate (Parini, R. et al., Orphanet J. Rare Dis. 12:112 (2017)). Clinical manifestations of MPS I include a rough facial appearance, polyostosis, hepatosplenomegaly, cardiac disease, and respiratory failure. MPS is further classified into three clinical subtypes: Hurler syndrome (MPS IH, severe), Hurler-Scheie syndrome (MPS IH / S, moderate), and Scheie syndrome (MPS IS, attenuated; formerly known as MPS V) (Oussoren, E. et al., Mol. Gen. Metab. 109:377-381 (2013)). Within each phenotype, considerable heterogeneity and partial agreement can be found regarding symptoms and their severity. Early progressive neurological regression is a prominent feature of Hurler syndrome. If left untreated, premature death is common, followed by cardiac and respiratory failure. Noh, H. et al., J. Clin. Pharm. Ther. 39:215-224 (2014). Early recognition of the phenotype in patients with MPS I is essential for initiating the most appropriate treatment strategy in a timely manner (Oussoren, E. et al., Mol. Gen. Metab. 109:377-381 (2013)). Clinical diagnosis of MPS I is confirmed based on elevated levels of dermatan sulfate and heparan sulfate in urine, and deficiency of IDUA enzyme activity in leukocytes or fibroblasts (Oussoren, E. et al., Mol. Gen. Metab. 109:377-381 (2013)). Treatments for lysosomal storage disorders

[0007] Several approaches to treat LSD are being used or explored, including hematopoietic stem cell transplantation, gene therapy, and enzyme replacement therapy. Furthermore, researchers have identified several small molecules for single-use in the management of LSD. Other disease-specific approaches are also under consideration. HSCT

[0008] Hematopoietic stem cell transplantation (HSCT) is possible for MPS. While major challenges remain, such as finding a suitable donor and reducing morbidity and mortality associated with medical procedures, HSCT can modify the disease course in severe MPS I (Hurler syndrome) and MPS VI by providing a lifelong source of enzymes to rapidly reduce GAG ​​accumulation. Restoration of enzyme function and subsequent improvement of disease complications, such as joint mobility, vision, hearing, and cardiopulmonary function, can occur through the mutual correction of enzyme deficiencies by transplanted donor cells. In particular, HSCT has been shown to protect cognitive function and improve survival in patients with Hurler syndrome when performed before the age of two and before the onset of serious psychiatric involvement. (Noh, H. et al., J. Clin. Pharm. Ther. 39:215-224 (2014)). Clinical experience with HSCT in other MPS cases is very limited. Gene therapy

[0009] In patients with Fabry disease, it is considered feasible to replace the deficient enzyme using a recombinant retrovirus containing cDNA encoding α-Gal A for transfection of dermal fibroblasts obtained from Fabry disease patients (Medin JA et al., 1996, Correction in Trans for Fabry Disease: Expression, Secretion, and Uptake of α-Galactosidase A in Patient-Derived Cells Driven by a High-Titer Recombinant Retroviral Vector, Proc. Natl. Acad. Sci. USA 93, 7917-7922).

[0010] In vitro studies also suggest that gene therapy may be feasible in Pompe disease. Vectors have been developed from both recombinant retroviruses and recombinant adenoviruses (Zaretsky JZ et al., 1997, Retroviral Transfer of Acid α-Glucosidase cDNA to Enzyme-Deficient Myoblasts Results in Phenotypic Spread of the Genotypic Correction by Both Secretion and Fusion, Human Gene Therapy 8, 1555-1563; Pauly DF et al., 1998, Complete Correction of Acid α-Glucosidase Deficiency in Pompe Disease Fibroblasts in Vitro, and Lysosomally Targeted Expression in Neonatal Rat Cardiac and Skeletal Muscle, Gene Therapy 5, 473-480).

[0011] Furthermore, the introduction and expression of a normal α-L-iduronidase gene into autologous bone marrow via retroviral gene transfer has also been demonstrated in nonclinical studies of Hurler syndrome (Fairbairn et al., 1996, Long-Term in vitro Correction of α-L-Iduronidase Deficiency (Hurler Syndrome) in Human Bone Marrow, Proc. Natl. Acad. Sci. USA 93, 2025-2030). Enzyme replacement therapy

[0012] Currently, the most effective treatment for MPS is enzyme replacement therapy (ERT). Since the advent of ERT, the clinical status and quality of life of many patients have improved significantly. However, major challenges associated with ERT remain, including its high cost, the need for frequent administration, and the inability to prevent adverse effects on the disease skeletal structure and CNS. Noh, H. et al., J. Clin. Pharm. Ther. 39:215-224 (2014). Approved ERT is only available for MPS I, II, and VI. It is generally recognized that ERT should be offered to all patients with MPS I at diagnosis and continued until severe neurological impairment or any other condition that may affect the prognosis due to negligence develops.

[0013] Laronidase is a recombinant human α-L-idulonidase (rhIDUA) indicated for the treatment of MPS I. In a phase 3 trial, 45 patients (Hurler, 1; Hurler-Scheie, 37; Scheie, 7) with a mean age of 16 years (ranging from 6 to 43 years) were randomly assigned to receive either 0.58 mg / kg of laronidase or placebo weekly for 26 weeks. By 4 weeks, mean urinary GAG levels approached the normal range in the active treatment group. After 26 weeks, the active treatment group showed a significant improvement of 5–6% in forced vital capacity (FVC) compared to placebo (Noh, H. et al., J. Clin. Pharm. Ther. 39:215-224 (2014)). Recombinant IDUA (laronidase, Aldurazyme®) was developed as an intravenous ERT for the treatment of MPS I (see U.S. Patent No. 9,044,473), but since the enzyme does not cross the blood-brain barrier, laronidase is ineffective against cognitive decline in MPS I (Gugliani, R. et all, Orphanet J. Rare. Dis. 13:110 (2018)). To enable BBB transport, IDUA was reengineered as an IgG-IDUA fusion protein, in which case the IgG domain targets the BBB human insulin receptor, enabling the enzyme to be transported to the brain. Preliminary clinical studies of the fusion protein in MPS I have shown that, due to the dual targeting mechanism of this fusion protein, it is transported to both the CNS and peripheral organs (Gugliani, R. et all, Orphanet J. Rare. Dis. 13:110 (2018)). Small molecule therapy

[0014] Recently, various studies have been conducted using several small molecules to treat storage disorders. One class of molecules works by inhibiting the upstream production of lysosomal hydrolase substrates, thereby easing the input load on the deficient enzyme. This approach has been called "substrate depletion" therapy. An example of a molecule in this class is N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of ceramide-specific glucosyltransferase (i.e., glucosylceramide synthase), which catalyzes the first step in the synthesis of glycosphingolipids (GSLs). NB-DNJ has been tested in mouse models of Sandhoff disease (Jeyakumar et al., (1999), Proc. Natl. Acad. Sci. USA, (1996), 6388-6393), Tee-Sachs disease (Platt et al., (1997), Science 276, 428-431), and in humans with Gaucher disease (Cox et al., (2000), Lancet 355, 1481-1485), resulting in symptom improvement in each of these diseases. Various deoxynojirimycin (DNJ) derivatives have also been synthesized as research tools intended for selective inhibition of non-lysosomal glucosylceramidase at concentrations that do not affect glucosylceramide synthase and other enzymes (Overkleeft et al., (1998), J. Biol. Chem. 273, 26522-26527). Certain uses of DNJ-type glucosylceramide synthase inhibitors, either alone (International Publication No. 00 / 62780) or in combination with glycosphingolipid-degrading enzymes (International Publication No. 00 / 62779), are described.

[0015] Another example of molecular substrate depletion is aminoceramide-like small molecules developed to inhibit glucosylceramide synthase. Glucosylceramide synthase catalyzes the first glycosylation step in the synthesis of glucosylceramide-based glycosphingolipids. Glucosylceramide itself is a precursor to hundreds of different glycosphingolipids. Aminoceramide-like compounds have been developed for use in Fabry disease (Abe et al., 2000, J. Clin. Invest. 105, 1563-1571; Abe et al., 2000, Kidney Int'l 57, 446-454) and Gaucher disease (Shayman et al., 2000, Meth. Enzymol. 31, 373-387; U.S. Patent Nos. 5,916,911; 5,945,442; 5,952,370; 6,030,995; 6,040,332 and 6,051,598). Various aminoceramide-like analogs have been synthesized as improved inhibitors of glucosylceramide synthase (see, for example, Lee et al., 1999, J. Biol. Chem. 274, 14662-14669). Aminoglycosides such as gentamicin and G418 are small molecules that promote readthrough of immature stop codon mutations. These so-called stop mutation regulators have been used in Hurler cells to restore low levels of α-L-iduronidase activity (Keeling et al., 2001, Hum. Molec. Genet. 10, 291-299). They have also been developed for use in the treatment of individuals with cystic fibrosis who have stop mutations (U.S. Patent No. 5,840,702). The compound of formula (I) was surprisingly found to enable the stabilization of the IDUA enzyme against denaturation. Increasing the effective concentration of the IDUA enzyme, laronidase, can collectively enhance the effectiveness of current treatments for MPS1. [Prior art documents] [Patent Documents]

[0016] [License 1] International Publication No. 00 / 62780 [License 2] International Publication No. 00 / 62779 [License 3] U.S. Patent No. 5,916,911 [License 4] U.S. Patent No. 5,945,442 [Patent Document 5] U.S. Patent No. 5,952,370 [License 6] U.S. Patent No. 6,030,995 [License 7] U.S. Patent No. 6,040,332 [License 8] U.S. Patent No. 6,051,598 [License 9] U.S. Patent No. 5,840,702 [Non-licensed literature]

[0017] [Non-licensed Document 1] Noh, H. et al., J. Clin. Pharm. Ther. 39:215-224 (2014) [Non-licensed Document 2] Neufeld et al., 1995, The Mucopolysaccharidoses, In: The Metabolic and Molecular Bases of Inherited Diseases, Scriver et al., eds., McGraw-Hill, New York, 7th ed., pages 2465-2494 [Non-licensed Document 3] van Horssen, J. et al., Lancet Neurology 2:482-492 (2003) [Non-licensed Document 4] Spillantini, MG et al., Acta Neuropathol. 97:585-594 (1999)

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[0018] Brief summary of the invention This disclosure relates to the finding that the compounds represented by formulas (I) and (I') are capable of binding to wild-type and / or mutated IDUA and are therefore useful in treating or preventing in subjects conditions associated with altered α-L-idulonidase activity, e.g., MPS1, valvular heart disease, polyosynostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), disease conditions associated with lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders and developmental disorders.

[0019] In one embodiment, the present disclosure provides a method for treating or preventing a condition related to alteration of α-L-iduronidase activity in a patient in need thereof, comprising the step of administering, if necessary, an effective amount of a compound of formula (I) or formula (I') described herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with an effective amount of α-L-iduronidase, or an analog or variant thereof, such as laronidase. The compounds represented by formulas (I) and (I'), as well as their pharmaceutically acceptable salts and solvates, are collectively referred to herein as “Compounds of the Present Disclosure” (each individually referred to as “Compounds of the Present Disclosure”).

[0020] In another embodiment, the Disclosure provides a method for treating or prophylactically treating MPS1 in a patient in need, by administering, if necessary, an effective amount of the compound of the Disclosure in combination with an effective amount of α-L-iduronidase, or its analog or variant, such as laronidase.

[0021] In another aspect, the Disclosure provides a method for treating or preventing heart valve disease, polyosynostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), lipoprotein metabolism-related disease conditions (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders, or developmental disorders by administering, if necessary, an effective amount of the Compounds of the Disclosure in combination with an effective amount of α-L-iduronidase or its analog or variant, e.g., laronidase, to a patient in need thereof.

[0022] In one embodiment, the method described herein does not include the step of administering an effective amount of α-L-iduronidase, or its analog or variant, such as laronidase.

[0023] In other embodiments, the method described herein includes the step of administering an effective amount of the compound of the present disclosure in combination with an effective amount of laronidase. In some embodiments, an effective amount of the compound of the present disclosure and an effective amount of α-L-iduronidase, or its analog or variant, e.g., laronidase, are administered to the patient simultaneously. In some embodiments, an effective amount of the compound of the present disclosure and an effective amount of α-L-iduronidase, or its analog or variant, e.g., laronidase, are administered to the patient sequentially. In some embodiments, an effective amount of the compound of the present disclosure and an effective amount of α-L-iduronidase, or its analog or variant, e.g., laronidase, are administered to the patient in separate pharmaceutical compositions. In some embodiments, an effective amount of the compound of the present disclosure and an effective amount of laronidase are administered to the patient in a single pharmaceutical composition.

[0024] In another embodiment, the method described herein further comprises the step of administering at least one other therapeutic agent to a patient. In another embodiment, the therapeutic agent is an effective amount of a low molecular weight chaperone. In another embodiment, the low molecular weight chaperone competitively binds to an enzyme. In another embodiment, the low molecular weight chaperone is selected from the group consisting of iminoalditols, imino sugars, amino sugars, thiophenyl glycosides, glycosidases, sulfatases, glycosyltransferases, phosphatases, and peptidase inhibitors. In another embodiment, the low molecular weight chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol, and miglustat. In another embodiment, the low molecular weight chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), and ambroxol. In another embodiment, the low molecular weight chaperone is miglustat.

[0025] In another embodiment, the therapeutic agent is an effective amount of a substrate reducing agent for substrate reduction therapy. In yet another embodiment, the substrate reducing agent is miglustat.

[0026] Several compounds useful for the treatment or prevention described herein have not been previously reported. Accordingly, one aspect of this disclosure relates to novel compounds of formulas (I) and (I'), as well as their salts and solvates.

[0027] In another embodiment, the present disclosure provides compounds of formula (I'), as well as salts and solvates thereof.

[0028] In another embodiment, the present disclosure provides compounds of the present disclosure described herein for use in treating or preventing conditions in patients that are associated with alteration of α-L-iduronidase activity, in combination with α-L-iduronidase or its analogues or variants, such as laronidase, as necessary.

[0029] In another aspect, the Disclosure provides, as needed, compounds of the Disclosure described herein, in combination with an effective amount of α-L-iduronidase, or its analog or variant, e.g., laronidase, for use in patients in need of treatment or prevention of MPS1, valvular heart disease, polyosynostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), disease conditions related to lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders and developmental disorders.

[0030] In another aspect, the disclosure also relates to the use of the compounds of the disclosure described herein, in combination as necessary with α-L-iduronidase, or its analogues or variants, such as laronidase, for the treatment or prevention of conditions associated with alteration of α-L-iduronidase activity, such as MPS1, in patients who require it.

[0031] In another embodiment, the Disclosure provides a pharmaceutical composition comprising the compounds of the Disclosure described herein and at least one pharmaceutically acceptable excipient.

[0032] In another embodiment, the present disclosure provides compounds of the present disclosure described herein, in combination with α-L-iduronidase, or its analogues or variants, such as laronidase, as necessary, for use as pharmaceuticals.

[0033] In another aspect, the present disclosure provides the use of the compounds of the present disclosure as described herein in the preparation of a pharmacopoeia for the prevention or treatment of a condition related to the alteration of α-L-iduronidase activity, such as MPS1 described herein, in a patient in need thereof, the pharmacopoeia comprising, as necessary, an effective amount of α-L-iduronidase, or an analog or variant thereof, such as laronidase.

[0034] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure described herein, as described herein, and at least one pharmaceutically acceptable excipient, for use in the treatment or prevention of a condition related to alteration of α-L-iduronidase activity, such as MPS1 described herein, in a patient in need thereof. In some embodiments, the pharmaceutical composition comprises an effective amount of α-L-iduronidase, or an analog or variant thereof, such as laronidase.

[0035] In other embodiments, the Disclosure relates to a pharmaceutical composition comprising an effective amount of the Compound of the Disclosure, an effective amount of α-L-iduronidase, or an analog or variant thereof, such as laronidase, and a pharmaceutically acceptable excipient. In some embodiments, the Compound of the Disclosure is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the Compound of the Disclosure is a compound of formula (I') as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0036] In other embodiments, the Disclosure covers the compounds of the Disclosure and combinations comprising α-L-iduronidase, or its analogs or variants, such as laronidase. In some embodiments, the compounds of the Disclosure are compounds of formula (I) as described herein, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compounds of the Disclosure are compounds of formula (I') as described herein, or pharmaceutically acceptable salts or solvates thereof.

[0037] Other aspects and advantages of this disclosure will be readily apparent from the following detailed description of this disclosure. Embodiments and advantages of this disclosure will be recognized and achieved in particular by the elements and combinations pointed out in the appended claims.

[0038] It should be understood that neither the summary above nor the detailed description below are illustrative or descriptive, and do not limit the claimed disclosure. [Brief explanation of the drawing]

[0039] [Figure 1] Figure 1 is a line graph showing the thermal shift dose-response curve from a differential scanning fluorescence (DSF) assay for compound A (i.e., the compound from Example 8).

[0040] [Figure 2]Figure 2 is a line graph showing the results for compound A in an IDUA denaturation prevention assay using L-iduronic acid as a reference compound. The results indicate that compound A (30 μM) prevented IDUA denaturation.

[0041] [Figure 3] Figure 3 is a line graph showing the results for compound A in the IDUA inhibition assay. The results indicate that compound A does not inhibit IDUA.

[0042] [Figure 4A] Figures 4A-4E show the results of cell-based assays in fibroblasts for compound A. Figure 4A is a graph showing that co-administration of compound A (50 μM) promoted cellular uptake of IDUA (96 hours). Figure 4B is a line graph showing that the effect of compound A is dose-dependent (EC50 = 16 μM) (96 hours). Figure 4C is a graph showing that compound A is active across a panel of patient-derived fibroblasts (96 hours). Figure 4D is a graph showing that the effect of compound A in fibroblasts increases with longer incubation times. Figure 4E shows that compound A increases the amount of α-L-iduronidase in fibroblasts (96 hours). [Figure 4B] Same as above. [Figure 4C] Same as above. [Figure 4D] Same as above. [Figure 4E] Same as above.

[0043] [Figure 5] Figure 5 is a line graph showing that administration of compound A improves the pharmacokinetic profile of laronidase in mice.

[0044] [Figure 6] Figures 6A and 6B are graphs showing that co-administration of compound A with laronidase increases tissue exposure to laronidase in mouse bone marrow and articular cartilage, respectively.

[0045] [Figure 7] Figure 7 is a line graph showing the results of compounds from Examples 8, 40, 54, 39, and 72 in an IDUA denaturation prevention assay. The results show that, in addition to the compound from Example 8 (i.e., compound A), other exemplary compounds of the present disclosure prevent IDUA denaturation. [Modes for carrying out the invention]

[0046] Detailed description of the invention Current treatment for MPS1 is based on enzyme substitution therapy (ERT), in which an exogenous IDUA enzyme (laronidase) is administered intravenously once per week. As with other ERTs, the short half-life of the enzyme and the desensitization caused by its immunogenicity are limiting factors to its effectiveness. This results in low bioavailability, particularly in tissues with limited or no blood circulation, such as bone and cartilage, where treatment shows insufficient effectiveness. We have found that increasing the effective concentration of the IDUA enzyme laronidase can collectively increase the effectiveness of current treatments for MPS1. Combination therapy with pharmacological chaperones and ERTs can improve tissue uptake and reduce the immunogenicity of ERTs by stabilizing the enzyme in a properly folded and active form. We have found that certain compounds of this disclosure protect laronidase from pH-dependent denaturation and increase enzyme uptake by fibroblasts derived from MPS1 patients. The exemplary compounds described herein, when co-administered intravenously with laronidase in wild-type mice, were found to increase its plasma activity levels, peaking at 0.5 hours, and to prolong its enzymatic activity across multiple tissues, including bone and cartilage. These results open up novel therapeutic prospects for diseases involving hard-to-treat organs such as bone and cartilage tissue where unmet medical needs exist.

[0047] One aspect of the present disclosure is based on the use of the compounds of the present disclosure for binding to mutant IDUA. In view of this property, the compounds of the present disclosure are expected to be useful for treating or preventing conditions associated with altered IDUA activity in patients, such as MPS1.

[0048] Compounds of the present disclosure useful in this aspect of the present disclosure are compounds of formula (I):

Chemical formula

[0049] B is a fused benzene ring or a 5- or 6-membered fused heteroaromatic ring, and the benzene ring and the 5- or 6-membered heteroaromatic ring are optionally substituted,

[0050] R 1 is, -C 1~4 alkyl, -C 3~10 cycloalkyl, -C 1~4 alkyl-C 3~10 cycloalkyl, -C 6~10 aryl, -C 1~4 alkyl-C 6~10 aryl, (5- to 10-membered)-C 1~9 heteroaryl, -C 1~4 alkyl-(5- to 10-membered)-C 1~9 heteroaryl, (5- to 10-membered)-C 2~9 heterocyclyl and -C 1~4 alkyl-(5- to 10-membered)-C 2~9 heterocyclyl, and is selected from the group consisting of, and the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 alkyl (substituted optionally by one, two or three halogen atoms), optionally substituted C 6~10 aryl, optionally substituted (5- to 10-membered)-C1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring.

[0051] R 2 C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring.

[0052] R 3 , R 3’ , R 4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyl groups,

[0053] R 5 is hydrogen, C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring, or

[0054] R 1 and R 2 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or

[0055] R 1 and R 3 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or

[0056] R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or

[0057] R 2 and R 5These, together with the nitrogen atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, and the heterocyclic ring is condensed as necessary with a phenyl ring.

[0058] Ra is independently associated with hydrogen and -C. 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 (The heterocycline is a heterocycline, and the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.) That is the case.

[0059] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, where B is a fused benzene ring which is optionally substituted. In another embodiment, B is an unsubstituted fused benzene ring. In another embodiment, B is halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 A condensed benzene ring substituted with one or more substituents selected from the group consisting of cycloalkyls, wherein the aryl, heteroaryl, and heterocyclyl substituents are optionally condensed to a further (second) ring, and Ra is as defined above.

[0060] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, where B is a five-membered fused heteroaromatic ring which is optionally substituted. In another embodiment, B is an unsubstituted five-membered fused heteroaromatic ring. In another embodiment, B is halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 A five-membered condensed heteroaromatic ring substituted with one or two substituents independently selected from the group consisting of cycloalkyls, wherein the aryl, heteroaryl, and heterocyclyl substituents are optionally condensed to a further (second) ring, and Ra is as defined above. Preferred five-membered heteroaromatic rings include thiophenes, pyrazoles, imidazoles, and pyrroles, which may be unsubstituted or substituted as defined above.

[0061] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, where B is a six-membered fused heteroaromatic ring which is optionally substituted. In another embodiment, B is an unsubstituted six-membered fused heteroaromatic ring. In another embodiment, B is halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9Heteroaryl, -(5- to 10-membered)-C 2~9 Heterocyclyl and -C 3~10 A 6-membered fused heteroaromatic ring substituted with one, two or three substituents each independently selected from the group consisting of cycloalkyl, wherein said aryl, heteroaryl and heterocyclyl are optionally fused to a further (second) ring, and Ra is as defined above. Suitable 6-membered heteroaromatic rings include pyridine, pyrazine, pyrimidine and pyridazine, which may be unsubstituted or substituted as defined above.

[0062] In another embodiment of this aspect of the disclosure, the compounds of the disclosure are compounds of formula (I), and their pharmaceutically acceptable salts and solvates, wherein B is as follows

[0063] B1: [Chemical formula]

[0064] B2: [Chemical formula] and

[0065] B3: [Chemical formula] (wherein R 6 , R 7 , R 8 , R 9 and R 10 are hydrogen, halogen, hydroxy, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 alkyl (optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, CN, -ORa and -N(Ra)2), optionally substituted -C 6~10Aryl, optionally substituted-(5-membered to 10-membered)-C 1~9 Heteroaryl,-(5-membered to 10-membered)-C 2~9 Heterocyclyl and -C 3~10 Independently selected from the group consisting of cycloalkyl, said aryl, heteroaryl and heterocyclyl are optionally fused to a further (second) ring, and Ra is as described herein) Selected from the group consisting of.

[0067] In another embodiment of this aspect of the present disclosure, the compounds of the present disclosure are compounds of formula (I), and their pharmaceutically acceptable salts and solvates, and B is as follows

[0068] B4:

Chemical formula

[0069] B5:

Chemical formula

[0070] B6:

Chemical formula

[0071] In another embodiment of this aspect of the present disclosure, the compounds of the present disclosure are compounds of formula (I), and their pharmaceutically acceptable salts and solvates, and B is

Chemical formula

[0072] <e In another embodiment of this aspect of the present disclosure, the compounds of the present disclosure are compounds of formula (I), and their pharmaceutically acceptable salts and solvates, and B is

Chemical formula

[0073] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, where B is [ka] That is the case.

[0074] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, where B is [ka] That is the case.

[0075] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 1 is -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring.

[0076] R 3 , R 3’ , R 4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyl groups.

[0077] In some embodiments, the compounds of the present disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 1 is -C 1~4 Alkyl, -C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl, -phenyl, -C 1~4 Alkylphenyl, (5-membered or 6-membered)-C 1~5 Heteroaryl, -C 1~4 Alkyl-(5-membered or 6-membered)-C 1~5 Heteroaryl, (5-membered or 6-membered)-C 2~5 Heterocyclyl and -C 1~4 Alkyl-(5-membered or 6-membered)-C 2~5Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, phenyl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (as needed, substituted with 1, 2, or 3 halogen atoms), optionally substituted phenyl, optionally substituted (5-membered or 6-membered)-C 1~5 Heteroaryl and (5-membered or 6-membered)-C 2~5 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, phenyl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring.

[0078] In some embodiments, the compounds of the present disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 1 is -C 1~4 Alkyl, -C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Selected from the group consisting of cycloalkyl and -phenyl, the alkyl, cycloalkyl, alkylcycloalkyl and phenyl groups are halogen, hydroxy, -CN, -OH, -O(C 1~4 Alkyl), -SH, -S(C 1~4 Alkyl), -N(C 1~4 Alkyl)2 and -C 1~4 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups (which are optionally substituted with one, two, or three halogen atoms).

[0079] In some embodiments, the compounds of the present disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 1is -C 1~4 Alkyl and -C 3~6 Selected from the group consisting of cycloalkyls, wherein the alkyl and cycloalkyl are halogen, hydroxyl, -CN, -OH, -O(C 1~4 Alkyl), -SH, -S(C 1~4 Alkyl), -N(C 1~4 Alkyl)2 and -C 1~4 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups (which are optionally substituted with one, two, or three halogen atoms).

[0080] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 3 and R 4 is hydrogen, R 3’ and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyl groups.

[0081] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 3 , R 3’ , R 4 and R 4’ Each of them is hydrogen.

[0082] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 3 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 3’ , R 4 and R4’ This is as defined above.

[0083] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 3 , R 3’ and R 4’ This is as defined above.

[0084] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 3 , R 3’ and R 4’ Each of them is hydrogen.

[0085] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 2 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 3 , R 3’ , R 4 , R4’ and R 5 This is as defined above.

[0086] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 2 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 3 , R 3’ , R 4 and R 4’ Each of them is hydrogen, and R 5 This is as defined above.

[0087] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 2 C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring.

[0088] R 5 is hydrogen, C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9The rings are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl rings are optionally condensed to a further (second) ring.

[0089] In some embodiments, the compounds of the present disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 2 These are halogen, hydroxyl, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 A phenyl molecule optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl molecules are optionally condensed to a further (second) ring.

[0090] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 2 teeth, [ka] It is selected from the group consisting of the following.

[0091] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 5 is unsubstituted C 1~6 It is alkyl. In another embodiment, R 5 is unsubstituted C2~6 It is alkyl.

[0092] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 2 and R 5 These atoms, together with the nitrogen atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and one, two, or three of the carbon atoms of the heterocyclic ring are optionally replaced by heteroatoms selected from the group consisting of N, S, and O, and the heterocyclic ring is optionally condensed to a phenyl ring.

[0093] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, R 2 and R 5 Together with the nitrogen atom to which they are bonded, they form the following groups [ka] It forms.

[0094] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, where Ra is hydrogen or -C 1~4 It is an alkyl group (substituted as needed with one, two, or three fluorine atoms).

[0095] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I), as well as pharmaceutically acceptable salts and solvates thereof, where Ra is -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 It is a heterocycline, and the cycloalkyl or heterocycline group is optionally substituted with one, two, or three fluorine atoms.

[0096] In another embodiment, the compound of the present disclosure is a compound of formula (I'): [ka] as well as its pharmaceutically acceptable salts and solvates (in the formula,

[0097] B' is, B1': [ka] B2': [ka] and B3': [ka] A fused ring selected from the group consisting of,

[0098] R 1 is -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring.

[0099] R 2b is -C 3~5 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxyl, -CN, -ORa, -SRa, -N(Ra)2, and -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring.

[0100] R 3 , R 3’ , R 4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyl groups,

[0101] R 5b C 1~4 Alkyl, -C3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring, or

[0102] R 1 and R 2b These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or

[0103] R 1 and R 3These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or

[0104] R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or

[0105] R 2b and R 5b These, together with the nitrogen atom to which they are bonded, form halogens, hydroxyls, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (substituted as needed with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), -C 6~10 Ariel, -(5-10 members)-C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 A five- or six-membered heterocyclic ring is formed, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl groups, wherein one, two, or three carbon atoms of the heterocyclic ring are optionally replaced by heteroatoms selected from the group consisting of N, S, and O, and the heterocyclic ring is optionally condensed to a phenyl ring.

[0106] R 6’ , R 7’ and R 8’ These are hydrogen, halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring, provided that R 6’ , R 7’ and R 8’ The condition is that at least one of them is not hydrogen,

[0107] R 9’ and R 10’ These are halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring.

[0108] Ra is independently associated with hydrogen and -C. 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 (The heterocycline is a heterocycline, and the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.) That is the case.

[0109] In some embodiments, B' is B1' or B3', R 2b and R 5b However, when these atoms, together with the nitrogen atoms to which they are bonded, form a 5-membered or 6-membered heterocyclic ring, and one, two, or three of the carbon atoms in the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, then this heterocyclic ring is

[0110] 1) Halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (as needed, substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), -C 6~10 Ariel, -(5-10 members)-C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 It is substituted with at least one substituent selected from the group consisting of cycloalkyls (Ra is as defined above), or

[0111] 2) It is condensed on a phenyl ring,

[0112] However, the compound of formula (I') is [ka] This is conditional on the fact that it is not the case.

[0113] In some embodiments, R 1 and R 2b However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 5b is -C 3~10 Cycloalkyl, -C 6~10Ariel, (5-10 members) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxyl, -CN, -ORa, -SRa, -N(Ra)2, and -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 The compounds are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, aryl, heteroaryl, and heterocyclyl compounds are optionally condensed to a further (second) ring, provided that the compounds of formula (I') are [ka] This is conditional on the fact that it is not the case.

[0114] In some embodiments of this aspect of the Disclosure, the compounds of the Disclosure are the compounds of formula (I') defined above, as well as their pharmaceutically acceptable salts and solvates, B' and R 1 As defined above,

[0115] R 2b is -C 3~5 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxyl, -CN, -ORa, -SRa, -N(Ra)2, and -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring.

[0116] R 3 , R 3’ , R 4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyls, or

[0117] R 1 and R 3 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or

[0118] R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring, which is substituted as needed, and one, two, or three of the carbon atoms in the heterocyclic ring are replaced as needed by heteroatoms selected from the group consisting of N, S, and O.

[0119] R 5b C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring.

[0120] R 6’ , R 7’ and R 8’ These are hydrogen, halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring, provided that R 6’ , R7’ and R 8’ The condition is that at least one of them is not hydrogen,

[0121] R 9’ and R 10’ These are halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring.

[0122] Ra is independently associated with hydrogen and -C. 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 The material is a heterocycline, and the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.

[0123] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, where B' is B1': [ka] That is the case.

[0124] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, where B' is B2': [ka] That is the case.

[0125] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, where B' is B3': [ka] That is the case.

[0126] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, where B' is [ka] It is B3', selected from the group consisting of the following.

[0127] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, where B' is [ka] It is B3', selected from the group consisting of the following.

[0128] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 1 is -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring.

[0129] R 3 , R 3’ , R 4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyl groups.

[0130] In some embodiments, the compounds of the present disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 1 is -C 1~4 Alkyl, -C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Cycloalkyl, -phenyl, -C 1~4 Alkylphenyl, (5-membered or 6-membered)-C 1~5 Heteroaryl, -C 1~4 Alkyl-(5-membered or 6-membered)-C 1~5Heteroaryl, (5-membered or 6-membered)-C 2~5 Heterocyclyl and -C 1~4 Alkyl-(5-membered or 6-membered)-C 2~5 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, phenyl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (as needed, substituted with 1, 2, or 3 halogen atoms), optionally substituted phenyl, optionally substituted (5-membered or 6-membered)-C 1~5 Heteroaryl and (5-membered or 6-membered)-C 2~5 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, phenyl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring.

[0131] In some embodiments, the compounds of the present disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 1 is -C 1~4 Alkyl, -C 3~6 Cycloalkyl, -C 1~4 Alkyl-C 3~6 Selected from the group consisting of cycloalkyl and -phenyl, the alkyl, cycloalkyl, alkylcycloalkyl and phenyl groups are halogen, hydroxy, -CN, -OH, -O(C 1~4 Alkyl), -SH, -S(C 1~4 Alkyl), -N(C 1~4 Alkyl)2 and -C 1~4 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups (which are optionally substituted with one, two, or three halogen atoms).

[0132] In some embodiments, the compounds of the present disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 1 is -C 1~4 Alkyl and -C 3~6 Selected from the group consisting of cycloalkyls, wherein the alkyl and cycloalkyl are halogen, hydroxyl, -CN, -OH, -O(C 1~4 Alkyl), -SH, -S(C 1~4 Alkyl), -N(C 1~4 Alkyl)2 and -C 1~4 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl groups (which are optionally substituted with one, two, or three halogen atoms).

[0133] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 3 and R 4 is hydrogen, R 3’ and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyl groups.

[0134] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 3 , R 3’ , R 4 and R 4’ Each of them is hydrogen.

[0135] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 2bThese atoms, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring, which is substituted as needed, and one, two, or three of the carbon atoms in the heterocyclic ring are replaced as needed by heteroatoms selected from the group consisting of N, S, and O.

[0136] In some embodiments, the compounds of the present disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 2b These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 5b is -C 3~10 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxyl, -CN, -ORa, -SRa, -N(Ra)2, and -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 The compounds are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, aryl, heteroaryl, and heterocyclyl compounds are optionally condensed to a further (second) ring, provided that the compounds of formula (I') are [ka] This is conditional on the fact that it is not the case.

[0137] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 3 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 3’ , R 4 and R 4’ This is as defined above. In some embodiments, R 1 and R 3 These, together with the nitrogen atoms to which they are bonded, form a five-membered heterocyclic ring.

[0138] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 3 , R 3’ and R 4’ This is as defined above. In some embodiments, R 1 and R 4 These, together with the nitrogen atoms to which they are bonded, form a five-membered heterocyclic ring.

[0139] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 1 and R 4These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, R 3 , R 3’ and R 4’ Each of these is hydrogen. In some embodiments, R 1 and R 4 These, together with the nitrogen atoms to which they are bonded, form a five-membered heterocyclic ring.

[0140] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 2b is -C 3~5 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxyl, -CN, -ORa, -SRa, -N(Ra)2, and -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring.

[0141] R 5b C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 The rings are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl rings are optionally condensed to a further (second) ring.

[0142] In some embodiments, the compounds of the present disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 2b These are halogen, hydroxyl, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9A phenyl molecule optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl molecules are optionally condensed to a further (second) ring.

[0143] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 2b teeth, [ka] It is selected from the group consisting of the following.

[0144] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 5b is unsubstituted C 1~6 It is alkyl. In another embodiment, R 5b is unsubstituted C 2~6 It is alkyl.

[0145] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 2b and R 5b These, together with the nitrogen atom to which they are bonded, form halogens, hydroxyls, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (substituted as needed with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), -C 6~10 Ariel, -(5-10 members)-C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10A five- or six-membered heterocyclic ring is formed, optionally substituted by one, two, or three substituents independently selected from the group consisting of cycloalkyls, wherein one, two, or three carbon atoms of the heterocyclic ring are optionally replaced by heteroatoms selected from the group consisting of N, S, and O, and the heterocyclic ring is optionally fused to a phenyl ring, provided that B' is B1' or B3', the heterocyclic ring is as follows:

[0146] 1) Halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (as needed, substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), -C 6~10 Ariel, -(5-10 members)-C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 It is substituted with at least one substituent selected from the group consisting of cycloalkyls (Ra is as defined above), or

[0147] 2) Condensed to a phenyl ring On the condition that,

[0148] However, the compound of formula (I') is [ka] This is conditional on the fact that it is not the case.

[0149] In some embodiments, the compounds of the present disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 2b and R 5b Together with the nitrogen atom to which they are bonded, they form the following groups [ka] It forms.

[0150] In some embodiments, the compounds of the present disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, R 2b and R 5b Together with the nitrogen atom to which they are bonded, they form the following groups [ka] It forms.

[0151] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, where Ra is hydrogen or -C 1~4 It is an alkyl group (substituted as needed with one, two, or three fluorine atoms).

[0152] In another embodiment of this aspect of the Disclosure, the compounds of the Disclosure are compounds of formula (I'), as well as pharmaceutically acceptable salts and solvates thereof, where Ra is -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 It is a heterocycline, and the cycloalkyl or heterocycline group is optionally substituted with one, two, or three fluorine atoms.

[0153] In another embodiment, the compounds of the Disclosure that can be used in the methods of the Disclosure are [ka] This includes compounds of formula (I) selected from the group consisting of, as well as pharmaceutically acceptable salts and solvates thereof.

[0154] In another embodiment, the compounds of the Disclosure that can be used in the methods of the Disclosure are [ka] This includes compounds of formula (I) selected from the group consisting of, as well as pharmaceutically acceptable salts and solvates thereof.

[0155] In another embodiment, the compounds of the Disclosure that can be used in the methods of the Disclosure are [ka] This includes compounds of formula (I) selected from the group consisting of, as well as pharmaceutically acceptable salts and solvates thereof.

[0156] In another embodiment, the compounds of the present disclosure are [ka] [ka] The compound of formula (I'), selected from the group consisting of the following, as well as pharmaceutically acceptable salts and solvates thereof.

[0157] In another embodiment, the compounds of the present disclosure are [ka] [ka] The compound of formula (I'), selected from the group consisting of the following, as well as pharmaceutically acceptable salts and solvates thereof.

[0158] In another embodiment, the compounds of the present disclosure are [ka] [ka] [ka] The compound of formula (I'), selected from the group consisting of the following, as well as pharmaceutically acceptable salts and solvates thereof.

[0159] In another embodiment, the compounds of the present disclosure are [ka] The compound of formula (I'), selected from the group consisting of the following, and its pharmaceutically acceptable salts.

[0160] In some embodiments, the pharmaceutically acceptable salt of either one of the compounds of formula (I) and (I') is the hydrochloride salt (HCl salt).

[0161] As used herein, the term "halogen" or "halo" refers to -F, -Cl, -Br, or -I.

[0162] As used herein, the terms "hydroxyl" or "hydroxy" refer to the -OH group.

[0163] As used herein, the term “alkyl” means a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms that is unsaturated and bonded to the rest of the molecule by single bonds, and unless otherwise specified, alkyl radicals typically have 1 to 4 carbon atoms, i.e., C 1~4 It is alkyl. Exemplary C 1~4 The alkyl group can be methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, i-butyl, and sec-butyl. In another embodiment, the alkyl group is C 1~2 It is alkyl (methyl or ethyl).

[0164] As used herein, the term "C 1~4 "Alkoxy" refers to the above C 1~4 One of the alkyl groups, for example, C 1~2 This refers to oxygen atoms substituted with one alkyl group (e.g., methoxy, ethoxy, propoxy, iso-propoxy, butoxy, tert-butoxy, iso-butoxy, and sec-butoxy).

[0165] As used herein, the term “cycloalkyl” encompasses saturated carbocyclic radicals, and unless otherwise specified, cycloalkyl radicals typically have 3 to 6 carbon atoms. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. For example, cycloalkyls are cyclopropyl, cyclopentyl, and cyclohexyl. In another embodiment, the cycloalkyl is C 3~10 It is a cycloalkyl group.

[0166] As used herein, the term “alkylcycloalkyl” means, when used in the definition of a substituent, a cycloalkyl group as defined above, C 1~4 This refers to a cycloalkyl group that is linked to the core structure it substitutes for via an alkylene radical, such as an alkylene. For example, a cyclopentylethyl substituent is a substituent consisting of a cyclopentyl group linked to the core structure it substitutes for via an ethylene group.

[0167] As used herein, the terms “heterocyclyl” or “heterocyclic group” typically refer to monocyclic or polycyclic, non-aromatic, saturated or unsaturated carbon atoms such as 5- to 10-membered radicals. 2~10 It includes a carbocyclic ring in which one or more carbon atoms, for example, one, two, three, or four carbon atoms, for example, one or two carbon atoms, are replaced by heteroatoms selected from N, O, and S. In one embodiment, the heterocyclyl is C 3~7 A heterocyclyl is a heterocycle having 3 to 7 carbon atoms and at least one heteroatom. In another embodiment, the heterocyclyl is (5-10 membered)-C 2~9 A heterocycline is a heterocycle having 5 to 10 members, of which 2 to 9 members are carbon. In another embodiment, the heteroatom is nitrogen. In yet another embodiment, the heteroatom is oxygen.

[0168] In another embodiment, the heterocyclyl radical is saturated. The heterocyclic radical can be a monocyclic, bicyclic, or more fused rings, with at least one ring containing a heteroatom. If the heterocyclyl radical has one or more substituents, these substituents can be identical or different.

[0169] The heterocyclyls, which are substituted as needed, are typically substituted with one, two, or three substituents, which may be unsubstituted, identical, or different. Examples of heterocyclic radicals include piperidyl, pyrrolidyl, pyrrolinil, piperazinyl, morpholinil, thiomorpholinil, pyrazolinil, pyrazolidinil, quinuclidinyl, tetrazolyl, chromanil, isochromanil, imidazolidinyl, oxylanil, azalidinil, 4,5-dihydro-oxazolyl, and 3-aza-tetrahydrofuranil. The substituents are selected from, for example, halogen atoms, such as fluorine or chlorine atoms, hydroxyl groups, and alkoxycarbonyl groups, in which case the alkyl group consists of 1 to 4 carbon atoms, a hydroxycarbonyl group, a carbamoyl group, a nitro group, a cyano group, and C 1~4 Alkyl group (substituted as necessary with one or more halogen atoms), C 1~4 Alkoxy groups (which may be substituted as needed with one or more halogen atoms), and C 1~4 It contains a hydroxyalkyl group.

[0170] As used herein, the term “alkyl heterocyclyl” means, when used in the definition of substituents, a heterocyclyl group as defined above, which is linked to the core structure it substitutes via an alkylene radical. In one embodiment, the alkyl heterocyclyl is -C 1~4 Alkyl-(5-10 member)-C 2~9 It is a heterocycline.

[0171] As used herein, the term “aryl” usually refers to C such as phenyl and naphthyl.6~10 Represents a monocyclic or polycyclic aryl radical. In another embodiment, the aryl is phenyl. The optionally substituted aryl radical is typically substituted with one, two, or three substituents, which may be unsubstituted, identical, or different. The substituents are selected from, for example, halogen atoms, such as fluorine or chlorine atoms, hydroxyl groups, or alkoxycarbonyl groups, in which case the alkyl moiety consists of 1 to 4 carbon atoms, a hydroxycarbonyl group, a carbamoyl group, a nitro group, a cyano group, or C 1~4 Alkyl group (substituted as necessary with one or more halogen atoms), C 1~4 Alkoxy groups (which may be substituted as needed with one or more halogen atoms), and C 1~4 It has a hydroxyalkyl group. If the aryl aryl has two or more substituents, the substituents may be identical or different. Unless otherwise specified, substituents on the aryl group are usually unsubstituted themselves.

[0172] As used herein, the term “alkylaryl” means, when used in the definition of a substituent, an aryl group as defined above, C 1~4 This refers to an aryl group that is linked to the core structure it substitutes for via an alkylene radical, such as an alkylene.

[0173] As used herein, the term “heteroaryl” typically refers to a 5- to 10-membered ring system comprising at least one heteroaromatic ring and at least one heteroatom selected from O, S, and N, typically containing one, two, three, or four heteroatoms.

[0174] A heteroaryl group can contain a monocyclic, bicyclic, or more fused rings, in which case at least one ring contains a heteroatom. The optionally substituted heteroaryl group is usually substituted with one, two, or three substituents, which may be unsubstituted, identical, or different. The substituents are selected from, for example, halogen atoms, such as fluorine, chlorine, or bromine atoms, or alkoxycarbonyl groups, in which case the alkyl moiety consists of 1 to 4 carbon atoms, a carbamoyl group, a nitro group, a hydroxyl group, or C 1~4 Alkyl groups (which may be substituted as needed with one or more halogen atoms), and C 1~4 They have an alkoxy group (which may be substituted as needed with one or more halogen atoms). If a heteroaryl radical has two or more substituents, the substituents may be identical or different. Unless otherwise specified, substituents on a heteroaryl radical are usually unsubstituted themselves.

[0175] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, furyl, tetrazolyl, benzofuranil, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridinyl, benzothiazolyl, indolyl, indazolyl, prinyl, quinolyl, isoquinolyl, phthalazinyl, na This includes ftilidinyl, quinoxalinyl, quinazolinyl, quinolidinyl, sinnolinyl, triazolyl, indolidinyl, indolinyl, isoindolinyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, and various pyrrolopyridyl radicals.

[0176] In another embodiment, the heteroaryl is (5-membered to 10-membered)-C 2~9It is a heteroaryl. In another embodiment, the heteroaryl is halogen, hydroxyl, -CN, -ORb, -SRb, -N(Rb)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 The rings are optionally substituted with one, two, or three groups independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl rings are optionally condensed to a further (second) ring.

[0177] Where the heteroaryl radicals or the remainder as substituted as necessary within this disclosure refer to those containing an N atom, it is intended to include N-oxides that can be obtained from these radicals.

[0178] As used herein, the term “alkylheteroaryl” means, when used in the definition of substituents, a heteroaryl group as defined above, which is linked to the core structure it substitutes via an alkylene radical. In another embodiment, the alkylheteroaryl is -C 1~4 Alkyl-(5-10 member)-C 1~9 It is a heteroaryl compound.

[0179] As used herein, the term “alkenyl heteroaryl,” when used in the definition of substituents, refers to a heteroaryl group as defined above, which is linked to the core structure it substitutes for via an alkenylene radical. In another embodiment, the alkenyl heteroaryl is -C 2~4 Alkenil-(5-10 members)-C 1~9 It is a heteroaryl compound.

[0180] The term "pharmaceutically acceptable" means compositions and molecular entities that are physiologically tolerable and, when administered to humans or animals, do not typically cause allergic reactions or similar adverse reactions such as stomach upset, dizziness, and those of such kinds. For example, the term "pharmaceutically acceptable" means that it is approved by a state or central government regulatory agency or is included in the United States Pharmacopeia or any other generally recognized pharmacopoeia for use in animals, or more specifically, in humans.

[0181] The term “treatment” or “to treat” refers to administering a treatment in an effective amount, method, or form to improve a condition, symptom, or parameter related to the condition, or to prevent the progression of the condition to either a statistically significant extent or a level detectable by a person skilled in the art. The effective amount, method, or form may vary depending on the subject and may be adjusted to suit the individual patient.

[0182] The “effective” amount or “therapeutic effective amount” of a drug or pharmacological agent means a sufficient amount of the drug or agent that is non-toxic but produces the desired effect. The “effective” amount can vary from subject to subject, depending on the individual’s age and general condition, the specific agent or agent, etc. Therefore, it is not always possible to specify an exact “effective amount.” However, in any given case, an appropriate “effective” amount can be determined by a person skilled in the art using standard experiments.

[0183] The term "prevention" or "prevention" refers to reducing the risk of acquiring or developing a given disease or disability, or reducing or inhibiting recurrence or the disease or disability.

[0184] The term "patient," as used herein, refers to a human being. In some embodiments, the patient is an adult. In some embodiments, the patient is an elderly patient. In some embodiments, the patient is a child. In some embodiments, the patient is an infant. In some embodiments, the patient is a toddler. In some embodiments, the patient is pre-adolescent. In some embodiments, the patient is a young adult.

[0185] As used herein, the term “child” refers to a human being between birth and adolescence.

[0186] The term "puberty" refers to a physical change that occurs as a child's body matures into an adult body capable of sexual reproduction. On average, puberty begins in girls around 10-11 years old and ends around 15-17 years old. In boys, puberty begins around 11-12 years old and ends around 16-17 years old.

[0187] As used herein, the term "infant" is synonymous with "baby" and refers to a very young human child. The term "infant" usually refers to a young child under one year of age.

[0188] As used herein, the term “toddler” refers to a child between 12 and 36 months of age.

[0189] As used herein, the term “pre-adolescent” refers to a person between the ages of 10 and 13.

[0190] As used herein, the term “youth” refers to a person between the ages of 10 and 19.

[0191] When used herein in relation to a measured quantity, the term "about" refers to the normal variation in such a measured quantity that can be predicted by a person skilled in the art who performs the measurement and exercises a level of care appropriate to the purpose of the measurement and the accuracy of the measuring instrument. Typically, the term "about" includes a citation of ±10%. Thus, "about 10" means 9 to 11.

[0192] As used herein, the term “substituted as necessary” means a group that may be unsubstituted or may be substituted.

[0193] The term "solvate" means any form of the active compound of this disclosure having another molecule (e.g., a polar solvent such as water or ethanol, a cyclodextrin, or a dendrimer) bonded to it via a non-covalent bond. Methods of solvation are known in the art.

[0194] This disclosure also provides salts of the compounds of this disclosure. Non-limiting examples include sulfates, hydrohalides, phosphates, lower alkanesulfons, arylsulfons, one or more double bonds, aryl nuclei, or other functional groups such as hydroxy, amino, or keto. 1~20 Salts of aliphatic monobasic, dibasic, or tribasic acids, and salts of aromatic acids, wherein the aromatic nucleus may or may not be substituted with groups such as hydroxyl, lower alkoxyl, amino, lower monoalkyl, or dialkylaminosulfonamide. Similarly, within the scope of this disclosure are quaternary salts of tertiary nitrogen atoms with lower alkyl halides or alkyl sulfate esters, and oxygenated derivatives of tertiary nitrogen atoms such as N-oxides. When preparing dosage formulations, those skilled in the art will select pharmaceutically acceptable salts.

[0195] Solvates and salts can be prepared by methods known in the current art. It should be noted that pharmaceutically unacceptable solvates may be useful in preparing pharmaceutically acceptable salts and solvates, and therefore still fall within the scope of this disclosure.

[0196] The compounds of this disclosure also include compounds that differ only in the presence of one or more isotope-rich atoms. For example, the substitution of hydrogen with deuterium or tritium, or carbon 11 C, 13 C or 14 Replacement with carbon-rich carbon, or nitrogen15 Except for substitution with nitrogen-rich nitrogen, compounds having this structure are within the scope of this disclosure.

[0197] Some of the compounds disclosed herein may contain one or more chiral centers, and thus other stereoisomers such as enantiomers, diastereomers, and epimers may arise. This disclosure is intended to encompass all such possible forms, as well as their racemic and divided forms, and mixtures thereof. Individual enantiomers may be separated in view of this disclosure and according to methods known to those skilled in the art. Where a compound described herein contains an olefinic double bond or other centers of geometric chirality, and unless otherwise specified, this compound is intended to include both E and Z geometric isomers. All tautomers are also intended to be encompassed by this disclosure.

[0198] As used herein, the term “stereoisomer” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This includes non-mirror images (diastereomers), enantiomers, and isomers of compounds having more than one chiral center.

[0199] The term "chiral center" refers to a carbon atom to which four different groups are bonded.

[0200] The term "epimer" refers to a diastereomer in which only one of the two or more tetrahedral stereogenic centers present in an individual molecular entity has an opposite stereoconfiguration.

[0201] The term "stereogenic center" refers to an atom that has a group that, when any two of these groups are exchanged, results in a stereoisomer.

[0202] The terms "enantiomer" and "enantiomer" refer to molecules that cannot be superimposed onto each other as mirror images, and are therefore optically active. In this case, enantiomers rotate the plane of polarization in one direction, while their mirror image compounds rotate the plane of polarization in the opposite direction.

[0203] The term "racemic" refers to a mixture of enantiomers of equivalent parts, and this mixture is optically inert.

[0204] The term "splitting" refers to the separation, concentration, or removal of one of two enantiomers of a molecule.

[0205] The terms "a" and "an" refer to one or more items.

[0206] Some reactions for preparing the compounds of this disclosure involve the use of amino protecting groups. As used herein, “amine protecting group” or “amino protecting group” refers to a group that blocks (i.e., protects) amine functionality while the reaction is taking place on other functional groups or parts of the molecule. Those skilled in the art are familiar with the selection, bonding, and cleavage of amine protecting groups and recognize that a large number of different protecting groups are known in the art, and which protecting group is preferred depends on the specific synthetic scheme planned. Reference books on this subject are available, such as Wuts, PGM & Greene, TW, Greene's Protective Groups in Organic Synthesis, 4th Ed. (J. Wiley & Sons, 2007), which is incorporated herein by reference in its entirety. Suitable amine protecting groups include methyl carbamate, tert-butyloxycarbonyl (tert-butylcarbamate; BOC), 9-fluorenyl methyl carbamate, benzyl carbamate, 2-(trimethylsilyl)ethyl carbamate, trifluoroacetamide, benzylamine, allylamine, tritylamine, trichloroacetyl, trifluoroacetyl, p-toluenesulfonyl, and allyl carbamate. In another embodiment, the protecting amino group may be a phthalimide-protected amino group (NPhth).

[0207] The terms “parallel administration,” “combined administration,” “simultaneous administration,” and similar phrases mean administering two or more drugs in parallel to the subject being treated. “Parallel” means that each drug is administered either simultaneously or sequentially at different time points in any order. However, if they are not administered simultaneously, it means they can act synergistically by being administered to the individual consecutively and sufficiently close together to achieve the desired therapeutic effect. For example, the compounds and IDUAs (such as laronidase) of this disclosure can be administered at the same time or sequentially at different time points in any order. The compounds and IDUAs of this disclosure can each be administered individually in any suitable form and by any preferred route, for example, by SC and IV injection. If the compounds and IDUAs of this disclosure are not administered in parallel, it is understood that they can be administered in any order to the subject requiring them. For example, the compounds of this disclosure may be administered before IDUA (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week or less), concurrently with IDUA, or after IDUA (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week or less). In various embodiments, the compounds of the Disclosure and IDUA are administered at intervals of 1 minute, 10 minutes, 30 minutes, less than 1 hour, about 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, 11 to 12 hours, 24 hours or less, 48 ​​hours or less, 3 days or less, or 1 week or less. In one embodiment, the compounds of the Disclosure are administered 1 to 14 days before IDUA is administered.In one embodiment, the compound of the Disclosure is administered 1 to 7 days before the administration of IDUA. In another embodiment, the IDUA is administered on the same day as the administration of the compound of the Disclosure.

[0208] As used herein, the terms “enzyme replacement therapy” or “ERT” refer to the administration of exogenously produced natural or recombinant enzymes, or analogs thereof, to patients in need. In the case of lysosomal storage disorders (i.e., MPS1), for example, patients accumulate harmful levels of substrates (i.e., stored substances) in lysosomes due to a deficiency or absence of enzymes responsible for substrate metabolism, or a deficiency of enzyme activators necessary for proper enzymatic function. Enzyme replacement therapy results in a reduction (i.e., weight loss) of the levels of substrates accumulated in the affected tissue. Enzyme replacement therapy for treating MPS1 is known in the art. According to the combination therapy of this disclosure, in patients with MPS1, lysosomal enzymes, such as α-L-iduronidase (IDUA, laronidase) or its analogs or variants, can be used in enzyme replacement therapy to reduce the level of the corresponding substrate, i.e., α-L-iduronic acid.

[0209] Izuronidase (EC3.2.1.76, L-iduronidase, alpha-L-iduronidase, laronidase), marketed as ALDURAZYME®, is an enzyme with the systematic name glycosaminoglycan alpha-L-iduronohydrolase. This enzyme catalyzes the hydrolysis of unsulfated alpha-L-iduronoside linkages in dermatan sulfate. It is a glycoprotein enzyme found in cellular lysosomes. It is involved in the denaturation of glycosaminoglycans such as dermatan sulfate and heparan sulfate. This enzyme acts by hydrolyzing the terminal alpha-L-iduronic acid residues of these molecules, thereby breaking them down. The protein has been reported to have a mass of approximately 83 kilodaltons. ALDURAZYME® can be administered once weekly by intravenous infusion at a dose of 0.58 mg per kg of body weight.

[0210] As used herein, the term “substrate reduction therapy” or “SRT” refers to a therapeutic approach used to treat certain metabolic disorders, such as lysosomal storage disorders, in which the accumulation of substrates, such as glycolipids, is attenuated not by replacing the deficient enzyme, but by reducing the substrate level to a good balance with the residual activity of the deficient enzyme. See, for example, Coutinho et al., Int. J. Mol. Sci. 17:1065 (2016). Substrate reduction therapy and enzyme substitution therapy (see above) may have unique, independent, and potentially complementary mechanisms of action in the treatment of lysosomal storage disorders and other diseases.

[0211] The general principle of SRT is that a substrate reducing agent is administered to the patient to partially inhibit the biosynthesis of the substrate, which accumulates in the absence of specific lysosomal enzymes. As used herein, the term “substrate reducing agent” refers to a small molecule that reduces the number of substrate molecules requiring catabolism within the lysosome, thus contributing to a balance between the rate of synthesis and the rate of impaired catabolism. Substrate reducing agents are well known in the art.

[0212] As used herein, “effective dose” of enzyme means an amount sufficient to improve the clinical course of a lysosomal storage disorder (e.g., MPS1) when administered to a subject in the combination therapy of this disclosure, in which case the clinical improvement is measured by any of the various parameters well known to those skilled in the art.

[0213] As used herein, the term “low molecular weight chaperone” refers to compounds other than those described herein that can allosterically or competitively bind to a mutant enzyme, such as α-L-idulonidase, thereby stabilizing the enzyme from degradation. In some embodiments, the low molecular weight chaperone facilitates the proper folding of the enzyme and its transport to its site of action. Low molecular weight chaperones for treating lysosomal storage disorders are known in the art; see, for example, US2016 / 0207933(A1) and WO2011 / 049737(A1).

[0214] As used herein, the term “solid tumor” refers to a solid tumor caused by abnormal cell signaling of HS-dependent growth factors or by morphogens that increase tumor growth and associated angiogenesis.

[0215] As used herein, the term “infectious disease” refers to a disease selected from the group consisting of, for example, HIV, herpes simplex virus, and human papillomavirus. Various viral docking proteins, including pseudorabies virus gC protein, herpes simplex virus gC and gD proteins, P. falciparum erythrocyte membrane protein 1 (PfEMP1), human papillomavirus L1 capsid protein, and HIV-1 transactivator Tat, utilize HS proteoglycans on the host cell surface as receptors or co-receptors.

[0216] As used herein, “inflammatory disorder” refers to a disorder or condition in which HS protein interactions support several steps of the inflammatory process. Vascular endothelial HS acts as a ligand for L-selectin during neutrophil rolling, supporting chemokine transcytosis and preventing chemokines from reaching the luminal surface of the endothelium. Synthesis of the Compounds Disclosed

[0217] Another aspect of this disclosure refers to procedures for obtaining compounds of formula (I) and formula (I'). The following methods describe procedures for obtaining compounds of general formulas (I) and (I'), or their solvates or salts.

[0218] Various synthetic routes for synthesizing the compounds of formula (I) and formula (I') are summarized in the following scheme.

[0219] Scheme 1 illustrates a synthetic route for obtaining compounds of formulas (I) and (I'). Scheme 1 [ka]

[0220] (In the formula, B, R 1 , R 2 , R 3 , R 3’、 R 4 , R 4’ and R 5 (This is as defined above with respect to equation (I)).

[0221] Method 1

[0222] Step 1 (Reaction A)

[0223] In the first method of this disclosure, as illustrated in reaction A of the scheme above (Scheme 1), B can be converted from a compound of formula (II) as defined above to a compound of formula (III) according to this disclosure.

[0224] Subsequently, the cyano group of the compound of formula (II) is reduced to a suitable aldehyde group under standard reducing conditions, for example, at about -78°C, room temperature, reflux, or microwave irradiation, in the presence of a suitable reducing agent or catalyst (e.g., diisobutylaluminum hydride, sodium hypophosphite, lithium aluminum hydride, nickel, aluminum oxide, platinum oxide), a suitable solvent (e.g., dichloromethane, tetrahydrofuran, ether, methanol, ethanol, water, or mixtures thereof), and at room temperature, reflux, or microwave irradiation. This reaction can also be carried out in the presence of an acid or base such as acetic acid (e.g., pyridine), or under a hydrogen atmosphere.

[0225] Step 2 (Reaction B)

[0226] In the first method of this disclosure, as illustrated in reaction B of the scheme (Scheme 1) above, the compound of formula (IV) (where X may be -OPG or a halogen, PG is a protecting group, and R 3 The compound of formula (V) according to this disclosure is obtained by reacting the compound (as defined above) with a (Z)-3-aminoacrylamide source.

[0227] Reaction B is carried out under standard condensation conditions, for example, in the presence of an activator (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) and hydroxybenzotriazole (HOBt) or pentafluorophenol (PFP) and N,N'-diisopropylcarbodiimide (DIC)), in the presence of diethylaminopyridine (DMAP) or (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), preferably in the presence of a base such as N-methylmorpholine (NMM) or N,N'-diisopropylethylamine (diidopropylethylamine) (DIEA), in a suitable solvent (e.g., dichloromethane, chloroform, dimethylformamide or a mixture thereof), and at, for example, approximately room temperature or reflux temperature.

[0228] The compound of formula (IV) is commercially available or can be obtained by procedures described in literature known to those skilled in the art.

[0229] This reaction can be carried out using existing protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999).

[0230] Step 3 (Reaction C)

[0231] In the first method according to this disclosure, as illustrated in reaction C of the scheme (Scheme 1) above, the compounds of formula (V) (B and R 3 As defined above, X can be a variety of leaving groups or leaving group precursors, and PG is a protecting group) and amine(VI)(R 1 , R 2 , R 4 and R 5 The compound of formula (I) according to this disclosure is obtained by reacting with (as defined above).

[0232] The X group of the compound of formula (V) can be converted to a leaving group by a standard method. For example, a hydroxyl group can be deprotected by a standard method and subsequently converted to a leaving group such as a halogen, triflate, tosylate, or mesylate group.

[0233] As illustrated in reaction C of the scheme above (Scheme 1), the leaving group of the compound of formula (V) is converted to the corresponding amine group by reaction with amine (VI) to obtain the compound of formula (I) according to this disclosure. Reaction C is carried out under standard nucleophilic substitution conditions in the presence of a suitable base (e.g., N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, triethylamine, pyridine, ammonium chloride, sodium hydride, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, or sodium nitrite) and a suitable solvent (e.g., acetonitrile, dichloromethane, tetrahydrofuran, benzene, diethyl ether, toluene, dimethylformamide, water, ethanol, or a mixture thereof). In such a reaction, a base or acid such as acetic acid, hydrogen chloride, or sodium hydroxide may be used in a further step.

[0234] This reaction mixture is stirred or heated at low or room temperature until the starting materials are consumed. The reaction can be carried out using any existing protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999). Scheme 2 [ka]

[0235] B and R 3 and R 3’This is as defined above with respect to equation (I).

[0236] Method 2

[0237] Step 5 (Reaction A)

[0238] In the second method of this disclosure, as illustrated in reaction A of the scheme (Scheme 2) above, the compound (R) of formula (IX) is used. 3 A compound of formula (X) according to this disclosure is obtained by reacting (Z)-3-aminoacrylic acid source (where Y is a small alkyl group (VIII)) with a (Z)-3-aminoacrylic acid source.

[0239] The ester group of compound (VIII) can be hydrolyzed to a carboxylic acid group according to the following standard method, and then this acid can be hydrolyzed under standard condensation or amide coupling conditions with a suitable coupling agent (e.g., 1,1'-carbonyldiimidazole, N,N'-cyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or its hydrochloride), N,N'-disuccinimidyl carbonate, benzotriazole-1-yloxytris(dimethylamino)phosphonium). Hexafluorophosphate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (i.e., O-(1H-benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), benzotriazole-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate, 2-(1H-benzotriazole-1- It can be converted to an amide in the presence of O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, or O-benzotriazole-1-yl-N,N,N',N'-tetramethyluronium hexafluoroborate), and optionally in the presence of a suitable base (e.g., sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and / or lithium diisopropylamide (or variants thereof)) and a suitable solvent (e.g., tetrahydrofurane, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine). Such reactions may be carried out in the presence of further additives, such as 1-hydroxybenzotriazole hydrate.

[0240] Reaction A can be carried out under standard condensation conditions, for example, in the presence of an activator (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) and hydroxybenzotriazole (HOBt) or pentafluorophenol (PFP) and N,N'-diisopropylcarbodiimide (DIC)), in the presence of diethylaminopyridine (DMAP) or (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), preferably in the presence of a base such as N-methylmorpholine (NMM) or N,N'-diisopropylethylamine (DIEA), in a suitable solvent (e.g., dichloromethane, chloroform, dimethylformamide or a mixture thereof), and, for example, at approximately room temperature or reflux temperature. Compounds of formula (VIII) are commercially available or can be obtained by procedures described in literature known to those skilled in the art.

[0241] This reaction can be carried out using existing protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999).

[0242] Step 6 (Reaction B)

[0243] In the second method of this disclosure, as illustrated in reaction B of the scheme above (Scheme 2), the compound (R) of formula (X) is used. 3 The above-defined compound can be converted into the compound of formula (V) according to this disclosure.

[0244] Reaction B is carried out under standard radical halogenation conditions, for example, in the presence of UV light or an acid such as glacial acetic acid, and under radical bromination conditions by treatment with Br2 or a bromine source (e.g., NBS) at, for example, 40°C or reflux temperature.

[0245] This reaction can be carried out using existing protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999). Scheme 3 [ka]

[0246] (In the formula, B, R 1 , R 2 , R 3 , R 3’ , R 4 , R 4’ and R 5 (This is as defined above with respect to equation (I)).

[0247] Method 3

[0248] Step 7 (Reaction A)

[0249] In the third method of this disclosure, as illustrated in reaction A of the scheme above (Scheme 3), the compound of formula (XII) (where Z can be -Cl, -OPG, or -NH2, R 3 and R 1 The compound of formula (XIII) according to this disclosure is obtained by reacting the (as defined above) with a (Z)-3-aminoacrylamide (A=-NH2) source or a (Z)-3-aminoacrylic acid source (A=-OH)(XI).

[0250] Reaction A is carried out under standard condensation conditions, for example, in the presence of an activator (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) and hydroxybenzotriazole (HOBt) or pentafluorophenol (PFP) and N,N'-diisopropylcarbodiimide (DIC)), in the presence of diethylaminopyridine (DMAP) or (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), preferably in the presence of a base such as N-methylmorpholine (NMM) or N,N'-diisopropylethylamine (DIEA), in a suitable solvent (e.g., dichloromethane, chloroform, dimethylformamide or a mixture thereof), and at approximately room temperature or reflux temperature. Compounds of formula (XII) are commercially available or can be obtained by procedures described in literature known to those skilled in the art.

[0251] This reaction can be carried out using existing protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999).

[0252] Step 8 (Reaction B)

[0253] In the third method of this disclosure, as illustrated in reaction B of the scheme (Scheme 3) above, the compound of formula (XIII) (B, R 1 and R 3 As defined above, compound (XIV)(R 2 and R 5 The compound of formula (I) according to this disclosure is obtained by reacting with (as defined above, where X can be various leaving groups or leaving group precursors, and PG is a protecting group).

[0254] The X group of the compound of formula (XIV) can be converted to a leaving group by standard methods. For example, a hydroxyl group can be deprotected by standard methods and subsequently converted to a leaving group such as a halogen, triflate, tosylate, or mesylate group.

[0255] As illustrated in reaction B of the scheme above (Scheme 3), the leaving group of the compound of formula (XIV) is converted to the corresponding amine group by reaction with amine (XIII) to obtain the compound of formula (I) according to this disclosure. Reaction B is carried out under standard nucleophilic substitution conditions in the presence of a suitable base (e.g., N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, triethylamine, pyridine, ammonium chloride, sodium hydride, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, or sodium nitrite) and a suitable solvent (e.g., acetonitrile, dichloromethane, tetrahydrofuran, benzene, diethyl ether, toluene, dimethylformamide, water, ethanol, or a mixture thereof). In a further step, a base or acid such as acetic acid, hydrogen chloride, or sodium hydroxide may be used in such a reaction.

[0256] This reaction mixture is stirred or heated at low or room temperature until the starting materials are consumed. The reaction can be carried out using any existing protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999). Use of the compounds disclosed herein

[0257] The compounds of this disclosure have the ability to stabilize α-L-idulonidase (IDUA), thereby increasing the activity of this enzyme. Therefore, the compounds of this disclosure can be used / administered in patients to treat and / or prevent conditions associated with altered IDUA activity, such as mucopolysaccharidosis 1 (MPS1), valvular heart disease, polyostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), disease conditions related to lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders and developmental disorders. For example, Parini, R., et al., Oprhanet Journal of Rare Diseases 12:112 (1027); Morishita, K. and Petty, RE, Rheumatology 50:v19-v25 (2011); Van Horssen, J., et al., Lancet Neurology 2:482-492 (2003); Spillatini, MG, et al., Acta Neuropathol 97:585-594 (1999); Snow, AD, et al., American Journal of Pathology 137(5):1253-1270 (1990); Tran-Lundmark, K., et al., Circulation Research 44:43-52 (2008); and Lindahl, U. and Kjellen, L., J. Intern. Med. 273:555-571 See (2013). In one embodiment, the state associated with the alteration of IDUA activity is MPS1.In another embodiment, conditions associated with alteration of IDUA activity are selected from the group consisting of valvular heart disease, polyostosis, eye diseases (e.g., glaucoma, corneal opacity, and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), and inflammatory arthritis. In yet another embodiment, conditions associated with alteration of IDUA activity are selected from the group consisting of amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases, and AL amyloidosis), disease conditions related to lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders, and developmental disorders.

[0258] In some embodiments, MPS1 is Hurler's disease, Hurler-Scheie syndrome, or Scheie syndrome.

[0259] In another embodiment, the Disclosure relates to a method for treating or preventing a condition associated with alteration of IDUA activity in a patient in need thereof, the method comprising the step of administering to the patient in need an effective amount of the compound of the Disclosure, in combination, if necessary, an effective amount of α-L-iduronidase, or an analog or variant thereof, such as laronidase. In some embodiments, the compound of the Disclosure is the compound of formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of the Disclosure is the compound of formula (I') described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the Method comprises the step of administering an effective amount of the compound of the Disclosure. In some embodiments, the Method comprises the step of administering an effective amount of the compound of the Disclosure in combination with an effective amount of α-L-iduronidase, or an analog or variant thereof, such as laronidase. In some embodiments, the method includes the step of simultaneously administering to a patient an effective amount of the compound of the disclosure and an effective amount of α-L-iduronidase, or its analog or variant, such as laronidase. In some embodiments, the method includes the step of sequentially administering to a patient an effective amount of the compound of the disclosure and an effective amount of α-L-iduronidase, or its analog or variant, such as laronidase. In some embodiments, administration to a patient of the compound of the disclosure in combination with an effective amount of α-L-iduronidase, or its analog or variant, such as laronidase, includes the step of administering to a patient the compound of the disclosure and α-L-iduronidase, or its analog or variant, such as laronidase, in separate pharmaceutical compositions. In some embodiments, the administration of the compound of the present disclosure to a patient in combination with laronidase involves the step of administering together an effective amount of the compound of the present disclosure and an effective amount of α-L-iduronidase, or an analog or variant thereof, e.g., laronidase, in a single pharmaceutical composition.

[0260] In other embodiments, the Disclosure relates to a method for treating or prophylactically treating MPS1 in a patient in need, comprising the step of administering an effective amount of the compound of the Disclosure. In some embodiments, the compound of the Disclosure is the compound of formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of the Disclosure is the compound of formula (I') described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method comprises the step of administering an effective amount of the compound of the Disclosure simultaneously with an effective amount of α-L-iduronidase, or an analog or variant thereof, for example, laronidase. In some embodiments, the method comprises the step of administering an effective amount of the compound of the Disclosure simultaneously with an effective amount of α-L-iduronidase, or an analog or variant thereof, for example, laronidase.

[0261] In another embodiment, the Disclosure relates to a method for treating or preventing, in a patient in need, a valvular heart disease, polyosynostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), a disease condition related to lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders, or developmental disorders, the method comprising the step of administering an effective amount of the compound of the Disclosure. In some embodiments, the compound of the Disclosure is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound of the Disclosure is the compound of formula (I') described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method includes the step of administering an effective amount of the compound of the Disclosure simultaneously with an effective amount of α-L-iduronidase, or an analog or variant thereof, such as laronidase. In some embodiments, the method includes the step of administering an effective amount of the compound of the Disclosure simultaneously with an effective amount of α-L-iduronidase, or an analog or variant thereof, such as laronidase.

[0262] In another embodiment, any method described herein may further include the step of administering at least one other therapeutic agent to a patient. In another embodiment, the therapeutic agent is an effective amount of a low molecular weight chaperone. In another embodiment, the low molecular weight chaperone competitively binds to an enzyme. In another embodiment, the low molecular weight chaperone is selected from the group consisting of iminoalditols, imino sugars, amino sugars, thiophenyl glycosides, glycosidases, sulfatases, glycosyltransferases, phosphatases, and peptidase inhibitors. In another embodiment, the low molecular weight chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol, and miglustat. In another embodiment, the low molecular weight chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), and ambroxol. In another embodiment, the low molecular weight chaperone is miglustat. In another embodiment, the therapeutic agent is an effective amount of a substrate reducing agent for substrate reduction therapy. In yet another embodiment, the substrate reducing agent is miglustat.

[0263] In another embodiment, the Disclosure relates to the compounds of the Disclosure described herein for use in the prevention or treatment of conditions related to the alteration of IDUA activity in patients in need thereof. In some embodiments, the compounds of the Disclosure are the compounds of formula (I) described herein, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compounds of the Disclosure are the compounds of formula (I') described herein, or pharmaceutically acceptable salts or solvates thereof.

[0264] In some embodiments, the Disclosure relates to compounds of the Disclosure described herein for use in the prevention or treatment of conditions related to the alteration of IDUA activity, in combination with an effective amount of α-L-iduronidase, or its analog or variant, e.g., laronidase, in patients requiring such use. In some embodiments, the compounds of the Disclosure are compounds of formula (I) described herein, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compounds of the Disclosure are compounds of formula (I') described herein, or pharmaceutically acceptable salts or solvates thereof.

[0265] In other embodiments, the Disclosure relates to the Compounds of the Disclosure described herein, for use alone or in combination with an effective amount of α-L-iduronidase, or its analog or variant, such as laronidase, in the prevention or treatment of MPS1. In some embodiments, the Compounds of the Disclosure are the Compound of Formula (I) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the Compounds of the Disclosure are the Compound of Formula (I') described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0266] In another aspect, the Disclosure relates to the Compounds of the Disclosure described herein, for use alone or in combination with an effective amount of α-L-iduronidase, or its analogs or variants, such as laronidase, for the prevention or treatment of heart valve disease, polyosynostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), disease conditions related to lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders or developmental disorders. In some embodiments, the compounds of the Disclosure are compounds of formula (I) as described herein, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compounds of the Disclosure are compounds of formula (I') as described herein, or pharmaceutically acceptable salts or solvates thereof.

[0267] In other embodiments, the Disclosure relates to the compounds of the Disclosure described herein for use as pharmaceuticals. In some embodiments, the compounds of the Disclosure are the compounds of formula (I) described herein, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compounds of the Disclosure are the compounds of formula (I') described herein, or pharmaceutically acceptable salts or solvates thereof.

[0268] In another embodiment, the Disclosure relates to the use of the compounds of the Disclosure described herein in the preparation of pharmaceuticals for the prevention or treatment of conditions related to the alteration of IDUA activity, such as MPS1, valvular heart disease, polyosynostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), disease conditions related to lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid cancers, infections, inflammatory disorders or developmental disorders, in patients who require such treatment. In some embodiments, the compounds of the Disclosure are the compounds of formula (I) described herein, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compounds of the present disclosure are compounds of formula (I') as described herein, or pharmaceutically acceptable salts or solvates thereof.

[0269] In another aspect, the Disclosure relates to pharmaceutical compositions comprising the compounds of the Disclosure described herein and at least one pharmaceutically acceptable excipient for use in patients in need of such treatment or prevention of conditions related to the alteration of IDUA activity, such as MPS1, valvular heart disease, polyosynostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), disease conditions related to lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders or developmental disorders. In some embodiments, the compounds of the Disclosure are compounds of formula (I) as described herein, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the compounds of the Disclosure are compounds of formula (I') as described herein, or pharmaceutically acceptable salts or solvates thereof.

[0270] Pharmaceutical composition This disclosure also relates to pharmaceutical compositions comprising an effective amount of the compounds of this disclosure and at least one pharmaceutically acceptable excipient. In some embodiments, the composition comprises an effective amount of the compound of formula (I) or formula (I') described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0271] The compounds of this disclosure can be used in human pharmaceuticals due to their activity. As described above, the compounds of this disclosure are useful for treating or preventing, for example, MPS1, heart valve disease, polyosynostosis, eye diseases (e.g., glaucoma, corneal opacity and retinal degeneration), ear diseases (e.g., hearing loss), respiratory obstruction or dysfunction, nerve compression (e.g., carpal tunnel syndrome), inflammatory arthritis, amyloid-related disorders (e.g., AA amyloidosis, Alzheimer's disease, TTR amyloidosis, type A diabetes, Parkinson's disease, amyotrophic lateral sclerosis (ALS), prion diseases and AL amyloidosis), disease conditions related to lipoprotein metabolism (e.g., atherosclerosis and Alzheimer's disease), solid tumors, infections, inflammatory disorders, or developmental disorders. The compounds of this disclosure can be administered to any patient suffering from any of the aforementioned conditions. The term “patient” as used herein means any human being who may benefit from the beneficial effects of the compounds of this disclosure.

[0272] The compounds of this disclosure can be administered to a patient as components of a composition containing pharmaceutically acceptable excipients or carriers.

[0273] The compounds of this disclosure can be administered in combination with at least one other therapeutic agent. The administration of the compounds of this disclosure with at least one other therapeutic agent may be sequential or simultaneous. In another embodiment, the compounds of the present invention and at least one other therapeutic agent are administered in separate dosage forms. In another embodiment, the compounds of the present invention and at least one other therapeutic agent are administered simultaneously in the same dosage form.

[0274] The term “excipient” refers to a vehicle, diluent, or adjuvant administered together with the active ingredient. Such pharmaceutical excipients can be sterile liquids such as water and oil, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and similar substances. For example, aqueous solutions of water or saline for injectable formulations, as well as aqueous solutions of dextrose and glycerol, can be used as vehicles. Suitable pharmaceutical vehicles are incorporated herein by reference in “Remington's Pharmaceutical Sciences” (by EW Martin), 21 st This is described in the 2005 edition; or in "Handbook of Pharmaceutical Excipients," Rowe CR; Paul JS; Marian EQ, Sixth Edition.

[0275] Examples of pharmaceutical compositions include solid compositions (such as tablets, pills, capsules, or granules) or liquid compositions (such as liquids, suspensions, or emulsions) intended for oral, topical, or parenteral administration.

[0276] In another embodiment, the pharmaceutical composition is in an orally deliverable form. Suitable pharmaceutical forms for oral administration may be tablets and capsules, which may contain binders, such as conventional excipients known in the art, such as syrup, gum arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sugar, corn starch, calcium phosphate, sorbitol, or glycine; lubricants for preparing tablets, such as magnesium stearate; and disintegrants, such as pharmaceutically acceptable wetting agents, such as starch, polyvinylpyrrolidone, sodium starch glycolate, or microcrystalline cellulose, or sodium lauryl sulfate.

[0277] Solid oral compositions can be prepared by conventional methods of blending, filling, and tablet preparation. Repeated blending operations can be used to distribute the active ingredient in all compositions using large amounts of filler. Such operations are common in the art. Tablets can be prepared, for example, by dry granulation or wet granulation, and can be coated, if necessary, by well-known methods in normal pharmaceutical practice, particularly using enteric coatings.

[0278] The pharmaceutical composition can also be adapted for parenteral administration in appropriate unit dosage forms, such as sterile solutions, suspensions, or lyophilized products. Suitable excipients such as fillers, buffers, or surfactants may be used.

[0279] The specified preparations may be prepared using standard methods, such as those described or referenced in the Spanish and U.S. Pharmacopoeias and similar reference texts.

[0280] In general, the effective dose of the compound of this disclosure administered depends on the relative efficacy of the selected compound, the severity of the condition or disorder being treated, and the patient's body weight. The active compound may be administered once or multiple times daily, for example, once, twice, three or four times daily, and the total typical daily dose ranges from about 0.01 mg / kg body weight / day to about 1000 mg / kg body weight / day. In another embodiment, the effective dose of the compound of this disclosure is about 500 mg / kg body weight / day or less. In another embodiment, the effective dose of the compound of this disclosure is about 100 mg / kg body weight / day or less. In another embodiment, the effective dose of the compound disclosed is in the range of about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day; in another embodiment, the compound disclosed is in the range of about 0.02 mg / kg body weight / day to about 50 mg / kg body weight / day; and in yet another embodiment, the compound disclosed is in the range of about 0.025 mg / kg body weight / day to about 20 mg / kg body weight / day.

[0281] The compositions of the present disclosure can be prepared by a method comprising the step of mixing the compound of the present disclosure with a pharmaceutically acceptable excipient or carrier. The mixing can be carried out using known methods for mixing the compound with a pharmaceutically acceptable excipient or carrier. In another embodiment, the compound of the present disclosure is present in an effective amount in the composition.

[0282] In other embodiments, the Disclosure relates to a pharmaceutical composition comprising an effective amount of the Compound of the Disclosure, an effective amount of laronidase, and a pharmaceutically acceptable excipient. In some embodiments, the Compound of the Disclosure is a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the Compound of the Disclosure is a compound of formula (I') as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0283] The following examples illustrate, but are not limited to, the compounds, compositions, and methods of the Disclosure. In view of the Disclosure, suitable modifications and adaptations of various conditions and parameters that are commonly encountered in clinical treatment and are obvious to those skilled in the art are within the spirit and scope of the Disclosure. [Examples]

[0284] Hereafter in this specification, the term "h" means time, "eq" means equivalent, "min" means minute, "HPLC" means high-performance liquid chromatography, "TLC" means thin-layer chromatography, "LC-MS" or "HPLC-MS" means liquid chromatography-mass spectrometry, "CDCl3" means deuterated chloroform, "DMSO-d6" means deuterated dimethyl sulfoxide, "RINKAN" means ethyl acetate, "THF" means tetrahydrofuran, "DMF" means dimethylformamide, "DCM" means dichloromethane, and "DMEDA" means 1,2-dimethylethylenediamine.

[0285] 11H NMR spectra were recorded using a Bruker (400 MHz and 500 MHz).

[0286] HPLC spectra were recorded using Waters 2695 and Waters UPLC-H class HPLC.

[0287] LC-MS analysis of the compound was performed according to one of the following methods.

[0288] Method A: Aquity UPLC BEH C18 (50 mm × 2.1 mm, 1.7 μm); Wavelength: 215 nm; Flow rate: 0.6 mL / min; Run time: 4.2 min; Mobile phase A: 0.1% formic acid in water and B: 0.1% formic acid in acetonitrile; Time and mobile phase gradient (time / %A in minutes): 0 / 95, 0.3 / 95, 2.0 / 5, 3.5 / 5, 3.6 / 95, MASS: Waters Acquity UPLC (ESI / APCI) equipped with SQD.

[0289] Method B: Acquity UPLC BEH C18 (50 mm × 2.1 mm, 1.7 μm); Wavelength: MaxPlot; Flow rate: 0.6 mL / min; Run time: 10 min; Mobile phase A: 10 mm ammonium acetate in water and B: acetonitrile; Time and mobile phase gradient (time in minutes / %B): 0 / 3, 1 / 3, 7.5 / 100, 9.0 / 3, 10.0 / 3; Instrument: Waters Acquity UPLC, MASS: SQ detector 2 (ESI / APCI).

[0290] Method - C: X-BRIDGE C18 (4.6 mm × 75 mm 3.5 μm); Wavelength: 215 nm; Flow rate: 2 mL / min; Run time: 5.0 min; Mobile phase A: 10 mM acetonitrile in water and B: 100% acetonitrile; Time and mobile phase gradient (time / %B in minutes): 0.0 / 10, 0.2 / 10, 2.5 / 75, 3.0 / 100, 4.8 / 100, 5.0 / 10; MASS: Agilent 1200 SERIES, Mass: 6130 SQD (ESI / APCI).

[0291] Method-D: Aquity UPLC BEH C18 (50 mm × 2.1 mm, 1.7 μm); Wavelength: 215 nm; Flow rate: 0.8 mL / min; Run time: 3.2 min; Mobile phase A: 0.1% formic acid in water and B: 1.0% formic acid in acetonitrile; Time and mobile phase gradient (time / %B in minutes): 0.0 / 2, 0.2 / 2, 1.5 / 98, 2.6 / 98, 2.61 / 2, 3.2 / 2; MASS: Agilent 1290 infinity, Mass: 6150 SQD (ESI / APCI).

[0292] Method-E: Aquity UPLC BEH C18 (50 mm × 2.1 mm, 1.7 μm); Wavelength: 215 nm; Flow rate: 0.6 mL / min; Run time: 6 min; Mobile phase A: 0.1% formic acid in water and B: 0.1% formic acid in acetonitrile; Time and mobile phase-gradient (time / %B in minutes): 0.0 / 5, 0.3 / 5, 2 / 95, 0.6 / 98, 3.7 / 95, 4.2 / 5, 5.7 / 5; MASS: Agilent 1290 infinity, Mass: 6150 SQD (ESI / APCI).

[0293] Method-F: Aquity UPLC BEH C18 (50 mm × 2.1 mm, 1.7 μm); Wavelength: 215 nm; Flow rate: 0.5 mL / min; Run time: 6 min; Mobile phase A: 0.1% formic acid in water and B: 0.1% formic acid in acetonitrile; Time and mobile phase-gradient (time / %B in minutes): 0.0 / 5, 0.3 / 5, 2 / 95, 0.6 / 98, 3.7 / 95, 4.2 / 5, 5.7 / 5; MASS: Agilent 1290 infinity, Mass: 6150 SQD (ESI / APCI).

[0294] Method-G: SunFire C18 (50 mm × 2.1 mm, 5 μm); Wavelength: PDA MaxPlot 210.0~400 nm; Flow rate: 0.30 mL / min; Column temperature: 35 °C; Run time: 9 min; Mobile phase A: ACN / MeOH (50:50), B: 100 mM ammonium acetate solution, C: Water; Gradient: A:B:C 10:5:85 for 0.5 min + 4 min from 10:5:85 to 95:5:0 + 95:5:0 for 4.5 min; Chromatography system: Waters Alliance HT 2795 and PDA 2996; Mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0295] Method - H: SunFire C18 (100 mm × 2.1 mm, 3.5 μm); Wavelength: PDA MaxPlot 210.0~400 nm; Flow rate: 0.30 mL / min; Column temperature: 35 °C; Run time: 30 min; Mobile phase A: ACN / MeOH (50:50), B: 100 mM ammonium acetate solution, C: Water; Gradient: A:B:C 10:5:85 for 5 min + 15 min from 10:5:85 to 95:5:0 + 95:5:0 for 10 min; Chromatography system: Waters Alliance HT 2795 and PDA 2996; Mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0296] Method I: Sunfire C18 (150mm × 19mm, 10μm); Wavelength: Wavelength selected considering the UV maximum absorption of the target; Flow rate: 10mL / min; Column temperature: 30℃; Run time: 30min; Mobile phase, A:ACNB: 10mM ammonium bicarbonate solution (pH7); Gradient: A:B 25:75 for 1min + 25:75 to 85:15 + 85:15 for 22min; Chromatography system: Dionex 3000 (PLCP001) equipped with foxy R1 fraction collector.

[0297] Method-J: BEH phenyl (100 mm × 2.1 mm, 1.7 μm); Wavelength: PDA MaxPlot 215.0~400 nm; Flow rate: 0.40 mL / min; Column temperature: 35 °C; Run time: 9 min; Mobile phase A: Water adjusted to pH 3 with formic acid, B: MeOH + 0.1% HCOOH; Gradient: A:B 90:10 for 0.5 min + 4.5 min from 90:10 to 15:85 + 15:85 for 4 min; Chromatography system: Acquity H Class UPLC; Mass spectrometer: Acquity QDa. Synthesis of Examples 1-7 Synthesis of Intermediate 1: Synthesis scheme: [ka]

[0298] (2-chloro-N-(2-chlorophenyl)acetamide): [ka]

[0299] To a stirred solution of 2-chloroaniline (20.0 g, 157.4 mmol, 1 equivalent) and trimethylamine (25.4 g, 251.9 mmol, 1.6 equivalents) in DCM (300 mL), chloroacetyl chloride (21.1 g, 188.9 mmol, 1.2 equivalents) was added dropwise at 0°C. The reaction mixture was stirred at 0-5°C for 30 minutes, then at room temperature for 3 hours. The reaction mixture was quenched with the smallest possible amount of NaHCO3 aqueous solution, and the organic product was extracted using DCM (3 × 500 mL). The combined organic extract was dehydrated with anhydrous Na2SO4. The solvent was distilled under reduced pressure to obtain the crude compound.

[0300] Yield: (21.0g, 15%).

[0301] ES-MS[M+H] + :204.00;Rt=1.86 minutes (Method-A).

[0302] N-(2-chlorophenyl)-2-iodo-N-methylacetamide: [ka]

[0303] To a stirred solution of NaH (60% dispersion in mineral oil) (4.9 g, 206.9 mmol, 2.0 equivalents) in THF (50 mL), 2-chloro-N-(2-chlorophenyl)acetamide (21.0 g, 103.4 mmol, 1.0 equivalent) in THF (150 mL) was added at 0°C and stirred at room temperature for 30 minutes. MeI (29.3 g, 206.9 mmol, 2.0 equivalents) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 6 hours. After consumption of the starting materials, the reaction mixture was cooled and quenched with ice water, and the organic product was extracted with RINKAN (3 × 400 mL). The combined organic extract was dehydrated with anhydrous Na₂SO₄. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (silica gel 230-400 mesh; eluent: 10-25% ethyl phosphate in petroleum ether) to obtain 6.4 g of N-(2-chlorophenyl)-2-iodo-N-methylacetamide.

[0304] Yield: (6.4g, 20%).

[0305] ES-MS[MH] + :309.87;Rt=1.81 minutes (Method-A).

[0306] 1 H NMR (400 MHz, CDCl3): δ 7.54-7.44 (m, 2H), 7.39-7.37(m, 2H), 3.65-3.62 (d, J =10.4 Hz, 1H), 3.39-3.35 (d, J =10 Hz, 1H), 3.23 (s, 3H).

[0307] Intermediate 1: N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide [ka]

[0308] To a stirred solution of NaH (60% dispersion in mineral oil) (0.994 g, 41.4 mmol, 2.0 equivalents), N-(2-chlorophenyl)-2-iodo-N-methylacetamide (6.4 g, 20.7 mmol, 1.0 equivalent) in THF (40 mL) was added at 0°C. The reaction mixture was then stirred at room temperature for 30 minutes, and MeNH2 (2.0 mol solution in THF, 31 mL, 62.1 mmol, 3.0 equivalents) in THF (20 mL) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 6 hours. After consumption of the starting materials (the reaction was monitored by TLC), the reaction mixture was cooled and quenched with ice water, and the organic product was extracted with 10% MeOH in DCM (3 × 250 mL). The combined organic extract was dehydrated with anhydrous Na2SO4. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (silica gel 230-400 mesh; eluent: 10-15% MeOH in DCM) to obtain 1.5 g of N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide.

[0309] Yield: (1.5g, 34%).

[0310] ES-MS[MH] + :213.01;Rt=1.15 minutes (Method-A). Synthesis of Example 1: [ka]

[0311] Intermediate 2: (5-amino-1-phenyl-1H-pyrazole-4-carbonitride): [ka]

[0312] To a suspension of the compound phenylhydrazine (1.0 g, 9.2 mmol, 1 equivalent) in EtOH (15 mL), (ethoxymethylene)malononitrile (1.1 g, 9.2 mmol, 1 equivalent) was added at 0°C. The reaction mixture was heated to 100°C for 3 hours. The reaction was monitored by TLC. The reaction mixture was concentrated under vacuum, and the product was extracted with SiO2 (3 × 50 mL). The combined organic extract was dehydrated with anhydrous Na2SO4. The solvent was distilled under reduced pressure to obtain the crude compound.

[0313] Yield: (1.0g).

[0314] ES-MS[MH] + :184.92;Rt=1.56 minutes (Method-A).

[0315] Intermediate 3: (5-amino-1-phenyl-1H-pyrazole-4-carboxamide) [ka]

[0316] To a stirred solution of the compound (5-amino-1-phenyl-1H-pyrazole-4-carbonitride) (1.0 g, 5.43 mmol, 1 equivalent) in DMSO:water (10 mL:4.0 mL), potassium hydroxide (1.5 g, 27.1 mmol, 5 equivalents) was added at 0°C. This reaction mixture was stirred at the same temperature for 15 minutes, then 3 mL, 5 equivalents of 30% aqueous hydrogen peroxide solution were added dropwise at the same temperature, and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was diluted with water and extracted with RINKAN (3 × 100 mL). The combined organic layers were dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound (5-amino-1-phenyl-1H-pyrazole-4-carboxamide).

[0317] Yield: (0.8g).

[0318] ES-MS[M+H] + :202.99;Rt=1.34 minutes (Method-A).

[0319] Intermediate 4: (6-(chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4-ol): [ka]

[0320] To a stirred solution of the compound (5-amino-1-phenyl-1H-pyrazole-4-carboxamide) (0.8 g, 3.96 mmol, 1 equivalent) in DMF:toluene (16 mL:1.6 mL), chloroacetyl chloride (0.532 g, 4.75 mmol, 1.2 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours, then refluxed for 5 hours. The reaction mixture was cooled and concentrated under reduced pressure, then quenched with the minimum amount of NaHCO3 aqueous solution, and the organic product was extracted with RINKAN (3 × 25 mL). The combined organic extract was dehydrated with anhydrous Na2SO4. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (silica gel 230-400 mesh; eluent: 10-20% phenylethylamine in petroleum ether) to obtain 180 mg of (6-(chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4-ol).

[0321] Yield: (0.18g, 18%).

[0322] ES-MS[M+H] + :261.02;Rt=1.84 minutes (Method-A).

[0323] 1 H NMR (400 MHz, DMSO-d6): δ 10.94(s, 1H), 8.31(s, 1H), 7.58-7.50(m, 5H), 4.32(s, 2H).

[0324] (Example 1) (N-(2-chlorophenyl)-2-(((4-hydroxy-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide): [ka]

[0325] To a solution of N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide (0.14 g, 0.692 mmol, 1.0 equivalent) in THF (5 mL), NaH was added at 0°C and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, a solution of (6-(chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-4-ol) (0.18 g, 0.692 mmol, 1.0 equivalent) in THF (5 mL) was added and the mixture was stirred at 70°C for 5 hours. The reaction mixture was quenched with ice water, and the organic product was extracted with ELISA (3 × 50 mL). The combined organic extract was dehydrated with anhydrous Na₂SO₄. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by reverse-phase preparative HPLC to obtain 50 mg of H-(N-(2-chlorophenyl)-2-(((4-hydroxy-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide) as a white solid.

[0326] Yield: (0.05g, 17%).

[0327] ES-MS[MH] - :435.17;Rt=1.81 minutes (Method-A).

[0328] 1 H NMR (400 MHz, CDCl3): δ 10.69 (s, 1H), 7.92 (s, 1H), 7.58-7.43 (m, 6H), 7.38-7.26 (m, 3H) 3.20-3.18 (m, 5H), 3.04-2.92 (q, J =16.8 Hz, 2H), 2.32 (s, 3H). Synthesis of Example 2: [ka]

[0329] Intermediate 5: (5-amino-1-o-tolyl-1H-pyrazole-4-carbonitride): [ka]

[0330] Intermediate 2 was prepared according to the procedure described.

[0331] Yield: (1.5g).

[0332] ES-MS[MH] + :198.98;Rt=1.63 minutes (Method-A).

[0333] Intermediate 6: (5-amino-1-o-tolyl-1H-pyrazole-4-carboxamide): [ka]

[0334] Intermediate 3 was prepared according to the procedure described.

[0335] Yield: (1.50g, crude).

[0336] ES-MS[M+H] + :216.94;Rt=1.38 minutes (Method-A).

[0337] Intermediate 7: (6-(chloromethyl)-1-o-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4-ol): [ka]

[0338] Intermediate 4 was prepared according to the procedure described.

[0339] Yield: (0.3g, 16%).

[0340] ES-MS[MH] + :273.04;Rt=1.78 minutes (Method-A).

[0341] 1 H NMR (400 MHz, DMSO-d6): δ 10.77(s, 1H), 8.28 (s, 1H), 7.46-7.34(m, 3H), 7.25-7.23(m, 1H), 4.20(s, 2H), 2.01(s, 3H).

[0342] (Example 2) (N-(2-chlorophenyl)-2-(((4-hydroxy-1-o-tolyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide): [ka]

[0343] To a solution of N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide (0.232 g, 1.09 mmol, 1 equivalent) in THF (8 mL), NaH (60% of mineral oil, 0.35 g, 8.64 mmol, 8 equivalents) was added at 0°C and stirred at the same temperature for 15 minutes. Then, a solution of (6-(chloromethyl)-1-o-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4-ol) (0.3 g, 1.09 mmol, 1.0 equivalent) in THF (8 mL) was added and stirred at 70°C for 5 hours. The reaction mixture was quenched with ice water, and the organic product was extracted with RINKAN (3 × 50 mL). The combined organic extract was dehydrated with anhydrous Na₂SO₄. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by reverse-phase preparative HPLC to obtain 49 mg of H-(N-(2-chlorophenyl)-2-(((4-hydroxy-1-o-tolyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide) as a pale yellow solid.

[0344] Yield: (0.08g, 16%).

[0345] ES-MS[MH] - :449.27;Rt=1.87 minutes (Method-A).

[0346] 1 H NMR (400 MHz, CDCl3): δ 10.46(s, 1H), 7.94 (s, 1H), 7.52-7.50 (m, 1H), 7.38-7.22 (m, 7H), 3.14-3.12 (m, 5H), 2.92-2.80 (q, J =16.4 Hz, 2H), 2.17 (s, 3H), 2.15 (s, 3H). Synthesis of Example 3: [ka]

[0347] Intermediate 8: (5-amino-1-m-tolyl-1H-pyrazole-4-carbonitride): [ka]

[0348] Intermediate 2 was prepared according to the procedure described.

[0349] Yield: (1.0g, crude).

[0350] ES-MS[MH] + :198.98;Rt=1.73 minutes (Method-A).

[0351] Intermediate 9: (5-amino-1-m-tolyl-1H-pyrazole-4-carboxamide): [ka]

[0352] Intermediate 3 was prepared according to the procedure described.

[0353] Yield: (1.1g).

[0354] ES-MS[M+H] + :216.91;Rt=1.50 minutes (Method-A).

[0355] Intermediate 10: (6-(chloromethyl)-1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4-ol): [ka]

[0356] Intermediate 4 was prepared according to the procedure described.

[0357] Yield: (0.18g, 13%).

[0358] ES-MS[M+H] + :275.05;Rt=1.92 minutes (Method-A).

[0359] 1 H NMR (400 MHz, DMSO-d6): δ 12.73 (s, 1H), 8.33 (s, 1H), 7.85-7.83 (m, 2H), 7.47-7.43 (t, J =7.6 Hz, 1H), 7.25-7.23 (d, J =7.2 Hz, 1H), 4.62 (s, 2H), 2.41 (s, 3H).

[0360] (Example 3) (N-(2-chlorophenyl)-2-(((4-hydroxy-1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide): [ka]

[0361] To a 5 mL THF solution of N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide (14.0 g, 6.56 mmol, 1 equivalent), NaH (60% mineral oil, 2.09 g, 52.48 mmol, 8 equivalents) was added at 0°C and stirred at the same temperature for 15 minutes. Then, a 5 mL THF solution of (6-(chloromethyl)-1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4-ol) (0.18 g, 6.56 mmol, 1 equivalent) was added and stirred at 70°C for 5 hours. The reaction mixture was quenched with ice water, and the organic product was extracted with SiO2 (3 × 25 mL). The combined organic extract was dehydrated with anhydrous Na2SO4. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by reverse-phase preparative HPLC to obtain 93 mg of (N-(2-chlorophenyl)-2-(((4-hydroxy-1-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide) as a white solid.

[0362] Yield: (0.09g, 15%).

[0363] ES-MS[MH] - :449.23;Rt=1.87 minutes (Method-A).

[0364] 1 H NMR (400 MHz, CDCl3): δ 11.09 (s, 1H), 8.22 (s, 1H), 7.86-7.83 (m,2H), 7.56-7.53 (m, 1H), 7.40-7.34 (m, 3H), 7.29-7.27 (m, 1H), 7.16-7.14 (m,1H), 3.79-3.67 (q, J =16.4 Hz, 2H), 3.24 (s, 2H), 3.16-3.05 (q, J =16.8 Hz, 2H), 2.43 (s, 3H), 2.40 (s, 3H). Synthesis of Example 4: [ka]

[0365] Intermediate 11: (5-amino-1-p-tolyl-1H-pyrazole-4-carbonitride): [ka]

[0366] Intermediate 2 was prepared according to the procedure described.

[0367] Yield: (1.5g, crude).

[0368] ES-MS[M+H] + :198.98;Rt=1.72 minutes (Method-A).

[0369] Intermediate 12: (5-amino-1-p-tolyl-1H-pyrazole-4-carboxamide): [ka]

[0370] Intermediate 3 was prepared according to the procedure described.

[0371] Yield: (0.35g, 18%).

[0372] ES-MS[M+H] + :217.01;Rt=1.50 minutes (Method-A).

[0373] Intermediate 13: (6-(chloromethyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4-ol): [ka]

[0374] Intermediate 4 was prepared according to the procedure described.

[0375] Yield: (0.25g, 71%).

[0376] ES-MS[M+H] +:275.02;Rt=1.86 minutes (Method-A).

[0377] (Example 4) (N-(2-chlorophenyl)-2-(((4-hydroxy-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide): [ka]

[0378] To a THF (5 mL) solution of N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide (0.19 g, 0.91 mmol, 1 equivalent), NaH (60% of mineral oil, 0.05 g, 1.36 mmol, 1.5 equivalents) was added at 0°C and stirred at the same temperature for 15 minutes. Then, a THF solution of (6-(chloromethyl)-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidine-4-ol) (0.2 g, 0.91 mmol, 1 equivalent) was added and stirred at 70°C for 5 hours. The reaction mixture was quenched with ice water, and the organic product was extracted with SiO (3 × 25 mL). The combined organic extract was dehydrated with anhydrous Na₂SO₄. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by reverse-phase preparative HPLC to obtain 0.015 g of (N-(2-chlorophenyl)-2-(((4-hydroxy-1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide) as an off-white solid.

[0379] Yield: (0.015g, 3%).

[0380] ES-MS[MH] + :449.17;Rt=1.94 minutes (Method-A).

[0381] 1H NMR (400 MHz, DMSO-d6): δ 10.61(s, 1H), 7.89 (s, 1H), 7.53-7.51 (m, 1H), 7.45-7.43 (m, 2H), 7.38-7.36 (m, 2H), 7.26 (s, 3H), 3.18 (s, 5H), 3.03-2.91 (m, 2H), 2.40(s, 3H), 2.32 (s, 3H). Synthesis of Example 5: [ka]

[0382] Intermediate 14: (5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carbonitrile): [ka]

[0383] Intermediate 2 was prepared according to the procedure described.

[0384] Yield: (1.5g, crude).

[0385] ES-MS[M+H] + :215.03;Rt=1.54 minutes (Method-A).

[0386] Intermediate 15: (5-amino-1-(2-methoxyphenyl)-1H-pyrazole-4-carboxamide): [ka]

[0387] Intermediate 3 was prepared according to the procedure described.

[0388] Yield: (0.35g, 21%).

[0389] ES-MS[M+H] + :233.16;Rt=1.91 minutes (Method-E).

[0390] Intermediate 16: (6-(chloromethyl)-1-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol): [ka]

[0391] Intermediate 4 was prepared according to the procedure described.

[0392] Yield: (0.25g, 57%).

[0393] ES-MS[M+H] + :291.08;Rt=1.72 minutes (Method-A).

[0394] (Example 5) (N-(2-chlorophenyl)-2-(((4-hydroxy-1-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide): [ka]

[0395] To a THF (5 mL) solution of N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide (0.14 g, 0.68 mmol, 1 equivalent), NaH (60% of mineral oil, 0.04 g, 1.03 mmol, 1.5 equivalents) was added at 0°C and stirred at the same temperature for 15 minutes. Then, a THF solution of (6-(chloromethyl)-1-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol (0.2 g, 0.68 mmol, 1 equivalent) was added and stirred at 70°C for 5 hours. This reaction mixture The mixture was quenched with ice water, and the organic product was extracted with SiO2 (3 × 25 mL). The combined organic extract was dehydrated with anhydrous Na2SO4. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by reverse-phase preparative HPLC to obtain 0.015 g of (N-(2-chlorophenyl)-2-(((4-hydroxy-1-(2-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide) as an off-white solid.

[0396] Yield: (0.015g, 4%).

[0397] ES-MS[MH] + :465.14;Rt=1.84 minutes (Method-A).

[0398] 1 H NMR (400 MHz, CDCl3): δ 10.12 (s, 1H), 7.92 (s, 1H), 7.52-7.50 (m, 1H), 7.46-7.42 (m, 2H), 7.37-7.33 (m, 2H), 7.19-7.21 (br s, 1H), 7.10-7.05 (m, 2H), 3.92 (s, 3H), 3.15 (s, 5H), 2.94-2.79 (m, 2H), 2.21 (s, 3H). Synthesis of Example 6: [ka]

[0399] Intermediate 17: (5-amino-1-(3-methoxyphenyl)-1H-pyrazole-4-carbonitrile): [ka]

[0400] Intermediate 2 was prepared according to the procedure described.

[0401] Yield: (1.3g, crude).

[0402] ES-MS[M+H] + :215.14;Rt=3.06 minutes (Method-F).

[0403] Intermediate 18: (5-amino-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxamide): [ka]

[0404] Intermediate 3 was prepared according to the procedure described.

[0405] Yield: (0.7g, 50%).

[0406] ES-MS[M+H] + :233.02;Rt=1.43 minutes (Method-A).

[0407] Intermediate 19: (6-(chloromethyl)-1-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol): [ka]

[0408] Intermediate 4 was prepared according to the procedure described.

[0409] Yield: (0.25g, 28%).

[0410] ES-MS[M+H] + :291.00;Rt=1.76 minutes (Method-A).

[0411] (Example 6) (N-(2-chlorophenyl)-2-(((4-hydroxy-1-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide): [ka]

[0412] To a THF (5 mL) solution of N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide (0.14 g, 0.68 mmol, 1 equivalent), NaH (60% of mineral oil, 0.04 g, 1.02 mmol, 1.5 equivalents) was added at 0°C and stirred at the same temperature for 15 minutes. Then, a THF solution of (6-(chloromethyl)-1-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol) (0.2 g, 0.68 mmol, 1 equivalent) was added and stirred at 70°C for 5 hours. The reaction mixture was quenched with ice water, and the organic product was extracted with SiO (3 × 25 mL). The combined organic extract was dehydrated with anhydrous Na₂SO₄. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by reverse-phase preparative HPLC to obtain 0.015 g of (N-(2-chlorophenyl)-2-(((4-hydroxy-1-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide) as an off-white solid.

[0413] Yield: (0.050g, 12%).

[0414] ES-MS[MH] + :465.28;Rt=1.86 minutes (Method-A).

[0415] 1H NMR (400 MHz, CDCl3): δ 10.71 (s, 1H), 7.91 (s, 1H), 7.54-7.51 (m, 1H), 7.38-7.34 (m, 3H), 7.31-7.27 (m, 1H), 7.15-7.11 (m, 2H), 6.99-6.96 (s, 1H), 3.84 (s, 3H), 3.21-3.18 (m, 5H), 3.04-2.92 (q, J=16.8 Hz, 2H), 2.32 (s, 3H). Synthesis of Example 7: [ka]

[0416] Intermediate 20: (5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile): [ka]

[0417] Intermediate 2 was prepared according to the procedure described.

[0418] Yield: (1.3g, crude).

[0419] ES-MS[M+H] + :214.93;Rt=1.61 minutes (Method-A).

[0420] Intermediate 21: (5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxamide): [ka]

[0421] Intermediate 3 was prepared according to the procedure described.

[0422] Yield: (0.7g, crude).

[0423] ES-MS[M+H]+ :232.99;Rt=1.39 minutes (Method-A).

[0424] Intermediate 22: (6-(chloromethyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol): [ka]

[0425] Intermediate 4 was prepared according to the procedure described.

[0426] Yield: (0.25g, 28%).

[0427] ES-MS[M+H] + :289.02;Rt=1.74 minutes (Method-A).

[0428] (Example 7) (N-(2-chlorophenyl)-2-(((4-hydroxy-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide): [ka]

[0429] To a 5 ml THF solution of N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide (0.14 g, 0.68 mmol, 1 equivalent), NaH (60% of mineral oil, 0.04 g, 1.02 mmol, 1.5 equivalents) was added at 0°C and stirred for 15 minutes at the same temperature. Then, a THF solution of (6-(chloromethyl)-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-ol) (0.2 g, 0.68 mmol, 1 equivalent) was added and stirred at 70°C for 5 hours. The reaction mixture was quenched with ice water, and the organic product was extracted with SiO2 (3 × 25 mL). The combined organic extract was dehydrated with anhydrous Na2SO4. The solvent was distilled under reduced pressure to obtain the crude compound. The crude product was purified by reverse-phase preparative HPLC to obtain 0.018 g of (N-(2-chlorophenyl)-2-(((4-hydroxy-1-(4-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)(methyl)amino)-N-methylacetamide) as an off-white solid.

[0430] Yield: (0.018g, 5%).

[0431] ES-MS[MH] + :465.14;Rt=1.83 minutes (Method-A).

[0432] 1 H NMR (400 MHz, CDCl3): δ 10.59(s, 1H), 7.89(s, 1H), 7.53-7.51 (m, 1H), 7.48-7.45(m, 2H), 7.38-7.35(m, 2H), 7.29-7.27(m, 1H), 6.99-6.96 (m, 2H), 3.85(s, 3H), 3.20-3.18(m, 5H), 3-02-2.90(m, 2H), 2.32(s, 3H). (Examples 8-37)

[0433] The following examples 8-37 were purchased and tested using the differential scanning fluorescence (DSF) assay described below. The test results are shown in Table 2 below. (Example 8)

[0434] N-(2,6-dichlorophenyl)-2-(ethyl((4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)acetamide [ka] (Example 9)

[0435] N-(3-fluorophenyl)-2-(methyl((4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)acetamide [ka] (Example 10)

[0436] 2-(ethyl((4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)-N-(3-methoxyphenyl)acetamide [ka] (Example 11)

[0437] N-(2,4-difluorophenyl)-2-(((4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)(propyl)amino)acetamide [ka] (Example 12)

[0438] N-(2-chlorophenyl)-2-(methyl((4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)acetamide [ka] (Example 13)

[0439] N-(tert-butyl)-2-(ethyl((4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)acetamide [ka] (Example 14)

[0440] 2-(methyl((4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)-N-(4-methylthiazole-2-yl)acetamide [ka] (Example 15)

[0441] 2-(((2-(indolin-1-yl)-2-oxoethyl)(propyl)amino)methyl)thieno[3,2-d]pyrimidine-4(3H)-one [ka] (Example 16)

[0442] N-(2,6-dichlorophenyl)-2-(ethyl((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)aminoacetamide [ka] (Example 17)

[0443] 2-((2-methoxyethyl)((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)-N-(p-tolyl)acetamide [ka] (Example 18)

[0444] 2-(methyl((4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-(naphthalene-1-yl)acetamide [ka] (Example 19)

[0445] 2-(ethyl((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)-N-phenylacetamide [ka] (Example 20)

[0446] 2-(ethyl((4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-(o-tolyl)acetamide [ka] (Example 21)

[0447] 2-(methyl((4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-(quinoline-5-yl)acetamide [ka] (Example 22)

[0448] N-(2-chlorophenyl)-2-(ethyl((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)aminoacetamide [ka] (Example 23)

[0449] N-(2,6-dimethylphenyl)-2-(methyl((4-oxo-3,4-dihydroquinazoline-2-yl)methyl)aminoacetamide [ka] (Example 24)

[0450] 1-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)-N-phenylpyrrolidine-2-carboxamide [ka] (Example 25)

[0451] N-(benzo[c][1,2,5]thiadiazole-4-yl)-2-(ethyl((4-oxo-3,4-dihydroquinazoline-2-yl)methyl)aminoacetamide) [ka] (Example 26)

[0452] 2-(ethyl((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)-N-isobutylacetamide [ka] (Example 27)

[0453] N-methyl-2-(methyl((4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-phenylacetamide [ka] (Example 28)

[0454] N-ethyl-2-(methyl((4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-(naphthalene-1-yl)acetamide [ka] (Example 29)

[0455] 2-(((2-(3,4-dihydroquinoline-1(2H)-yl)-2-oxoethyl)(methyl)amino)methyl)quinazoline-4(3H)-one [ka] (Example 30)

[0456] N-(3,4-dichlorophenyl)-2-(methyl((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)acetamide [ka] (Example 31)

[0457] 2-(methyl((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)-N-(p-tolyl)acetamide [ka] (Example 32)

[0458] N-(3-fluorophenyl)-2-(methyl((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)acetamide [ka] (Example 33)

[0459] 2-(methyl((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)-N-phenylacetamide [ka] (Example 34)

[0460] N-(2-methoxyethyl)-2-(methyl((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)acetamide [ka] (Example 35)

[0461] 1-Methyl-6-((methyl(2-oxo-2-(pyrroridine-1-yl)ethyl)amino)methyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one [ka] (Example 36)

[0462] N,N-dimethyl-2-(methyl((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)acetamide [ka] (Example 37)

[0463] N-cyclohexyl-N-methyl-2-(methyl((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)acetamide [ka] Synthesis of Examples 38-94 General Procedure A [ka]

[0464] A mixture of a suitable amine (1.0 equivalent) and potassium carbonate (2 or 1 equivalent) in acetone (0.33 M) was cooled to 0°C and stirred for 30 minutes. Chloroacetyl chloride (1.5 or 1 equivalent) was added dropwise to the cooled mixture with vigorous stirring. The resulting mixture was warmed and stirred at room temperature for 3 hours or overnight. This reaction was quenched with water (70 mL), and the resulting suspension was cooled to 0-5°C and stirred for 1 hour. The suspended solid was isolated by suction filtration and vacuum-dried at 60°C for 4 hours to obtain the desired acetamide compound.

[0465] In the same case, the reaction was quenched with water (75 mL) and the pH was adjusted to 7.0-8.0 using 3N NaOH. This was extracted with Depositphotos (100 mL). The organic phase was dehydrated with anhydrous sodium sulfate, filtered, and concentrated to dryness. The reaction was quenched with water, and the resulting suspended solid was stirred at room temperature for 1 hour. This solid was isolated by suction filtration and vacuum-dried overnight at 60°C to obtain the corresponding 2-chloroacetamide as a solid, which may then be recrystallized in Depositphotos / Hex. Intermediate 23: 2-Chloro-1-(isoindorin-2-yl)ethane-1-one: [ka]

[0466] To precipitate acetamide, it was necessary to make the solution basic to pH 4.5-5.0 using 1N NaOH. Appearance: Dark brown solid.

[0467] Yield: (0.35g, 36%).

[0468] ES-MS[M+H] + :196.0 / 198.1, Rt=5.362 minutes (Method-G). Intermediate 24: 2-Chloro-1-(indoline-1-yl)ethane-1-one: [ka]

[0469] Appearance: Solid beige color.

[0470] Yield: (0.92g, 93%).

[0471] ES-MS[M+H] + :196.0 / 198.0, Rt=5.618 minutes (Method-G). Intermediate 25: 2-Chloro-N-(4-methylthiazole-2-yl)acetamide: [ka]

[0472] It was isolated as a pale yellow solid.

[0473] Yield: (0.86g, 51%).

[0474] ES-MS[M+H] + :191.0 / 192.9, Rt=4.878 minutes (Method-G). Intermediate 26: 2-chloro-N-(2,6-dichlorophenyl)acetamide: [ka]

[0475] It was isolated as a white solid. Yield: (0.45 g, 78%).

[0476] ES-MS[M+H] + :238.0 / 239.9, Rt=5.260 minutes (Method-G). Intermediate 27: 2-Chloro-N-(2,6-dichlorophenyl)acetamide: [ka]

[0477] It was isolated as an off-white solid.

[0478] Yield: (4.43g, 97%).

[0479] ES-MS[M+H] + :236.2 / 238.2 / 240.1, Rt=6.239 minutes (Method-G). Intermediate 28: 2-chloro-N-(2-fluorophenyl)acetamide: [ka]

[0480] It was isolated as an off-white solid.

[0481] Yield: (6.92g, 82%).

[0482] ES-MS[M+H] + :188.0, Rt=5.333 minutes (Method-G). Intermediate 29: 2-Chloro-N-methyl-N-(4-methylthiazole-2-yl)acetamide and 2-iodo-N-methyl-N-(4-methylthiazole-2-yl)acetamide: [ka]

[0483] To an aqueous solution of 2-chloro-N-(4-methylthiazole-2-yl)acetamide (3.0 g, 16 mmol, 1.0 equivalent) in anhydrous THF (46 mL), NaH (0.48 g, 24 mmol, 1.25 equivalent) was added and the mixture was stirred at room temperature for 30 minutes. Next, iodomethane (1.27 mL, 20 mmol, 1.25 equivalent) was added dropwise. The reaction mixture was stirred for 5 hours. Since no transformation was observed, a 1 M solution of tBuOK in THF (8 mL, 8 mmol, 0.5 equivalent) and iodomethane (1.27 mL, 20 mmol, 1.25 equivalent) were added and the mixture was stirred overnight. The reaction was quenched with water (40 mL), and the aqueous layer was extracted with ethyl acetate (3×). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and distilled to dryness. Purification of the crude product obtained by flash column chromatography (siRNA / Hex 20-60%) yielded a mixture of 2-chloro-N-methyl-N-(4-methylthiazole-2-yl)acetamide and 2-iodo-N-methyl-N-(4-methylthiazole-2-yl)acetamide in a ratio of approximately 3:1 as a yellow solid.

[0484] Yield: (0.67g, 18%).

[0485] ES-MS[M+H] + :205.0 / 207.0, Rt=4.769 min (Method-G); Chloride compound.

[0486] ES-MS[M+H] + :296.9, Rt=5.163 min (Method-G); Iodide compound. Intermediate 30: 2-chloro-N-(2,6-dichlorophenyl)-N-methylacetamide and 2-iodo-N-(2,6-dichlorophenyl)-N-methylacetamide: [ka]

[0487] To an aqueous solution of 2-chloro-N-(2,6-dichlorophenyl)acetamide (0.39 g, 1.63 mmol, 1 equivalent) in 10 mL of THF, NaH (0.04 g, 1.79 mmol, 1.25 equivalents) was added in small amounts. This mixture was cooled to -78°C and stirred for 30 minutes. Iodomethane (0.11 mL, 1.79 mmol, 1.25 equivalents) was added dropwise to the cooled reaction mixture. This mixture was stirred for 5 hours. This reaction was quenched with water (25 mL), and the aqueous layer was extracted with ethyl acetate (3×). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and distilled to dryness to obtain a mixture of isolated 2-chloro-N-(2,6-dichlorophenyl)-N-methylacetamide and 2-iodo-N-(2,6-dichlorophenyl)-N-methylacetamide as a yellow oily substance.

[0488] Yield: (0.49g).

[0489] ES-MS[M+H] + : 251.9 / 253.9 / 256.0, Rt=5.996 min (Method-G); Chloride compound.

[0490] ES-MS[M+H] + :343.9 / 345.9, Rt=6.197 min (Method-G); Iodide compound. Intermediate 31: 2-Chloro-N-(3,4-dichlorophenyl)-N-methylacetamide: [ka]

[0491] 2-chloro-N-(2,6-dichlorophenyl)acetamide (1.74 g, 7.30 mmol, 1 equivalent) was placed in a three-necked round-bottom flask and dissolved in anhydrous DMF (73 mL) under an N2 atmosphere. This solution was cooled to 0°C, and NaH (0.35 g, 8.75 mmol, 1.2 equivalents) was added in small portions. The resulting mixture was stirred at this temperature for 20 minutes, and MeI (3.14 g, 21.89 mmol, 3 equivalents) was added dropwise. The reaction mixture was stirred at 0°C for 2 hours. After this time, saturated NH4Cl aqueous solution was carefully added, and the aqueous phase was extracted with SiO2 (3×). The organic layers were washed twice with water, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (hexane / siRNA, 25%-100%) to obtain 2-chloro-N-(3,4-dichlorophenyl)-N-methylacetamide, which was isolated as a yellow solid.

[0492] Yield: (1.46g, 75% yield).

[0493] ES-MS[M+H] + :251.9 / 253.9, Rt=6.251 minutes (Method-G). Intermediate 32: 2-chloro-N-(2-fluorophenyl)-N-methylacetamide and 2-iodo-N-(2-fluorophenyl)-N-methylacetamide: [ka]

[0494] In a 100 mL round-bottom flask equipped with a magnetic stirrer and condenser, 2-chloro-N-(2-fluorophenyl)acetamide (4.50 g, 23.99 mmol, 1.0 equivalent) and K2CO3 (9.95 g, 71.96 mmol, 3 equivalents) were added. 68 mL of THF:DMF 9 / 1 mixture was added, followed by iodomethane (4.6 mL, 71.96 mmol, 3 equivalents). This mixture was stirred overnight at 45°C. The reaction product was warmed to room temperature. Subsequently, it was quenched with water (250 mL) and acidified to pH 7.0-7.2 with 3N hydrochloric acid solution. The organic solvent was removed by distillation under reduced pressure, and the aqueous layer was extracted with ethyl acetate (3×). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and distilled to dryness. The resulting crude product was purified by flash column chromatography (20-50% siRNA / hexane) to obtain a mixture of 2-chloro-N-(2-fluorophenyl)-N-methylacetamide and 2-iodo-N-(2-fluorophenyl)-N-methylacetamide in a ratio of approximately 1:3, which were isolated as a yellow oily substance.

[0495] Yield: (1.27g, 20%).

[0496] ES-MS[M+H] + :202.0, Rt=5.441 min (Method-G); Chloride compound.

[0497] ES-MS[M+H] + :293.9, Rt=5.702 min (Method-G); Iodide compound. General Procedure B [ka] (wherein X is Cl or I, and R is methyl or ethyl).

[0498] A 2M amine solution in THF (methylamine and ethylamine, 10-20 equivalents), or cyclopropylamine dissolved in THF (10 equivalents), or propylamine dissolved in THF (10 equivalents) was added to a mixture of 2-chloro-N-(2-chlorophenyl)-N-methylacetamide and 2-iodo-N-(2-chlorophenyl)-N-methylacetamide (1.0 equivalent). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness, and the crude product was treated with ethyl acetate (50 mL). The organic layer was washed twice with water (25 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (Â / hexane, 20-50%) or (DCM / DCM:MeOH(90:10) (sometimes containing 2% NH3), 0-50%) to obtain the corresponding acetamide. Intermediate 33: 1-(isoindorin-2-yl)-2-(methylamino)ethane-1-one: [ka]

[0499] Appearance: Dark brown solid.

[0500] Yield: (0.25g, 73%).

[0501] ES-MS[M+H] + :191.0, Rt=4.950 minutes (Method-G).

[0502] 1 H NMR (400 MHz, Chloroform-d) δ 7.32 - 7.29 (m, 2H), 7.28 - 7.23 (m, 2H), 4.83 (s, 2H), 4.78 (s, 2H), 3.44 (s, 2H), 2.50 (s, 3H). Intermediate 34: 1-(indoline-1-yl)-2-(methylamino)ethane-1-one: [ka]

[0503] Appearance: Light brown solid.

[0504] Yield: (0.38g, 77%).

[0505] ES-MS[M+H] + :191.1, Rt=5.057 minutes (Method-G).

[0506] 1 H NMR (400 MHz, Chloroform-d) δ 8.23 ​​(d, J = 8.0 Hz, 1H), 7.20 (ddd, J = 10.0, 7.5, 1.7 Hz, 2H), 7.02 (td, J = 7.5, 1.1 Hz, 1H), 4.00 (t, J = 8.5 Hz, 2H), 3.46 (s, 2H), 3.21 (t, J = 8.4 Hz, 2H), 2.51 (s, 3H) Intermediate 35: N-(2-chlorophenyl)-N-methyl-2-(methylamino)acetamide: [ka]

[0507] It was isolated as a yellow, oily substance.

[0508] Yield: (0.33g, 52%).

[0509] ES-MS[M+H] + :213.0 / 215.0, Rt=5.438 minutes (Method-G). Intermediate 36: N-(2-chlorophenyl)-N-methyl-2-(ethylamino)acetamide: [ka]

[0510] It was isolated as a yellow, oily substance.

[0511] Yield: (0.54g, 73%).

[0512] ES-MS[M+H] + :227.1 / 229.0, Rt=5.560 minutes (Method-G). Intermediate 37: N-(2-chlorophenyl)-N-methyl-2-(cyclopropylamino)acetamide: [ka]

[0513] It was isolated as a yellow, oily substance.

[0514] Yield: (0.64g, 93%).

[0515] ES-MS[M+H] + :239.1 / 241.1, Rt=5.707 minutes (Method-G).

[0516] 1 H NMR (400 MHz, DMSO-d6) δ 7.69 - 7.63 (m, 1H), 7.57 - 7.52 (m, 1H), 7.50 - 7.44 (m, 2H), 3.10 (s, 3H), 2.99 (d, J = 16.2 Hz, 1H), 2.81 (d, J = 16.2 Hz, 1H), 2.06 (qt, J = 6.7, 3.6 Hz, 1H), 0.28 - 0.23 (m, 2H), 0.09 - 0.05 (m, 2H). Intermediate 38: N-(2-chlorophenyl)-N-methyl-2-(propylamino)acetamide: [ka]

[0517] It was isolated as a yellow, oily substance.

[0518] Yield: (0.45g, 58%).

[0519] ES-MS[M+H]+ :241.1 / 243.1, Rt=5.560 minutes (Method-G).

[0520] 1 H NMR (400 MHz, DMSO-d6) δ 7.68 - 7.63 (m, 1H), 7.56 - 7.51 (m, 1H), 7.49 - 7.43 (m, 2H), 3.10 (s, 3H), 2.95 (d, J = 16.2 Hz, 1H), 2.75 (d, J = 16.2 Hz, 1H), 2.39 - 2.25 (m, 2H), 1.30 (q, J = 7.3 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H). Intermediate 39: N-(2,6-dichlorophenyl)-2-(ethylamino)-N-methylacetamide: [ka]

[0521] It was isolated as a yellow, oily substance.

[0522] Yield: (0.20g, 40%).

[0523] ES-MS[M+H] + :261.1 / 263.0 / 265.0, Rt=5.706 minutes (Method-G).

[0524] 1 H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.2 Hz, 2H), 7.53 - 7.49 (m, 1H), 3.06 (s, 3H), 2.84 (s, 2H), 2.41 (q, J = 7.1 Hz, 2H), 0.91 (t, J = 7.1 Hz, 3H). Intermediate 40: N-(3,4-dichlorophenyl)-N-methyl-2-(methylamino)acetamide: [ka]

[0525] Yield: (0.66g, 84%).

[0526] ES-MS[M+H] + :247.0 / 248.8, Rt=5.838 minutes (Method-G).

[0527] 1 H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.5, 2.5 Hz, 1H), 3.26 (s, 3H), 3.13 (s, 2H), 2.39 (s, 3H). Intermediate 41: N-(2-fluorophenyl)-N-methyl-2-(methylamino)acetamide: [ka]

[0528] It was isolated as a yellow, oily substance.

[0529] Yield: (0.38g, 45%).

[0530] ES-MS[M+H] + :197.0, Rt=5.188 minutes (Method-G). Intermediate 42: N-methyl-2-(methylamino)-N-(4-methylthiazole-2-yl)acetamide: [ka]

[0531] A mixture of 2-chloro-N-methyl-N-(4-methylthiazole-2-yl)acetamide and 2-iodo-N-methyl-N-(4-methylthiazole-2-yl)acetamide (0.67 g, 2.26 mmol, 1.0 equivalent) was mixed with a 2M methylamine solution in THF (17 mL, 33.94 mmol, 15 equivalents). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to dryness, and the crude product was treated with ethyl acetate (50 mL). The organic layer was washed with 1M NaOH (25 mL) and water (25 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by flash column chromatography (DCM / DCM:MeOH(90:10) (containing 32% NH), 0%~50%) to obtain N-methyl-2-(methylamino)-N-(4-methylthiazole-2-yl)acetamide as a yellow oily substance.

[0532] Yield: (0.115g, 25%).

[0533] ES-MS[M+H] + :200.0, Rt=4.837 minutes (Method-G). Intermediate 43: N-methyl-2-(ethylamino)-N-(4-methylthiazole-2-yl)acetamide: [ka]

[0534] A mixture of 2-chloro-N-methyl-N-(4-methylthiazole-2-yl)acetamide and 2-iodo-N-methyl-N-(4-methylthiazole-2-yl)acetamide (0.19 g, 0.64 mmol, 1.0 equivalent) was mixed with a 2M ethylamine solution in THF (3.2 mL, 31.06 mmol, 10 equivalents), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness, and the crude product was treated with DCM (50 mL). The organic layer was washed with water (15 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (DCM / DCM:MeOH (90:10) (containing 32% NH), 0%~50%) to obtain N-methyl-2-(ethylamino)-N-(4-methylthiazole-2-yl)acetamide as a yellow solid.

[0535] Yield: (0.05g, 36%).

[0536] ES-MS[M+H] + :214.1, Rt=5.060 minutes (Method-G). General Procedure C [ka] (In the formula, R a is methyl and R b is H or R a is H and R b is methyl, and R 1 , R 2 and R 5 (As defined above) Step 1:

[0537] To a stirred solution of methyl 3-amino-4-methylthiophene-2-carboxylate (1.0 equivalent) or methyl 3-amino-5-methylthiophene-2-carboxylate (1.0 equivalent) in 4M hydrochloric acid (6.4 equivalents) in dioxane, chloroacetonitrile (1.3 equivalents) was added. The resulting mixture was stirred for 15 hours. The reaction mixture was concentrated to dryness, and the crude product was treated with water (15 mL) and made basic with sodium bicarbonate until the pH was 8.0. The resulting suspended solid was collected by suction filtration, washed with water, and vacuum-dried overnight at 60°C to obtain 2-(chloromethyl)-7-methylthieno[3,2-d]pyrimidine-4(3H)-one or 2-(chloromethyl)-6-methylthieno[3,2-d]pyrimidine-4(3H)-one as a solid. Step 2:

[0538] DIPEA (1.0 equivalent) was added to a stirred mixture consisting of 2-(chloromethyl)-7-methylthieno[3,2-d]pyrimidine-4(3H)-one or 2-(chloromethyl)-6-methylthieno[3,2-d]pyrimidine-4(3H)-one (1.0 equivalent) and one of the intermediates 33-43 (1.0 equivalent) in ethanol (1.5 mL). This mixture was heated to 90°C and stirred for 16 hours. The reaction was quenched with water (10 mL). The aqueous layer was extracted by DCM (×3). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (DCM / DCM:MeOH (90:10), 0%-50%) to obtain the corresponding product as a solid. Intermediate 44: 2-(chloromethyl)-7-methylthieno[3,2-d]pyrimidine-4(3H)-one: [ka]

[0539] The gray solid was isolated.

[0540] Yield: (3.02g, quantitative).

[0541] ES-MS[M+H] + :215.0 / 216.9, Rt=4.820 minutes (Method-G).

[0542] 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.2 Hz, 1H), 4.55 (s, 2H), 2.29 (d, J = 1.2 Hz, 3H). Intermediate 45: 2-(chloromethyl)-7-methylthieno[3,2-d]pyrimidine-4(3H)-one: [ka]

[0543] This reaction was carried out at 60°C. The gray solid was isolated.

[0544] Yield: (1.10g, 92%).

[0545] ES-MS[M+H] + :215.0 / 216.9, Rt=4.562 minutes (Method-G).

[0546] 1 H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.14 (q, J = 1.0 Hz, 1H), 4.55 (s, 2H), 2.59 (d, J = 1.2 Hz, 3H). (Example 38) 2-(((2-(isoindorin-2-yl)-2-oxoethyl)(methyl)amino)methyl)-7-methylthieno[3,2-d]pyrimidine-4(3H)-one [ka]

[0547] The reaction mixture was treated with water (2.5 mL), after which the product precipitated. The suspended solid was isolated by suction filtration and vacuum-dried overnight at 60°C.

[0548] Yield: (0.058g, 56%).

[0549] ES-MS[M+H] + :369.2 / 370.1, Rt=17.100 min (Method-H).

[0550] 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.31 (d, J = 2.8 Hz, 3H), 4.83 (s, 2H), 4.68 (s, 2H), 3.68 (s, 2H), 3.58 (s, 2H), 2.44 (s, 3H), 2.28 (d, J = 1.1 Hz, 3H). (Example 39) 2-(((2-(indolin-1-yl)-2-oxoethyl)(methyl)amino)methyl)-7-methylthieno[3,2-d]pyrimidine-4(3H)-one [ka]

[0551] Yield: (0.023g, 65%).

[0552] ES-MS[M+H] + :369.2, Rt=17.760 minutes (Method-H).

[0553] 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.33 - 7.21 (m, 1H), 7.16 (td, J = 7.7, 1.4 Hz, 1H), 7.00 (td, J = 7.4, 1.1 Hz, 1H), 4.09 (t, J = 8.4 Hz, 2H), 3.75 (s, 2H), 3.64 (s, 2H), 3.14 (t, J = 8.4 Hz, 2H), 2.46 (s, 3H), 2.29 (d, J = 1.1 Hz, 3H). (Example 40) 2-(N-((3,4-dihydro-7-methyl-4-oxothieno[3,2-d]pyrimidine-2-yl)methyl)-N-methylamino)-N-(3,4-dichlorophenyl)-N-methylacetamide [ka]

[0554] Yield: (0.079g, 80%).

[0555] ES-MS[M+H] + :425.1 / 426.9, Rt=19.307 minutes (Method-H).

[0556] 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 8.6, 2.5 Hz, 1H), 3.64 (s, 2H), 3.19 (s, 3H), 2.50 (p, J = 1.9 Hz, 2H), 2.36 (s, 3H), 2.26 (d, J = 1.2 Hz, 3H). (Example 41) N-(2-chlorophenyl)-N-methyl-2-(methyl((7-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)acetamide [ka]

[0557] The product was purified by flash column chromatography using (DCM / Â, 0%~50%) to obtain the corresponding product as a solid.

[0558] Yield: (0.041g, 39%).

[0559] ES-MS[M+H] + :391.3 / 392.9, Rt=17.978 minutes (Method-H).

[0560] 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.79 (d, J = 1.4 Hz, 1H), 7.61 - 7.48 (m, 2H), 7.39 (dd, J = 6.0, 3.5 Hz, 2H), 3.58 (d, J = 1.5 Hz, 2H), 3.27 - 3.15 (m, 1H), 3.09 (s, 3H), 3.01 (d, J = 16.4 Hz, 1H), 2.33 (s, 3H), 2.24 (d, J = 1.2 Hz, 3H). (Example 42) N-(2-chlorophenyl)-2-(ethyl((7-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)-N-methylacetamide [ka]

[0561] Yield: (0.044g, 47%).

[0562] ES-MS[M+H]+ :405.1 / 407.1, Rt=18.887 minutes (Method-H).

[0563] 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.80 (q, J = 1.1 Hz, 1H), 7.69 - 7.60 (m, 1H), 7.60 - 7.51 (m, 1H), 7.50 - 7.38 (m, 2H), 3.75 - 3.57 (m, 2H), 3.29 - 3.21 (m, 1H), 3.11 (s, 4H), 2.63 (q, J = 7.2 Hz, 2H), 2.26 (d, J = 1.2 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H). (Example 43) N-(2-chlorophenyl)-2-(cyclopropyl((7-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)-N-methylacetamide [ka]

[0564] Yield: (0.026g, 33%).

[0565] ES-MS[M+H] + :417.1, Rt=19.063 min (Method-H).

[0566] 1H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.68 - 7.57 (m, 1H), 7.58 - 7.48 (m, 1H), 7.49 - 7.31 (m, 2H), 3.86 (d, J = 4.0 Hz, 2H), 3.25 - 3.13 (m, 2H), 3.10 (s, 3H), 2.40 (dq, J = 6.5, 3.4 Hz, 1H), 2.26 (d, J = 1.1 Hz, 3H), 0.30 (dd, J = 6.6, 2.4 Hz, 2H), 0.20 - 0.15 (m, 2H). (Example 44) N-(2-chlorophenyl)-N-methyl-2-(((7-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)(propyl)amino)acetamide [ka]

[0567] Yield: (0.042g, 43%).

[0568] ES-MS[M+H] + :419.1 / 421.0, Rt=19.756 minutes (Method-H).

[0569] 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 7.80 (t, J = 1.2 Hz, 1H), 7.70 - 7.61 (m, 1H), 7.60 - 7.53 (m, 1H), 7.45 - 7.45 (m, 2H), 3.79 - 3.58 (m, 2H), 3.27 (d, J = 7.2 Hz, 1H), 3.12 (s, 3H), 3.07 (d, J = 16.9 Hz, 1H), 2.62 - 2.51 (m, 2H), 2.26 (d, J = 1.1 Hz, 3H), 1.24 (h, J = 7.3 Hz, 2H), 0.70 (t, J = 7.3 Hz, 3H). (Example 45) N-(2-chlorophenyl)-N-methyl-2-(methyl((6-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)acetamide [ka]

[0570] Yield: (0.059, 64%).

[0571] ES-MS[M+H] + :391.1 / 392.9, Rt=17.404 minutes (Method-H).

[0572] 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.67 - 7.56 (m, 1H), 7.53 (dd, J = 6.0, 3.5 Hz, 1H), 7.41 (dd, J = 6.0, 3.6 Hz, 2H), 7.05 (d, J = 1.1 Hz, 1H), 3.54 (s, 2H), 3.18 (d, J = 16.4 Hz, 1H), 3.09 (s, 3H), 2.97 (d, J = 16.5 Hz, 1H), 2.57 (d, J = 1.1 Hz, 3H), 2.31 (s, 3H). (Example 46) N-(2-chlorophenyl)-2-(ethyl((6-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)-N-methylacetamide [ka]

[0573] Yield: (0.040, 42%).

[0574] ES-MS[M+H] + :405.3 / 407.0, Rt=18.331 minutes (Method-H).

[0575] 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.63 (dd, J = 5.9, 3.6 Hz, 1H), 7.57 (dd, J = 6.1, 3.4 Hz, 1H), 7.44 (dd, J = 6.0, 3.6 Hz, 2H), 7.05 (d, J = 1.2 Hz, 1H), 3.74 - 3.55 (m, 2H), 3.31 - 3.17 (m, 1H), 3.11 (s, 3H), 3.03 (d, J = 16.8 Hz, 1H), 2.72 - 2.58 (m, 2H), 2.57 (d, J = 1.1 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H). (Example 47) N-(2-chlorophenyl)-2-(cyclopropyl((6-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)-N-methylacetamide [ka]

[0576] Yield: (0.070g, 72%).

[0577] ES-MS[M+H] +:417.2, Rt=18.917 min (Method-H).

[0578] 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 7.67 - 7.60 (m, 1H), 7.58 - 7.51 (m, 1H), 7.49 - 7.39 (m, 2H), 7.07 (d, J = 1.1 Hz, 1H), 3.90 - 3.72 (m, 2H), 3.28 (d, J = 6.9 Hz, 1H), 3.13 (d, J = 16.7 Hz, 1H), 3.10 (s, 3H), 2.58 (d, J = 1.1 Hz, 3H), 2.38 (tt, J = 6.7, 3.6 Hz, 1H), 0.33 - 0.22 (m, 2H), 0.22 - 0.11 (m, 2H). (Example 48) N-methyl-2-(methyl((7-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)-N-(4-methylthiazole-2-yl)acetamide [ka]

[0579] Yield: (0.046g, 54%).

[0580] ES-MS[M+H] + :378.1 / 379.0 / 380.0, Rt=15.695 minutes (Method-H).

[0581] 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (bs, 1H), 7.80 (s, 1H), 6.65 (s, 1H), 3.74 (s, 2H), 3.63 (s, 3H), 3.54 (s, 2H), 2.43 (s, 3H), 2.29 (s, 6H). (Example 49) N-(2,6-dichlorophenyl)-2-(ethyl((7-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)-N-methylacetamide [ka]

[0582] Yield: (0.042g, 48%).

[0583] ES-MS[M+H] + :439.2 / 441.2, Rt=5.801 min (Method-J).

[0584] 1 H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.44 (dd, J = 8.7, 7.6 Hz, 1H), 3.67 (s, 2H), 3.19 (s, 2H), 3.06 (s, 3H), 2.68 (q, J = 7.2 Hz, 2H), 2.25 (d, J = 1.1 Hz, 3H), 0.88 (t, J = 7.1 Hz, 3H). (Example 50) N-(3-fluorophenyl)-N-methyl-2-(methyl((7-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)acetamide [ka]

[0585] Yield: (0.061g, 66%).

[0586] ES-MS[M+H] + :375.1 / 376.1, Rt=17.272 minutes (Method-H).

[0587] 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 7.80 (t, J = 1.2 Hz, 1H), 7.44 (td, J = 8.2, 6.6 Hz, 1H), 7.31 (d, J = 10.2 Hz, 1H), 7.20 (ddd, J = 10.0, 5.5, 1.8 Hz, 2H), 3.62 (s, 2H), 3.32 (s, 2H), 3.19 (s, 3H), 2.34 (s, 3H), 2.26 (d, J = 1.1 Hz, 3H). (Example 51) N-(3-fluorophenyl)-N-methyl-2-(methyl((6-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)acetamide [ka]

[0588] Yield: (0.063g, 72%).

[0589] ES-MS[M+H] + :375.1 Rt=16.763 minutes (Method-H).

[0590] 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 7.45 (td, J = 8.2, 6.6 Hz, 1H), 7.31 (d, J = 10.2 Hz, 1H), 7.24 - 7.13 (m, 2H), 7.07 (d, J = 1.2 Hz, 1H), 3.57 (s, 2H), 3.28 (s, 2H), 3.19 (s, 3H), 2.57 (d, J = 1.1 Hz, 3H), 2.32 (s, 3H). (Example 52) 2-(((2-(indolin-1-yl)-2-oxoethyl)(methyl)amino)methyl)-6-methylthieno[3,2-d]pyrimidine-4(3H)-one [ka]

[0591] Yield: (0.048g, 50%).

[0592] ES-MS[M+H] + :369.2, Rt=16.151 min (Method-H).

[0593] 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 7.20 - 7.12 (m, 1H), 7.08 (t, J = 1.1 Hz, 1H), 7.00 (td, J = 7.4, 1.1 Hz, 1H), 4.07 (t, J = 8.5 Hz, 2H), 3.69 (s, 2H), 3.62 (s, 2H), 3.14 (t, J = 8.4 Hz, 2H), 2.57 (d, J = 1.1 Hz, 3H), 2.44 (s, 3H). (Example 53) 2-(((2-(isoindolin-2-yl)-2-oxoethyl)(methyl)amino)methyl)-6-methylthieno[3,2-d]pyrimidine-4(3H)-one [ka]

[0594] Yield: (0.035g, 50%).

[0595] ES-MS[M+H] + :369.2, Rt=16.538 minutes (Method-H).

[0596] 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 7.50 - 7.23 (m, 4H), 7.07 (s, 1H), 4.82 (s, 2H), 4.67 (s, 2H), 3.63 (s, 2H), 3.55 (s, 2H), 2.57 (s, 3H), 2.41 (s, 3H). (Example 54) N-(2-chlorophenyl)-N-methyl-2-(((6-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)(propyl)amino)acetamide [ka]

[0597] Yield: (0.038g, 33%).

[0598] ES-MS[M+H] + :419.1 / 421.0, Rt=19.207 minutes (Method-H).

[0599] 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.68 - 7.62 (m, 1H), 7.61 - 7.54 (m, 1H), 7.47 (m, 02H), 7.06 (d, J = 1.2 Hz, 1H), 3.76 - 3.54 (m, 2H), 3.29 - 3.22 (d, J = 16.9 Hz, 1H), 3.12 (s, 3H), 3.04 (d, J = 16.9 Hz, 1H), 2.57 (d, J = 1.1 Hz, 3H), 2.53 (m, 2H), 1.22 (m, 2H), 0.69 (t, J = 7.3 Hz, 3H). (Example 55) N-(3,4-dichlorophenyl)-N-methyl-2-(methyl((6-methyl-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)methyl)amino)acetamide [ka]

[0600] Yield: (0.069g, 69%).

[0601] ES-MS[M+H] + :425.1 / 426.9. Rt=18.791 minutes (Method-H).

[0602] 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 7.73 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.38 (dd, J = 8.6, 2.5 Hz, 1H), 7.06 (d, J = 1.3 Hz, 1H), 3.57 (s, 2H), 3.33 (s, 2H), 3.18 (s, 3H), 2.57 (d, J = 1.1 Hz, 3H), 2.33 (s, 3H). General Procedure D [ka] Step 1:

[0603] The corresponding benzonitrile (1.0 equivalent) was dissolved in sulfuric acid (1.2 M). The reaction mixture was heated to 50°C and stirred for 2 hours. The mixture was slowly poured into cold water (100 mL), and the reaction was then quenched by making it basic with 25% w / w NaOH until a solid precipitate was observed. The suspension was stirred at 0°C for 1 hour, and the product was isolated by suction filtration and vacuum-dried overnight at 60°C to obtain the corresponding amide as a solid. Step 2

[0604] Chloroacetyl chloride (2.0 equivalents) was added to a mixture of the corresponding benzamide (1.0 equivalent) in acetic acid (1 M). This mixture was heated to reflux and stirred for 2 hours. The reaction mixture was cooled to room temperature and slowly poured into cold water (50 mL). The suspended solid was stirred at 0°C for 30 minutes, isolated by suction filtration, and vacuum-dried overnight at 60°C to obtain the corresponding chloride as a solid. Intermediate 46: 2-amino-5-fluorobenzamide: [ka]

[0605] A precipitate of amide was observed at pH = 2.8 to 3.2. The precipitate was a white solid.

[0606] Yield: (1.03g, 61%).

[0607] ES-MS[M+H] + :138.0 / 155.1, Rt=3.252 minutes (Method-G). Intermediate 47: 2-amino-4-fluorobenzamide: [ka]

[0608] A precipitate of amide was observed at pH = 1.8 to 2.0. It was a beige-colored solid.

[0609] Yield: (0.30g, 52%).

[0610] ES-MS[M+H] + :138.0 / 155.0, Rt=3.818 minutes (Method-G). Intermediate 48: 2-amino-5-methylbenzamide: [ka]

[0611] This reaction was carried out at room temperature.

[0612] Yield: (0.50g, 88%).

[0613] ES-MS[M+H] + :134.0 / 151.1, Rt=4.229 minutes (Method-G). Intermediate 49: 2-amino-4-methylbenzamide: [ka]

[0614] This reaction was carried out at room temperature.

[0615] Yield: (1.09g, 99%).

[0616] ES-MS[M+H] + :134.0 / 151.1, Rt=4.190 minutes (Method-G). Intermediate 50: 2-(chloromethyl)-6-fluoroquinazoline-4(3H)-one: [ka]

[0617] Yield: (1.50g, 97%).

[0618] ES-MS[M+H] + :213.0 / 215.0, Rt=4.900 minutes (Method-G).

[0619] 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 7.85 - 7.68 (m, 3H), 4.55 (s, 2H). Intermediate 51: 2-(chloromethyl)-7-fluoroquinazoline-4(3H)-one: [ka]

[0620] This reaction was maintained under reflux for 3 hours.

[0621] Yield: (0.26g, 70%).

[0622] ES-MS[M+H] + :213.0 / 215.0, Rt=5.011 minutes (Method-G).

[0623] 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.18 (dd, J = 8.8, 6.3 Hz, 1H), 7.49 (dd, J = 10.1, 2.5 Hz, 1H), 7.42 (td, J = 8.7, 2.6 Hz, 1H), 4.54 (s, 2H). Intermediate 52: 2-(chloromethyl)-6-methylquinazoline-4(3H)-one: [ka]

[0624] The solid was treated with methanol (10 mL) at room temperature for 30 minutes. The suspended solid was isolated by suction filtration and vacuum-dried at 60°C for 4 hours to obtain the product as an off-white solid.

[0625] Yield: (0.34g, 50%).

[0626] ES-MS[M+H] + :209.1 / 211.0, Rt=5.211 minutes (Method-G).

[0627] 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.37 (dd, J = 8.1, 1.7 Hz, 1H), 4.53 (s, 2H), 2.46 (s, 3H). Intermediate 53: 2-(chloromethyl)-7-methylquinazoline-4(3H)-one: [ka]

[0628] The solid was powdered in MeOH. The suspended solid was isolated by suction filtration and vacuum-dried at 60°C for 4 hours to obtain the product as a beige solid.

[0629] Yield: (0.88g, 58%).

[0630] ES-MS[M+H] + :209.1 / 211.0, Rt=5.211 minutes (Method-G).

[0631] 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 8.3, 2.1 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 4.53 (s, 2H), 2.45 (s, 3H). General Procedure E [ka] (In the formula, R 1 , R 2 and R 5 As defined above, R' and R'' are R 6 , R 7 and R 8 (As defined in relation to this.)

[0632] DIPEA (1.0 equivalent) was added to a stirred mixture consisting of the corresponding chloride (1.0 equivalent) and one of the intermediates 33-43 (1.0 equivalent) in ethanol (1.5 mL). This mixture was heated to 90°C and stirred for 16 hours. The reaction was quenched with water (10 mL). The aqueous layer was extracted by DCM (×3). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (DCM / DCM:MeOH (90:10), 0%-50%) to obtain the corresponding product as a solid. (Example 56) 6-Fluoro-2-(((2-(isoindolin-2-yl)-2-oxoethyl)(methyl)amino)methyl)quinazoline-4(3H)-one [ka]

[0633] The product was extracted using ethyl acetate (x3) instead of dimethyl methyl chloride (DCM).

[0634] Yield: (0.026g, 29%).

[0635] ES-MS[M+H] + :367.2, Rt=17.281 min (Method-H).

[0636] 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 7.79 (ddd, J = 8.7, 2.8, 0.7 Hz, 1H), 7.75 - 7.57 (m, 2H), 7.37 (td, J = 4.3, 3.9, 1.1 Hz, 1H), 7.34 - 7.18 (m, 3H), 4.83 (s, 2H), 4.68 (s, 2H), 3.64 (s, 2H), 3.58 (s, 2H), 2.44 (s, 3H). (Example 57) 6-Fluoro-2-(((2-(indolin-1-yl)-2-oxoethyl)(methyl)amino)methyl)quinazoline-4(3H)-one [ka]

[0637] Yield: (0.050g, 57%).

[0638] ES-MS[M+H] + :367.2, Rt=17.814 min (Method-H).

[0639] 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.82 - 7.75 (m, 1H), 7.75 - 7.62 (m, 2H), 7.24 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 8.1 Hz, 1H), 7.00 (td, J = 7.4, 1.1 Hz, 1H), 4.08 (t, J = 8.5 Hz, 2H), 3.70 (s, 2H), 3.64 (s, 2H), 3.14 (t, J = 8.6 Hz, 2H), 2.47 (s, 3H). (Example 58) N-(3,4-dichlorophenyl)-2-(((6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)(methyl)amino)-N-methylacetamide [ka]

[0640] Yield: (0.074g, 75%).

[0641] ES-MS[M+H] + :423.1 / 424.8, Rt=19.182 minutes (Method-H).

[0642] 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 7.80 - 7.75 (m, 1H), 7.74 (s, 1H), 7.71 - 7.66 (m, 2H), 7.65 (s, 1H), 7.39 (dd, J = 8.7, 2.5 Hz, 1H), 3.57 (s, 2H), 3.18 (s, 3H), 2.50 (p, J = 1.9 Hz, 2H), 2.35 (s, 3H). (Example 59) N-(2-chlorophenyl)-2-(((6-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)(methyl)amino)-N-methylacetamide [ka]

[0643] Yield: (0.080g, 61%).

[0644] ES-MS[M+H] + :389.1 / 391.1, Rt=17.984 minutes (Method-H).

[0645] 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 7.77 (ddd, J = 8.6, 2.4, 1.2 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.62 - 7.49 (m, 2H), 7.46 - 7.31 (m, 2H), 3.55 (d, J = 1.0 Hz, 2H), 3.21 (d, J = 16.5 Hz, 1H), 3.09 (s, 3H), 3.00 (d, J = 16.4 Hz, 1H), 2.33 (s, 3H). (Example 60) N-(2-chlorophenyl)-2-(ethyl((6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)-N-methylacetamide [ka]

[0646] The crude product required a second purification by flash column chromatography (acetate / Hex, 20%-100%).

[0647] Yield: (0.043g, 43%).

[0648] ES-MS[M+H] + :403.2 / 405.1, Rt=18.883 minutes (Method-H).

[0649] 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.80 - 7.72 (m, 1H), 7.70 - 7.63 (m, 3H), 7.63 - 7.52 (m, 2H), 7.47 - 7.33 (m, 2H), 3.62 (d, J = 7.9 Hz, 2H), 3.27 (d, J = 26.4 Hz, 1H), 3.09 (s, 3H), 3.03 (d, J = 16.9 Hz, 1H), 2.62 (q, J = 7.1 Hz, 2H), 0.82 (t, J = 7.1 Hz, 3H). (Example 61) N-(2-chlorophenyl)-2-(cyclopropyl((6-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-methylacetamide [ka]

[0650] The product was extracted using Â(×3) instead of DCM. Purification was performed using  / Hex (10%~65%).

[0651] Yield: (0.041g, 35%).

[0652] ES-MS[M+H] +:415.1 / 417.1, Rt=19.227 minutes (Method-H).

[0653] 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.66 - 7.56 (m, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.52 - 7.50 (m, 1H), 7.47 - 7.43 (m, 1H), 7.42 - 7.35 (m, 1H), 7.34 - 7.18 (m, 2H), 3.66 (d, J = 4.4 Hz, 2H), 3.15 - 3.13 (m, 1H), 3.00 (d, J = 16.7 Hz, 1H), 2.94 (s, 3H), 2.25 (tt, J = 6.7, 3.6 Hz, 1H), 0.18 - 0.09 (m, 2H), 0.02 (q, J = 3.3 Hz, 2H). (Example 62) N-(2-chlorophenyl)-2-(((6-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)(propyl)amino)-N-methylacetamide [ka]

[0654] Yield: (0.066g, 67%).

[0655] ES-MS[M+H] + :417.1 / 419.1, Rt=19.719 minutes (Method-H).

[0656] 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.89 - 7.72 (m, 1H), 7.68 (dd, J = 6.6, 1.6 Hz, 2H), 7.66 - 7.61 (m, 1H), 7.61 - 7.54 (m, 1H), 7.51 - 7.40 (m, 2H), 3.80 - 3.53 (m, 2H), 3.26 (d, J = 6.3 Hz, 1H), 3.12 (s, 3H), 3.06 (d, J = 17.0 Hz, 1H), 2.64 - 2.52 (m, 2H), 1.37 - 1.14 (m, 2H), 0.69 (t, J = 7.3 Hz, 3H). (Example 63) N-(2-chlorophenyl)-2-(((7-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)(methyl)amino)-N-methylacetamide [ka]

[0657] The product was extracted using ethyl acetate (x3) instead of dimethyl methyl chloride (DCM).

[0658] Yield: (0.025g, 24%).

[0659] ES-MS[M+H] + :389.1 / 391.1, Rt=18.140 minutes (Method-H).

[0660] 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.14 (ddt, J = 8.1, 6.3, 0.9 Hz, 1H), 7.69 - 7.46 (m, 2H), 7.46 - 7.14 (m, 4H), 3.54 (s, 2H), 3.25 (s, 1H), 3.07 (d, J = 0.9 Hz, 3H), 2.98 (d, J = 16.5 Hz, 1H), 2.32 (d, J = 0.9 Hz, 3H). (Example 64) N-(2-chlorophenyl)-2-(ethyl((7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)-N-methylacetamide hydrochloride [ka]

[0661] Since the free base was a yellow oily substance, the compound was obtained as a hydrochloride salt. Salt formation was carried out by adding a 4M HCl solution (1.2 equivalents) in dioxane to the free base N-(2-chlorophenyl)-2-(ethyl((7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)-N-methylacetamide (1.0 equivalent). This mixture was stirred at room temperature for 6 hours. The mixture was concentrated to dryness, and the resulting crude product was co-evaporated with diethyl ether to obtain the hydrochloride salt as a light brown solid.

[0662] Yield: (0.031g, 30%).

[0663] ES-MS[M+H] + :403.2 / 405.0, Rt=19.030 minutes (Method-H).

[0664] 1 H NMR (400 MHz, Methanol-d4) δ 7.63 - 7.59 (m, 1H), 7.54 - 7.46 (m, 1H), 8.28 (dd, J = 9.5, 6.1 Hz, 3H), 7.42 - 7.22 (m, 2H), 4.89 (s, 1H), 4.79 (s, 1H), 4.27 (s, 2H), 4.00 - 3.68 (m, 2H), 3.29 (s, 3H), 1.27 (t, J = 7.4 Hz, 3H). (Example 65) N-(2-chlorophenyl)-2-(cyclopropyl((6-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-methylacetamide [ka]

[0665] The product was extracted using ethyl acetate (x3) instead of dimethyl methyl chloride (DCM).

[0666] Yield: (0.057g, 49%).

[0667] ES-MS[M+H] + :415.1 / 417.1, Rt=19.298 min (Method-H).

[0668] 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.15 (dd, J = 8.8, 6.4 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.59 - 7.50 (m, 1H), 7.49 - 7.24 (m, 4H), 3.84 (d, J = 4.6 Hz, 2H), 3.32 (s, 1H), 3.20 (d, J = 17.8 Hz, 1H), 3.10 (s, 3H), 2.41 (td, J = 6.6, 3.3 Hz, 1H), 0.30 (dd, J = 6.5, 2.4 Hz, 2H), 0.18 (p, J = 3.8 Hz, 2H). (Example 66) N-(2-chlorophenyl)-N-methyl-2-(methyl((6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)acetamide [ka]

[0669] Yield: (0.036g, 40%).

[0670] ES-MS[M+H] + :385.2 / 387.0, Rt=18.060 min (Method-H).

[0671] 1H NMR (400 MHz, DMSO-d6) δ 11.73 - 11.57 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.67 - 7.57 (m, 1H), 7.57 - 7.49 (m, 1H), 7.47 - 7.34 (m, 3H), 7.31 (ddd, J = 8.1, 1.7, 0.7 Hz, 1H), 3.53 (s, 2H), 3.29 - 3.17 (m, 1H), 3.10 (s, 3H), 3.00 (d, J = 16.4 Hz, 1H), 2.44 (s, 3H), 2.32 (s, 3H). (Example 67) 2-(ethyl((6-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-methyl-N-(4-methylthiazole-2-yl)acetamide [ka]

[0672] Yield: (0.016g, 17%).

[0673] ES-MS[M+H] + :390.1 / 391.1, Rt=17.056 minutes (Method-H).

[0674] 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.78 (ddd, J = 8.6, 2.6, 0.9 Hz, 1H), 7.72 - 7.65 (m, 2H), 6.67 (q, J = 1.1 Hz, 1H), 3.74 (s, 2H), 3.65 (s, 3H), 3.60 (s, 2H), 2.74 (q, J = 7.1 Hz, 2H), 2.30 (d, J = 1.3 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H). (Example 68) 2-(((7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)(methyl)amino)-N-methyl-N-(4-methylthiazole-2-yl)acetamide [ka]

[0675] Yield: (0.019g, 21%).

[0676] ES-MS[M+H] + :376.2, Rt=16.055 minutes (Method-H).

[0677] 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.16 (dd, J = 8.8, 6.4 Hz, 1H), 7.41 (dd, J = 10.2, 2.6 Hz, 1H), 7.35 (td, J = 8.7, 2.6 Hz, 1H), 6.65 (d, J = 1.4 Hz, 1H), 3.71 (s, 2H), 3.63 (s, 3H), 3.55 (s, 2H), 2.44 (s, 3H), 2.29 (d, J = 1.2 Hz, 3H). (Example 69) 2-(N-ethyl-N-((6-fluoro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl)amino)-N-(2,6-dichlorophenyl)-N-methylacetamide [ka]

[0678] Purification was performed using æx / Hex (10% to 100%).

[0679] Yield: (0.038g, 38%).

[0680] ES-MS[M+H] + :437.3, Rt=5.947 min (Method-J).

[0681] 1 H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 7.77 (ddd, J = 8.6, 2.6, 0.9 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.66 - 7.58 (m, 2H), 7.46 (dd, J = 8.7, 7.7 Hz, 1H), 3.64 (s, 2H), 3.17 (s, 2H), 3.07 (s, 3H), 2.69 (q, J = 7.1 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H). (Example 70) 2-(N-((3,4-dihydro-7-methyl-4-oxoquinazoline-2-yl)methyl)-N-methylamino)-N-(2-chlorophenyl)-N-methylacetamide [ka]

[0682] Yield: (0.062g, 69%).

[0683] ES-MS[M+H] + :385.2, Rt=18.161 min (Method-H).

[0684] 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.89 (td, J = 1.5, 0.7 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.57 - 7.52 (m, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 5.9, 3.5 Hz, 2H), 3.53 (d, J = 1.2 Hz, 2H), 3.21 (d, J = 16.5 Hz, 1H), 3.09 (s, 3H), 2.99 (d, J = 16.5 Hz, 1H), 2.43 (s, 3H), 2.32 (s, 3H). (Example 71) 7-Fluoro-2-(((2-(isoindolin-2-yl)-2-oxoethyl)(methyl)amino)methyl)quinazoline-4(3H)-one [ka]

[0685] The reaction mixture was treated with water (2.5 mL), after which the product precipitated. The suspended solid was isolated by suction filtration and vacuum-dried overnight at 60°C.

[0686] Yield: (0.067g, 65%).

[0687] ES-MS[M+H] + :367.2 / 368.1, Rt=17.288 minutes (Method-H).

[0688] 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.18 (dd, J = 8.8, 6.3 Hz, 1H), 7.54 - 7.16 (m, 6H), 4.83 (s, 2H), 4.68 (s, 2H), 3.65 (s, 2H), 3.59 (s, 2H), 2.44 (s, 3H). (Example 72) 7-Fluoro-2-(((2-(indolin-1-yl)-2-oxoethyl)(methyl)amino)methyl)quinazoline-4(3H)-one [ka]

[0689] The crude product was treated with water (10 mL), and the suspended solid was stirred at room temperature for 30 minutes. The solid was isolated by suction filtration and vacuum-dried overnight at 60°C to obtain the product as a light brown solid.

[0690] Yield: (0.067g, 78%).

[0691] ES-MS[M+H] +:367.2, Rt=17.930 min (Method-H).

[0692] 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.17 (dd, J = 8.8, 6.3 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 10.2, 2.5 Hz, 1H), 7.35 (td, J = 8.7, 2.6 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.00 (td, J = 7.4, 1.1 Hz, 1H), 4.08 (t, J = 8.5 Hz, 2H), 3.71 (s, 2H), 3.64 (s, 2H), 3.14 (t, J = 8.5 Hz, 2H), 2.47 (s, 3H). (Example 73) 2-(N-ethyl-N-((7-fluoro-3,4-dihydro-4-oxoquinazoline-2-yl)methyl)amino)-N-(2,6-dichlorophenyl)-N-methylacetamide [ka]

[0693] Purification was performed using æx / Hex (10% to 100%).

[0694] Yield: (0.047g, 69%).

[0695] ES-MS[M+H] + :437.2, Rt=5.949 minutes (Method-H).

[0696] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.28 - 8.07 (m, 1H), 7.75 - 7.59 (m, 2H), 7.46 (dd, J = 8.6, 7.7 Hz, 1H), 7.36 (d, J = 9.4 Hz, 2H), 3.65 (s, 2H), 3.17 (s, 2H), 3.07 (s, 3H), 2.68 (q, J = 7.1 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H). (Example 74) 2-(((6-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)(methyl)amino)-N-(3-fluorophenyl)-N-methylacetamide [ka]

[0697] Yield: (0.060g, 64%).

[0698] ES-MS[M+H] + :373.1, Rt=17.300 min (Method-H).

[0699] 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 7.81 - 7.73 (m, 1H), 7.73 - 7.63 (m, 2H), 7.44 (td, J = 8.2, 6.6 Hz, 1H), 7.30 (d, J = 10.2 Hz, 1H), 7.24 - 7.13 (m, 2H), 3.57 (s, 2H), 3.33 (s, 2H), 3.19 (s, 3H), 2.34 (s, 3H). (Example 75) 2-(N-((7-fluoro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl)-N-methylamino)-N-(3,4-dichlorophenyl)-N-methylacetamide [ka]

[0700] Yield: (0.078g, 78%).

[0701] ES-MS[M+H] + :423.1 / 424.9, Rt=19.370 minutes (Method-H).

[0702] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.34 (dd, J = 8.8, 6.3 Hz, 1H), 6.92 (s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.68 - 6.43 (m, 3H), 2.76 (s, 2H), 2.37 (s, 3H), 1.68 (p, J = 1.8 Hz, 2H), 1.54 (s, 3H). (Example 76) N-(2-chlorophenyl)-2-(((7-fluoro-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)(propyl)amino)-N-methylacetamide [ka]

[0703] Yield: (0.063g, 64%).

[0704] ES-MS[M+H] + :417.0 / 419.0, Rt=19.876 minutes (Method-H).

[0705] 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 8.16 (dd, J = 8.7, 6.4 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.62 - 7.56 (m, 1H), 7.50 - 7.43 (m, 2H), 7.42 - 7.29 (m, 2H), 3.74 - 3.59 (m, 2H), 3.26 (d, J = 7.8 Hz, 1H), 3.12 (s, 3H), 3.06 (d, J = 17.0 Hz, 1H), 2.57 - 2.51 (m, 2H), 1.35 - 1.13 (m, 2H), 0.69 (t, J = 7.3 Hz, 3H). (Example 77) 2-(N-((7-fluoro-3,4-dihydro-4-oxoquinazolin-2-yl)methyl)-N-methylamino)-N-(3-fluorophenyl)-N-methylacetamide [ka]

[0706] Yield: (0.066g, 75%).

[0707] ES-MS[M+H] + :373.1, Rt=17.479 minutes (Method-H).

[0708] 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 8.16 (dd, J = 8.8, 6.3 Hz, 1H), 7.45 (td, J = 8.2, 6.6 Hz, 1H), 7.41 - 7.27 (m, 3H), 7.25 - 7.13 (m, 2H), 3.58 (s, 2H), 3.32 (s, 2H), 3.19 (s, 3H), 2.35 (s, 3H). (Example 78) 2-(N-cyclopropyl-N-((3,4-dihydro-6-methyl-4-oxoquinazoline-2-yl)methyl)amino)-N-(2-chlorophenyl)-N-methylacetamide [ka]

[0709] Yield: (0.022g, 23%).

[0710] ES-MS[M+H] + :410.8 / 413.1, Rt=19.226 minutes (Method-H).

[0711] 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.58 - 7.51 (m, 1H), 7.49 - 7.34 (m, 3H), 7.31 (dd, J = 8.3, 1.7 Hz, 1H), 3.87 - 3.74 (m, 2H), 3.35 (s, 1H), 3.20 (d, J = 17.9 Hz, 1H), 3.11 (s, 3H), 2.45 (s, 3H), 2.39 (dq, J = 6.7, 3.4 Hz, 1H), 0.43 - 0.22 (m, 2H), 0.24 - 0.08 (m, 2H). (Example 79) N-(2-chlorophenyl)-2-(ethyl((6-methyl-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-methylacetamide [ka]

[0712] Yield: (0.077g, 80%).

[0713] ES-MS[M+H] + :399.3, Rt=18.959 minutes (Method-H).

[0714] 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.63 (dd, J = 6.1, 3.4 Hz, 1H), 7.58 (dd, J = 6.0, 3.5 Hz, 1H), 7.44 (dd, J = 5.9, 3.6 Hz, 2H), 7.40 (dt, J = 1.6, 0.7 Hz, 1H), 7.34 - 7.27 (m, 1H), 3.72 - 3.49 (m, 2H), 3.30 - 3.19 (m, 1H), 3.11 (s, 3H), 3.05 (d, J = 16.8 Hz, 1H), 2.62 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 0.83 (t, J = 7.1 Hz, 3H). (Example 80) N-(2-chlorophenyl)-N-methyl-2-(((6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)(propyl)amino)acetamide [ka]

[0715] Yield: (0.073g, 73%).

[0716] ES-MS[M+H] + :413.1 / 415.0, Rt=19.804 minutes (Method-H).

[0717] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 7.99 (dd, J = 8.1, 1.8 Hz, 1H), 7.70 - 7.62 (m, 1H), 7.59 (dd, J = 6.2, 3.2 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.42 - 7.36 (m, 1H), 7.31 (dd, J = 8.1, 1.7 Hz, 1H), 3.74 - 3.47 (m, 2H), 3.33 - 3.19 (m, 1H), 3.12 (d, J = 1.8 Hz, 3H), 3.05 (d, J = 16.9 Hz, 1H), 2.51 (dd, J = 4.9, 3.0 Hz, 2H), 2.44 (s, 3H), 1.37 - 1.14 (m, 2H), 0.68 (t, J = 7.3 Hz, 3H). (Example 81) 2-(((2-(indoline-1-yl)-2-oxoethyl)(methyl)amino)methyl)-6-methylquinazoline-4(3H)-one [ka]

[0718] Yield: (0.064g, 54%).

[0719] ES-MS[M+H] + :363.1 / 364.1, Rt=17.869 minutes (Method-H).

[0720] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.31 (dd, J = 8.1, 1.7 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 7.20 - 7.12 (m, 1H), 7.00 (td, J = 7.4, 1.1 Hz, 1H), 4.08 (t, J = 8.4 Hz, 2H), 3.68 (s, 2H), 3.63 (s, 2H), 3.14 (t, J = 8.5 Hz, 2H), 2.65 (s, 3H), 2.44 (s, 3H) (Example 82) N-(3-fluorophenyl)-N-methyl-2-(methyl((6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)acetamide [ka]

[0721] Yield: (0.055g, 60%).

[0722] ES-MS[M+H] + :369.2, Rt=17.482 minutes (Method-H).

[0723] 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.45 (td, J = 8.1, 6.6 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.37 - 7.26 (m, 2H), 7.26 - 7.11 (m, 2H), 3.55 (s, 2H), 3.32 (s, 2H), 3.19 (s, 3H), 2.44 (s, 3H), 2.34 (s, 3H). (Example 83) N-(2-chlorophenyl)-2-(cyclopropyl((7-methyl-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-methylacetamide [ka]

[0724] Yield: (0.068g, 68%).

[0725] ES-MS[M+H] + :411.3, Rt=19.243 min (Method-H).

[0726] 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.89 (dt, J = 2.4, 0.7 Hz, 1H), 7.61 (ddd, J = 8.3, 4.2, 2.1 Hz, 2H), 7.58 - 7.53 (m, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.46 - 7.38 (m, 2H), 3.89 - 3.72 (m, 2H), 3.29 (d, J = 8.0 Hz, 1H), 3.15 (d, J = 16.7 Hz, 1H), 3.10 (s, 3H), 2.43 (s, 3H), 2.39 (dt, J = 6.5, 3.1 Hz, 1H), 0.35 - 0.24 (m, 2H), 0.24 - 0.13 (m, 2H). (Example 84) N-(2-chlorophenyl)-2-(ethyl((7-methyl-4-oxo-3,4-dihydroquinazoline-2-yl)methyl)amino)-N-methylacetamide [ka]

[0727] Yield: (0.077g, 80%).

[0728] ES-MS[M+H] +:399.1 / 401.0, Rt=18.998 minutes (Method-H).

[0729] 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.68 - 7.61 (m, 1H), 7.61 - 7.55 (m, 2H), 7.49 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 5.9, 3.6 Hz, 2H), 3.74 - 3.48 (m, 2H), 3.24 (d, J = 3.2 Hz, 1H), 3.11 (s, 3H), 3.04 (d, J = 16.8 Hz, 1H), 2.62 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 0.83 (t, J = 7.1 Hz, 3H). (Example 85) N-(2-chlorophenyl)-N-methyl-2-(((7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)(propyl)amino)acetamide [ka]

[0730] The crude product required a second purification by flash column chromatography (Hex / Â, 25%-75%).

[0731] Yield: (0.030g, 30%).

[0732] ES-MS[M+H] + :413.2, Rt=19.888 min (Method-H).

[0733] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.03 - 7.81 (m, 1H), 7.70 - 7.63 (m, 1H), 7.63 - 7.55 (m, 2H), 7.50 (d, J = 8.3 Hz, 1H), 7.48 - 7.42 (m, 2H), 3.79 - 3.50 (m, 2H), 3.31 - 3.19 (m, 2H), 3.12 (s, 3H), 3.05 (d, J = 17.0 Hz, 1H), 2.60 - 2.50 (m, 1H), 2.43 (s, 3H), 1.30 - 1.17 (m, 2H), 0.68 (t, J = 7.3 Hz, 3H). (Example 86) 2-(((2-(indoline-1-yl)-2-oxoethyl)(methyl)amino)methyl)-7-methylquinazoline-4(3H)-one [ka]

[0734] Yield: (0.072g, 75%).

[0735] ES-MS[M+H] + :363.1, Rt=17.939 minutes (Method-H).

[0736] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.99 - 7.82 (m, 1H), 7.61 (ddd, J = 8.3, 2.1, 0.6 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.28 - 7.21 (m, 1H), 7.16 (ddd, J = 8.6, 7.5, 1.3 Hz, 1H), 7.00 (td, J = 7.4, 1.1 Hz, 1H), 4.08 (t, J = 8.5 Hz, 2H), 3.67 (s, 2H), 3.63 (s, 2H), 3.14 (t, J = 8.5 Hz, 2H), 2.45 (s, 3H), 2.44 (s, 3H). (Example 87) 2-(N-((3,4-dihydro-7-methyl-4-oxoquinazoline-2-yl)methyl)-N-methylamino)-N-(3-fluorophenyl)-N-methylacetamide [ka]

[0737] Yield: (0.068g, 77%).

[0738] ES-MS[M+H] + :369.2, Rt=17.508 minutes (Method-H).

[0739] 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.98 - 7.80 (m, 1H), 7.61 (ddd, J = 8.3, 2.1, 0.6 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.48 - 7.38 (m, 1H), 7.31 (d, J = 10.1 Hz, 1H), 7.25 - 7.14 (m, 2H), 3.55 (s, 2H), 3.33 (s, 2H), 3.19 (s, 3H), 2.43 (s, 3H), 2.33 (s, 3H). (Example 88) 2-(N-((3,4-dihydro-7-methyl-4-oxoquinazolin-2-yl)methyl)-N-methylamino)-N-(3,4-dichlorophenyl)-N-methylacetamide [ka]

[0740] Yield: (0.086g, 85%).

[0741] ES-MS[M+H] + :419.2 / 421.0, Rt=19.400 min (Method-H).

[0742] 1 H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.90 (dt, J = 2.2, 0.7 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.61 (ddd, J = 8.3, 2.1, 0.7 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.39 (dd, J = 8.6, 2.5 Hz, 1H), 3.55 (s, 2H), 3.32 (s, 2H), 3.18 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H). (Example 89) 2-(N-((3,4-dihydro-6-methyl-4-oxoquinazolin-2-yl)methyl)-N-methylamino)-N-(3,4-dichlorophenyl)-N-methylacetamide [ka]

[0743] Yield: (0.020g, 46%).

[0744] ES-MS[M+H] + :419.2 / 421.0, Rt=19.381 minutes (Method-H).

[0745] 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.51 - 7.38 (m, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.31 (ddd, J = 8.1, 1.7, 0.6 Hz, 1H), 3.56 (s, 2H), 3.32 (s, 2H), 3.19 (d, J = 4.3 Hz, 3H), 2.45 (s, 3H), 2.35 (s, 3H). Synthesis of intermediate 54 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one [ka] Step 1

[0746] 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (2.00 g, 16.38 mmol, 1.0 equivalent) was dissolved in sulfuric acid (1.2 M). The reaction mixture was stirred at room temperature for 2 hours. This mixture was slowly poured into cold water (50 mL), and then the mixture was quenched by making it basic with 25% w / w ammonium hydroxide solution to pH = 8.0. This suspended solid was cooled to 0°C and stirred for 1 minute. This solid was isolated by suction filtration and vacuum-dried overnight at 60°C to obtain 5-amino-1-methyl-1H-pyrazole-4-carboxamide as a yellow solid.

[0747] Yield: (2.0g, 59%).

[0748] ES-MS[M+H] + :141.0, Rt=0.920 min (Method-G). Step 2

[0749] 5-amino-1-methyl-1H-pyrazole-4-carboxamide (0.10 g, 0.71 mmol, 1.0 equivalent) was dissolved in anhydrous DMF (1.38 mL) and Et3N (0.11 mL, 0.78 mmol, 1.1 equivalents), and the mixture was cooled to 0°C in an ice bath. Next, 2-chloroacetyl chloride (60 μL, 0.78 mmol, 1.1 equivalents) was added, and the reaction mixture was stirred at 0°C for 30 minutes and then at room temperature for a further 2 hours. After this time, only open intermediate a was formed. This reaction was quenched with 2N HCl and extracted with SiO(3×). The combined organic layers were washed with saturated NaHCO3 solution, dehydrated with Na2SO4, filtered, and evaporated to dryness. Since only a very small weight of intermediate a was isolated, the pH of the aqueous phase was adjusted to 7.5, and it was extracted with DCM(3×). The combined organic layers were dehydrated with Na2SO4, filtered, and evaporated to dryness to obtain a white solid corresponding to the cyclized product. This crude product was purified by flash column chromatography (DCM / DCM:MeOH (90:10, 0%~50%)) to obtain 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one as a white solid.

[0750] Yield: (0.035g, 23%)

[0751] ES-MS[M+H] + :199.1, Rt=3.602 minutes (Method-G).

[0752] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.95 (s, 1H), 4.58 (s, 2H), 3.90 (s, 3H). General Procedure F [ka] (In the formula, R 1 , R 2 and R 5 (This is as defined above.)

[0753] A stirred mixture consisting of 6-(chloromethyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (1.0 equivalent) and one of the intermediates 33-43 (1.0 equivalent) in ethanol (1.5 mL) was mixed with DIPEA (1.0 equivalent). This mixture was heated to 90°C and stirred for 16 hours. The reaction was quenched with water (10 mL). The aqueous layer was extracted by DCM (×3). The organic layers were combined, dehydrated with anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (DCM / DCM:MeOH (90:10), 0%-50%) to obtain the corresponding product as a solid. (Example 90) 6-(((2-(isoindolin-2-yl)-2-oxoethyl)(methyl)amino)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one [ka]

[0754] Yield: (0.033g, 56%).

[0755] ES-MS[M+H] + :353.2, Rt=15.220 min (Method-H).

[0756] 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.01 (s, 1H), 7.65 - 7.15 (m, 4H), 4.84 (s, 2H), 4.67 (s, 2H), 3.86 (s, 3H), 3.67 (s, 2H), 3.58 (s, 2H), 2.44 (s, 3H). (Example 91) 6-(((2-(indolin-1-yl)-2-oxoethyl)(methyl)amino)methyl)-1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one [ka]

[0757] Yield: (0.047g, 67%).

[0758] ES-MS[M+H] + :353.2, Rt=15.654 minutes (Method-H).

[0759] 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.07 (d, J = 8.0 Hz,1H), 8.01 (d, J = 0.6 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.00 (td, J = 7.4, 1.1 Hz, 1H), 4.09 (t, J = 8.5 Hz, 2H), 3.86 (d, J = 0.6 Hz, 3H), 3.74 (s, 2H), 3.64 (s, 2H), 3.15 (t, J = 8.4 Hz, 2H), 2.46 (s, 3H). (Example 92) N-(2-chlorophenyl)-N-methyl-2-(methyl((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)acetamide [ka]

[0760] This product required a second purification by half-catenary HPLC (Method I).

[0761] Yield: (0.029g, 35%).

[0762] ES-MS[M+H] + :375.0 / 377.1, Rt=15.728 minutes (Method-H).

[0763] 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.00 (s, 1H), 7.68 - 7.57 (m, 1H), 7.57 - 7.46 (m, 1H), 7.46 - 7.31 (m, 2H), 3.83 (s, 3H), 3.58 (d, J = 2.4 Hz, 2H), 3.22 (d, J = 16.4 Hz, 1H), 3.09 (s, 3H), 3.01 (d, J = 16.4 Hz, 1H), 2.33 (s, 3H). (Example 93) 2-(N-ethyl-N-((4,5-dihydro-1-methyl-4-oxo-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)-N-(2,6-dichlorophenyl)-N-methylacetamide [ka]

[0764] Yield: (0.036g, 61%).

[0765] ES-MS[M+H] + :423.2, Rt=5.288 min (Method-J).

[0766] 1 H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.00 (s, 1H), 7.73 - 7.54 (m, 2H), 7.46 (dd, J = 8.6, 7.7 Hz, 1H), 3.84 (s, 3H), 3.67 (s, 2H), 3.18 (s, 2H), 3.07 (s, 3H), 2.67 (q, J = 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H). (Example 94) N-(3-fluorophenyl)-N-methyl-2-(methyl((1-methyl-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-6-yl)methyl)amino)acetamide [ka]

[0767] Yield: (0.057g, 65%).

[0768] ES-MS[M+H] + :359.2, Rt=15.241 min (Method-H).

[0769] 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.00 (s, 1H), 7.46 (td, J = 8.2, 6.6 Hz, 1H), 7.31 (d, J = 10.1 Hz, 1H), 7.25 - 7.14 (m, 2H), 3.85 (s, 3H), 3.61 (s, 2H), 3.32 (s, 2H), 3.19 (s, 3H), 2.34 (s, 3H). Biological assays

[0770] The compounds disclosed herein can stabilize α-L-iduronidase, thereby enhancing its activity. Differential scanning fluorescence (DSF)

[0771] The ability of the compounds disclosed herein to stabilize α-L-idulonidase was evaluated by differential scanning fluorescence (DSFluorescence) quantification. Thermal denaturation of purified human natural enzymes was monitored in the presence of the external fluorescent probe SYPRO Orange (Sigma-Aldrich, St. Louis, MO). The test compounds were dissolved in 100% DMSO and diluted in protein buffer to a final concentration of 1% DMSO.

[0772] 12.5 μL of 1.5 μM recombinant human α-L-idulonidase protein (purchased from R&D) was dispensed into 100 mM Hepes, 20 mM MgCl2 (pH 7) containing 12.5 μL of Sypro Orange 10X and various compound solutions into a 96-well PCR plate (final protein concentration 0.75 μM). The intensity of SYPRO Orange fluorescence was monitored using a Roche LightCycler® 480 II device (Roche Diagnostics) after regularly increasing the temperature.

[0773] The ability to stabilize α-L-iduronidase is expressed as follows:

[0774] Let A be the case where ΔTm GALC > 1;

[0775] Let B be the ΔTm GALC between 0.5 and 1;

[0776] Let C be the ΔTm GALC between 0.1 and 0.5; and

[0777] We denote ΔTm GALC values ​​less than 0.1 as D.

[0778] Figure 1 shows the thermal shift dose-response curve for compound A, an exemplary compound of this disclosure. The results show that compound A improved the thermal stability of IDUA. Compound A was evaluated using differential scanning fluorescence (DSF) assay (K D Recombinant human IDUA is stabilized at a maximum of 4°C (at 22 μM).

[0779] Tables 1, 2, and 3 below show the DSF assay results for Examples 1-7, 8-37, and 38-94, respectively. [Table 1] [Table 2-1] [Table 2-2] [Table 3-1] [Table 3-2] [Table 3-3] Prevention of degeneration

[0780] The ability of the compounds disclosed herein to stabilize α-L-iduronidase in a neutral pH buffer was evaluated using a denaturation prevention assay.

[0781] In short, recombinant human α-L-iduronidase protein (obtained at the Institute of Biotechnology and Biomedicine (Bellaterra, Spain), UAB) was combined with 5X SYPRO Orange and 30 μM of the corresponding compound at a final concentration of 1 μM in 100 mM Hepes, 20 mM MgCl2 (pH 7) buffer in a final reaction volume of 25 μL. The reaction was incubated at 37°C, and the fluorescence intensity of SYPRO Orange was monitored at the indicated time points using a Glomax® Discover microplate reader from Promega (Madison, WI, USA).

[0782] The results for compound A, an exemplary compound of this disclosure, are shown in Figure 2. Throughout this specification, the compound referred to as compound A is the compound of Example 8 described above. The results show that compound A prevented IDUA denaturation. Compound A (30 μM) slowed the pH-induced denaturation of recombinant human IDUA. The reference compound, L-iduronic acid (500 μM), showed minimal effect (T=37°C).

[0783] The compounds in Examples 8, 39, 40, 54, and 72 were also tested as described above, except that ALDURAZYME® was used instead of recombinant human α-L-iduronidase protein (obtained at the Institute of Biotechnology and Biomedicine (Bellaterra, Spain) in UAB). These results are shown in Figure 7. These results indicate that all test compounds prevent IDUA denaturation. IDUA Inhibition Assay

[0784] The ability of the compounds disclosed herein to inhibit IDUA was evaluated by the following assay.

[0785] Recombinant human α-L-iduronidase protein IDUA PR_06_WT_X (obtained at the Institute of Biotechnology and Biomedicine (Bellaterra, Spain) in the United Arab Emirates) was prepared in PBS at the desired concentration.

[0786] Recombinant human IDUA. HEK293f. Ala26-Pro653 with C-terminal 10_His tag. Protein buffer: 40 mM sodium acetate, 400 mM NaCl and 20% glycerol, pH=5. Generated by PPP IBB UAB.

[0787] The activity assay (using three samples per sample) included the following procedure:

[0788] In a dark 96-well plate suitable for a fluorometer:

[0789] 1) 25 μL of recombinant protein or PBS (in a blank sample);

[0790] 2) 1 μL of CO (50× concentrate, prepared in an intermediate plate) or DMSO for untreated samples;

[0791] 3) 25 μL of 200 μM substrate solution (from a 20 mM substrate storage solution in DMSO) in 0.4 M sodium formate (pH 3.5) and 0.2% triton®, containing 4-methylumbelliferyl alpha-L-idulonide (Glycosynth, 44076).

[0792] 4) Mixing (shaker);

[0793] 5) 60 minutes at 37°C;

[0794] 6) The reaction is stopped by adding 200 μL of 0.5 M glycine / 0.3 M NaOH (pH=10).

[0795] 7) Read the fluorescence at Ex / Em: 340 / 460 nm.

[0796] Figure 3 shows the results for compound A, an exemplary compound of this disclosure, in an IDUA inhibition assay. The results indicate that compound A does not inhibit human IDUA. Compound A is a silent allosteric modulator that does not affect the intrinsic enzymatic activity of recombinant human IDUA, even at high concentrations. Enzyme-enhancing activity of the compounds of this disclosure in combination with α-L-idulonidase protein

[0797] The effect of the compounds of this disclosure on enhancing IDUA enzyme activity can be tested as follows.

[0798] Patient-derived fibroblasts were placed in 12-well cell culture plates in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (P / S) (Thermo Fisher Scientific, Waltham, MA, USA) at a rate of 4 × 10⁶ per well. 4Cells were seeded individually and incubated overnight at 37°C and 5% CO2 to promote cell adhesion. Subsequently, cells were incubated for 4 days in the absence or presence of the compound and / or 1.25 nM recombinant human α-L-idulonidase protein (obtained from the Institute of Biotechnology and Biomedicine at UAB). After incubation, cells were washed with phosphate-buffered saline ("PBS") and cleaved using trypsin-EDTA solution (Sigma Aldrich, St. Louis, MO, USA) to prepare a cell pellet. This pellet was stored at -80°C until activity assays were performed. α-L-idulonidase activity in cell lysates was measured using a 4-methylumbelliferyl alpha-L-idulonide substrate (Glycosynth, Warrington, UK). In short, the lysate was resuspended in 25 μL of 0.9% NaCl containing 0.01% triton® X-100 lysis buffer to promote membrane disruption. This cell suspension was irradiated with ultrasound and centrifuged to remove insoluble material. Next, the lysate was mixed with 25 μL of 200 μM 4-MU-alpha-L-idulonide substrate in 0.4 M sodium formate (pH 3.5) and 0.2% triton® X-100 buffer at 37°C for 60 minutes. This reaction was terminated by adding 200 μL of 0.5 M glycine / 0.3 M NaOH buffer (pH=10). The freed 4-MU was measured by excitation at 340 nm and emission at 460 nm using a Promega Glomax® Discover microplate reader. Protein quantification was determined using the Pierce BCA protein assay kit (Thermo Fisher Scientific, Waltham, MA, USA). The measured values ​​were interpolated onto a 4-MU standard curve and normalized by the amount of protein.

[0799] The results for compound A, an exemplary compound of this disclosure, in cell-based assays are shown in Figures 4A-4E. Cell-based assays demonstrate the potential of compound A as an ERT combination therapy. Compound A increases the uptake and enzymatic activity of the rhIDUA protein under a wide range of conditions (rhIDUA concentration and cell type). The benefits are particularly evident with longer incubation times (4 days). These results show that in Hurler-Scheie fibroblasts (basal activity: 0.23), IDUA activity is improved in a dose-dependent manner after the addition of rhIDUA to the culture medium. Co-administration with compound A is shown to significantly improve cellular uptake of IDUA (compared to monotherapy) at two different concentrations and in a dose-dependent manner. Cell-based EC 50 (16 μM) is K by DSF (22 μM) D The results are in good agreement (Figure 4A). The results in Figure 4B indicate that the effect of compound A is dose-dependent. Figure 4C shows that compound A is active across a panel of patient-derived fibroblasts (96 hours). Figure 4D shows that the effect of compound A in fibroblasts increases with longer incubation times. Figure 4D shows that compound A increases the amount of α-L-iduronidase in fibroblasts (96 hours). In vivo activity of an exemplary compound (Compound A) of the present disclosure

[0800] Assay objective:

[0801] Evaluation of IDUA activity in mouse bone and articular cartilage samples obtained from the BIO-PCY-19-025 study, in which C57BL / 6 male mice were administered 1.2 mg / kg of Aldurazyme (iv bolus) in the presence and absence of compound A.

[0802] Group details:

[0803] G1: Vehicle 2 + Aldurazyme (1.2 mg / kg, iv) QD × 1 (n=6) [Vehicle 2: NMP (5%) + Solutol HS-15 (5%) + Standard saline (45%) + PEG-400 (45%)];

[0804] G2: Compound A (5mg / kg, iv) + Aldurazyme (1.2mg / kg, iv) QD×1 (n=6);

[0805] G3: Compound A (10 mg / kg, iv) + Aldurazyme (1.2 mg / kg, iv) QD×1 (n=6);

[0806] G4: Compound A (20 mg / kg, iv) + Aldurazyme (1.2 mg / kg, iv) QD × 1 (n=6); and

[0807] G5: Naive control (n=6).

[0808] IDUA assay in plasma:

[0809] Plasma samples were collected from mice at the indicated time points. The plasma samples were diluted in formate buffer, and the total protein content was estimated using Bradford's reagent. 25 μl of tissue homogenate and plasma samples were added to 25 μl of 0.18 mM 4MUI substrate and incubated at 37°C for 30 minutes. The reaction was stopped using 200 μl of stop solution (0.3 M glycine and 0.2 M sodium carbonate, pH 10.4). Plate readings were performed at excitation 355 nm and emission 460 nm. Two 4-MU standard curves were obtained in series from the concentration range of 10 μM to 0.002 μM.

[0810] IDUA assay in osteochondritis:

[0811] Bone and articular cartilage samples were collected from mice at the indicated time points. The tissue was homogenized in RIPA buffer, proteins were extracted, and diluted in water. Total protein content was estimated using Bradford reagent. 25 μl of tissue homogenate and plasma samples were added to 25 μl of 0.18 mM 4MUI substrate and incubated at 37°C for 30 minutes. The reaction was stopped using 200 μl of stop solution (0.3 M glycine and 0.2 M sodium carbonate, pH 10.4). Plate readings were performed at excitation 355 nm and emission 460 nm. Two 4-MU standard curves were obtained in series from the concentration range of 10 μM to 0.002 μM.

[0812] IDUA assay in bone marrow:

[0813] Bone marrow samples were collected from mice at the indicated time points. After repeated freeze-thaw cycles for protein extraction, the bone marrow samples were diluted in formate buffer (0.4 M, pH 3.5). Total protein content was estimated using Bradford reagent. 25 μl of tissue homogenate and plasma samples were added to 25 μl of 0.18 mM 4MUI substrate and incubated at 37°C for 30 minutes. The reaction was stopped using 200 μl of stop solution (0.3 M glycine and 0.2 M sodium carbonate, pH 10.4). Plate readings were performed at excitation 355 nm and emission 460 nm. Two 4-MU standard curves were obtained in series from the concentration range of 10 μM to 0.002 μM.

[0814] Plate reader:

[0815] TECAN Infinite M1000Pro.

[0816] Data analysis:

[0817] IDUA activity was evaluated from a 4-MU standard curve. The release of 4MU as μM values ​​from the 4MUI substrate reaction after a 30-minute incubation time was converted to n moles / ml and normalized against the total protein content (mg / ml) in each sample. The final IDUA enzyme activity was expressed as nmol / protein 1 mg / hour. Data were analyzed using one-way ANOVA with GraphPad prism software, followed by Dunnett's comparative test. Data are expressed as mean ± standard error.

[0818] In vivo, compound A improved the PK profile of laronidase and increased its plasma levels in a dose-dependent manner (see Figure 5). Compound A also increased IDUA enzyme activity in a panel of tissues, including those with the least benefit from ERT (bone marrow, cartilage) (see Figure 6). Compound A was safe at all tested doses (IV MTD 45 mg / kg).

[0819] These results indicate that co-administration of compound A with laronidase stabilizes the recombinant enzyme, leading to a dose-dependent increase in enzyme activity levels in plasma, bone, and cartilage. Bone and cartilage have the most pressing medical need due to insufficient ERT uptake. The benefits of combination therapy are particularly pronounced over longer periods.

[0820] All publications cited herein are incorporated herein by reference. While this disclosure is written with reference to specific embodiments, it will be understood that modifications can be made without departing from the spirit of this disclosure. Such modifications are intended to fall within the scope of the appended claims.

[0821] This disclosure also relates to the following specific embodiments, which are represented as follows: in the case of the first embodiment [1], in the case of the second embodiment [2], and so on.

[0822] [1] A method for treating or preventing a condition in a patient associated with alteration of α-L-iduronidase activity, wherein the patient is required to receive an effective amount of a compound of formula (I): [ka] A method comprising the step of administering, if necessary, an effective amount of laronidase or a pharmaceutically acceptable salt or solvate thereof in combination with laronidase (wherein, B is a fused benzene ring or a 5-membered or 6-membered fused heteroaromatic ring, and the benzene ring and the 5-membered or 6-membered heteroaromatic ring are substituted as necessary. R 1 is -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 2 C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 3 , R 3’ , R 4and R 4’ is independently selected from the group consisting of hydrogen, halogen, unsubstituted C 1~4 alkyl and substituted C 1~4 alkyl, or R 1 and R 3 together with the nitrogen and carbon atoms to which they are attached form a 5- to 10-membered heterocyclic ring optionally substituted, said heterocyclic ring optionally containing one, two or three additional heteroatoms selected from the group consisting of N, S or O, or R 1 and R 4 together with the nitrogen and carbon atoms to which they are attached form a 5- to 10-membered heterocyclic ring optionally substituted, said heterocyclic ring optionally containing one, two or three additional heteroatoms selected from the group consisting of N, S or O and R 5 is hydrogen, C 1~4 alkyl, -C 3~10 cycloalkyl, -C 1~4 alkyl-C 3~10 cycloalkyl, -C 6~10 aryl, -C 1~4 alkyl-C 6~10 aryl, (5- to 10-membered)-C 1~9 heteroaryl, -C<00​​​​​​​​​​​​Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring, or R 2 and R 5 These, together with the nitrogen atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two, or three additional heteroatoms selected from the group consisting of N, S, or O, and the heterocyclic ring is optionally condensed to a phenyl ring. Ra is independently associated with hydrogen and -C. 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 (The heterocycline is wherein the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.)

[0823] [2] A method for treating or prophylactically treating MPS1 in a patient, wherein an effective amount of a compound of formula (I) is given to the patient in need: [ka] A method comprising the step of administering, if necessary, an effective amount of laronidase or a pharmaceutically acceptable salt or solvate thereof in combination with laronidase (wherein, B is a fused benzene ring or a 5-membered or 6-membered fused heteroaromatic ring, and the benzene ring and the 5-membered or 6-membered heteroaromatic ring are substituted as necessary. R 1 is -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 2 C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 3 , R 3’ , R 4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyls, or R 1 and R 3 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, or R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two, or three additional heteroatoms selected from the group consisting of N, S, or O. R 5 is hydrogen, C1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Aryl, -C 1~4 Alkyl-C 6~10 Aryl, (5 - to 10 - membered)-C 1~9 Heteroaryl, -C 1~4 Alkyl-(5 - to 10 - membered)-C 1~9 Heteroaryl, (5 - to 10 - membered)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5 - to 10 - membered)-C 2~9 Selected from the group consisting of heterocyclyl, wherein the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted, if necessary, by one, two or three halogen atoms), optionally substituted C 6~10 Aryl, optionally substituted (5 - to 10 - membered)-C 1~9 Heteroaryl and (5 - to 10 - membered)-C 2~9 Heterocyclyl, optionally substituted by one, two or three substituents each independently selected from the group consisting of, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to a further (second) ring, or R 2 and R 5 together with the nitrogen atom to which they are attached form an optionally substituted 5 - to 10 - membered heterocyclic ring, the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, and the heterocyclic ring is optionally fused to a phenyl ring, Each Ra is independently hydrogen, -C 1~4 Alkyl, -C3~10 Cycloalkyl or -(5-10 member)-C 2~9 (The heterocycline is wherein the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.)

[0824] [3] MPS1 is Hurler disease, Hurler-Scheie syndrome or Scheie syndrome, in the manner of [1].

[0825] [4] A method for treating or preventing in a patient a heart valve disease, polyosynostosis, eye disease, ear disease, respiratory obstruction or dysfunction, nerve compression, inflammatory arthritis, amyloid-related disorder, a disease condition related to lipoprotein metabolism, solid tumor, infection, inflammatory disorder, or developmental disorder, wherein an effective amount of the compound of formula (I) is given to the patient in need: [ka] A method comprising the step of administering, if necessary, an effective amount of laronidase or a pharmaceutically acceptable salt or solvate thereof in combination with laronidase (wherein, B is a fused benzene ring or a 5-membered or 6-membered fused heteroaromatic ring, and the benzene ring and the 5-membered or 6-membered heteroaromatic ring are substituted as necessary. R 1 is -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 2 C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 3 , R 3’ , R 4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyls, or R 1 and R 3 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, or R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two, or three additional heteroatoms selected from the group consisting of N, S, or O. R 5 is hydrogen, C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring, or R 2 and R 5 These, together with the nitrogen atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two, or three additional heteroatoms selected from the group consisting of N, S, or O, and the heterocyclic ring is optionally condensed to a phenyl ring. Ra is independently associated with hydrogen and -C. 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 (The heterocycline is wherein the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.)

[0826] [5] Any one of the methods in [1] to [4], wherein B is a fused benzene ring which is substituted as needed.

[0827] [6] The method of [5], wherein B is an unsubstituted condensed benzene ring.

[0828] [7] B is halogen, hydroxy, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 A condensed benzene ring substituted with one or more substituents selected from the group consisting of cycloalkyl groups, wherein the aryl, heteroaryl, and heterocyclyl groups are optionally condensed to a further (second) ring, and Ra is independently hydrogen, -C 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 The method of [5], wherein the alkyl, cycloalkyl, or heterocyclyl group is optionally substituted with one, two, or three fluorine atoms.

[0829] [8] Any one of the methods in [1] to [4], wherein B is a five-membered fused heteroaromatic ring which is substituted as needed.

[0830] [9] B is an unsubstituted five-membered fused heteroaromatic ring, one of the methods in [1]-[4] or [8].

[0831]

[10] B is halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 A five-membered condensed heteroaromatic ring substituted with one or two substituents independently selected from the group consisting of cycloalkyl groups, wherein the aryl, heteroaryl, and heterocyclyl groups are optionally condensed to a further (second) ring, and Ra is independently substituted with hydrogen, -C 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 The heterocyclyl is wherein the alkyl, cycloalkyl, or heterocyclyl group is optionally substituted with one, two, or three fluorine atoms, as per any one of the methods of [1] to [4] or [8].

[0832]

[11] B is a six-membered fused heteroaromatic ring which is substituted as needed, in any of the ways of [1] to [4].

[0833]

[12] B is an unsubstituted 6-membered fused heteroaromatic ring, one of the methods in [1]-[4] or

[11] .

[0834]

[13] B is halogen, hydroxy, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10A six-membered condensed heteroaromatic ring substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl groups, wherein the aryl, heteroaryl, and heterocyclyl groups are optionally condensed to a further (second) ring, and Ra is independently hydrogen, -C 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 The heterocycline is wherein the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms, as per any one of the methods of [1] to [4],

[11] , or

[12] .

[0835]

[14] B said, B1: [ka] B2: [ka] and B3: [ka] (In the formula, R 6 , R 7 , R 8 , R 9 and R 10 These are hydrogen, halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. Ra is independent of hydrogen, -C 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 (The heterocycline is a heterocycline, and the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.) One of the following methods [1] to [4] is selected from the group consisting of the following.

[0836]

[15] B said, B4: [ka] B5: [ka] and B6: [ka] One of the following methods is selected from the group consisting of [1] to [4] or

[14] .

[0837]

[16] B said, [ka] This is one of the following methods: [1] to [4].

[0838]

[17] R 1 However, -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring. R 3 , R 3’ , R 4 and R 4’ However, hydrogen, halogens, and unsubstituted carbon 1~4 Alkyl and substituted C 1~4 One of the methods [1] to

[16] , each independently selected from the group consisting of alkyl groups.

[0839]

[18] R 3 and R 4 is hydrogen, R 3’ and R 4’ However, hydrogen, halogens, and unsubstituted carbon 1~4 Alkyl and substituted C 1~4 One of the methods [1] to

[17] , each independently selected from the group consisting of alkyl groups.

[0840]

[19] R 3 , R3’ , R 4 and R 4’ However, each of them is hydrogen, one of the methods [1] to

[18] .

[0841]

[20] R 1 and R 3 However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, R 3’ , R 4 and R 4’ However, one of the methods [1] to

[16] , as defined in [1].

[0842]

[21] R 1 and R 4 However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, R 3 , R 3’ and R 4’ However, one of the methods [1] to

[16] , as defined in [1].

[0843]

[22] R 1 and R 4 However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, R 3 , R 3’ and R 4’ Each of the following methods is hydrogen: [1] to

[16] .

[0844]

[23] R 2 However, C 1~4 Alkyl, -C 3~10Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring. R 5 However, hydrogen, C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 The cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally fused to a further (second) ring, in any of the methods of [1] to

[22] .

[0845]

[24] R 2 but, [ka] One of the methods [1] to

[23] is selected from the group consisting of the following.

[0846]

[25] R 5 However, non-substituted C 1-6 The alkyl group is one of the following methods [1] to

[24] .

[0847]

[26] R 2 and R 5However, together with the nitrogen atom to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, and the heterocyclic ring is optionally fused to a phenyl ring, one of any of the methods of [1] to

[22] .

[0848]

[27] R 2 and R 5 However, together with the nitrogen atoms to which they are bonded, they form the following group [ka] One of the following methods for forming [1] to

[22] or

[26] .

[0849]

[28] The compound of formula (I) is the compound of formula (I') [ka] or a pharmaceutically acceptable salt or solvate thereof (in the formula, B' is, B1': [ka] B2': [ka] and B3': [ka] A fused ring selected from the group consisting of, R 1 is -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 2b is -C 3~10 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxyl, -CN, -ORa, -SRa, -N(Ra)2, and -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. R 3 , R 3’ , R 4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyls, or R 1 and R 3 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, or R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two, or three additional heteroatoms selected from the group consisting of N, S, or O. R 5b C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 6’ , R 7’ and R 8’ These are hydrogen, halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring, provided that R 6’ , R 7’ and R 8’ The condition is that at least one of them is not hydrogen, R 9’ and R 10’These are halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. Ra is independently associated with hydrogen and -C. 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 (The heterocycline is a heterocycline, and the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.) This is one of the following methods: [1] to [4].

[0850]

[29] B' is B1': [ka] (In the formula, R 6’ , R 7’ and R 8’ The method of

[28] is as defined in

[31] .

[0851]

[30] B' is B2': [ka] (In the formula, R 9’ The method of

[28] , which is as defined in

[31] .

[0852]

[31] B' is, B3': [ka] (In the formula, R 10’ The method of

[28] , which is as defined in

[31] .

[0853]

[32] B' is, [ka] The method of

[28] or

[31] , wherein B3' is selected from the group consisting of the following.

[0854]

[33] R 1 However, -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring. R 3 , R 3’ , R 4 and R 4’ However, hydrogen, halogens, and unsubstituted carbon 1~4 Alkyl and substituted C 1~4 One of the methods

[28] to

[32] , each independently selected from the group consisting of alkyl groups.

[0855]

[34] R 3 and R 4 is hydrogen, R 3’ and R 4’ However, hydrogen, halogens, and unsubstituted carbon 1~4 Alkyl and substituted C 1~4 One of the methods

[28] to

[33] , each independently selected from the group consisting of alkyl groups.

[0856]

[35] R 3 , R 3’ , R 4 and R 4’ However, each is hydrogen, one of the methods

[28] to

[33] .

[0857]

[36] R 1 and R 3 However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, R 3’ , R 4 and R 4’ However, one of the methods

[28] to

[32] , as defined in

[28] .

[0858]

[37] R 1 and R 4 However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, R 3 , R 3’ and R 4’ However, one of the methods

[28] to

[32] , as defined in

[28] .

[0859]

[38] R 1 and R 4 However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, R 3 , R 3’ and R 4’ Each of the following methods is hydrogen:

[28] to

[32] .

[0860]

[39] R 2b However, -C 3~10 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. R 5b However, C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 The cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally fused to a further (second) ring, in any of the methods of

[28] to

[38] .

[0861]

[40] R 2b but, [ka] [ka] One of the methods

[28] to

[39] is selected from the group consisting of the following.

[0862]

[41] R 5b However, non-substituted C 1~6 The alkyl group is one of the methods

[28] to

[40] .

[0863]

[42] R 5b However, non-substituted C 2~6 The alkyl group is one of the methods

[28] to

[41] .

[0864]

[43] Ra is hydrogen or -C 1~4 The alkyl (substituted as necessary with one, two, or three fluorine atoms) is one of the methods [1] to

[42] .

[0865]

[44] Ra is -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 A heterocycline, wherein the cycloalkyl or heterocycline group is optionally substituted with one, two, or three fluorine atoms, in any one of the methods [1] to

[42] .

[0866]

[45] Compounds [ka] One of the methods [1] to [4], which is selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

[0867]

[46] The compound [ka] One of the methods [1] to [4], which is selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

[0868]

[47] The compound, [ka] A method according to any one of claims [1] to [4], wherein the salts or solvates are selected from the group consisting of the salts or solvates thereof.

[0869]

[48] ​​Compounds [ka] [ka] One of the methods [1]-[4] or

[28] , which is selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

[0870]

[49] Any one of the methods [1] to

[48] , which does not involve the step of administering an effective amount of laronidase.

[0871]

[50] Any one of the methods of [1] to

[48] , comprising the step of administering the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in combination with an effective amount of laronidase.

[0872]

[51] Any one of the methods of [1] to

[48] or

[50] , wherein an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and an effective amount of laronidase are administered to the patient simultaneously.

[0873]

[52] Any one of the methods of [1] to

[48] or

[50] , wherein an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and an effective amount of laronidase are administered sequentially to the patient.

[0874]

[53] Any one of the methods of

[50] to

[52] , wherein an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and an effective amount of laronidase are administered to a patient in a separate pharmaceutical composition.

[0875]

[54] Any one of the methods of

[50] to

[52] , wherein an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and an effective amount of laronidase are administered to a patient in a single pharmaceutical composition.

[0876]

[55] Compounds having formula (I'): [ka] or a pharmaceutically acceptable salt or solvate thereof (in the formula, B' is, B1': [ka] B2': [ka] and B3': [ka] A fused ring selected from the group consisting of, R 1 is -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 2b is -C 3~10 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxyl, -CN, -ORa, -SRa, -N(Ra)2, and -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. R 3 , R 3’ , R4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyls, or R 1 and R 3 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, or R 1 and R 4 These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two, or three additional heteroatoms selected from the group consisting of N, S, or O. R 5b C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 6’ , R 7’ and R 8’ These are hydrogen, halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9 Heterocyclyl and -C 3~10 Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring, provided that R 6’ , R 7’ and R 8’ The condition is that at least one of them is not hydrogen, R 9’ and R 10’ These are halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C 1~4 Alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C 6~10 Aaryl, substituted as needed - (5-10 members) - C 1~9 Heteroaryl, -(5-10 member)-C 2~9Heterocyclyl and -C 3~10 Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. Ra is independently associated with hydrogen and -C. 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 (The heterocycline is wherein the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.)

[0877]

[56] B' is, B1': [ka] The compound in

[55] .

[0878]

[57] B' is B2': [ka] The compound in

[55] .

[0879]

[58] B' is, B3': [ka] The compound in

[55] .

[0880]

[59] B' is, [ka] A compound

[55] or

[56] which is B3' selected from the group consisting of the following.

[0881]

[60] R 1 However, -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring. R 3 , R 3’ , R 4 and R 4’ However, hydrogen, halogens, and unsubstituted carbon 1~4 Alkyl and substituted C 1~4 One compound from

[55] to

[59] , independently selected from the group consisting of alkyl groups.

[0882]

[61] R 3 and R 4 is hydrogen, R 3’ and R 4’ However, hydrogen, halogens, and unsubstituted carbon 1~4 Alkyl and substituted C1~4 One compound from

[55] to

[60] , independently selected from the group consisting of alkyl groups.

[0883]

[62] R 3 , R 3’ , R 4 and R 4’ However, each is a hydrogen atom, and each of the compounds

[55] to

[61] is one of them.

[0884]

[63] R 1 and R 3 However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, R 3’ , R 4 and R 4’ However, one of the compounds

[55] to

[60] , as defined in

[54] .

[0885]

[64] R 1 and R 4 However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, R 3 , R 3’ and R 4’ However, one of the compounds

[55] to

[60] , as defined in

[54] .

[0886]

[65] R 1 and R 4 However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is optionally substituted, and the heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, R 3 , R 3’ and R 4’Each of these is a hydrogen atom, and each of the compounds

[55] to

[60] is one of them.

[0887]

[66] R 2b However, -C 3~10 Cycloalkyl, -C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. R 5b However, C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 Any one of the compounds

[55] to

[65] is optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring.

[0888]

[67] R 2b but [ka] [ka] One compound selected from the group consisting of 55 to 66.

[0889]

[68] R 5b is non-substituted C 1~6 One of the alkyl compounds

[55] to

[67] .

[0890]

[69] R 5b is non-substituted C 2~6 One of the alkyl compounds

[55] to

[68] .

[0891]

[70] Ra is hydrogen or -C 1~4One of the compounds

[55] to

[69] is alkyl (substituted as necessary with one, two, or three fluorine atoms).

[0892]

[71] Ra is -C 3~10 Cycloalkyl or -(5-10 member)-C 2~9 A heterocyclyl compound, wherein the cycloalkyl or heterocyclyl group is optionally substituted with one, two, or three fluorine atoms, one of the compounds

[55] to

[69] .

[0893]

[72] Below [ka] [ka] A compound of

[55] , or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above.

[0894]

[73] A pharmaceutical composition comprising an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) has the following structure: [ka] or a pharmaceutically acceptable salt or solvate thereof (in the formula, B is a fused benzene ring or a 5-membered or 6-membered fused heteroaromatic ring, and the benzene ring and the 5-membered or 6-membered heteroaromatic ring are substituted as necessary. R 1 is -C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9 Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 2 C 1~4 Alkyl, -C 3~10 Cycloalkyl, -C 1~4 Alkyl-C 3~10 Cycloalkyl, -C 6~10 Ariel, -C 1~4 Alkyl-C 6~10 Ariel, (5-10 members) - C 1~9 Heteroaryl, -C 1~4 Alkyl-(5-10 member)-C 1~9 Heteroaryl, (5-10 member)-C 2~9 Heterocyclyl and -C 1~4 Alkyl-(5-10 member)-C 2~9Selected from the group consisting of heterocyclyl groups, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra)2, -C 1~4 Alkyl (substituted as needed with one, two, or three halogen atoms), optionally substituted C 6~10 Aryl, substituted as needed (5-10 member) - C 1~9 Heteroaryl and (5- to 10-membered)-C 2~9 They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. R 3 , R 3’ , R 4 and R 4’ This is hydrogen, halogen, and unsubstituted C. 1~4 Alkyl and substituted C 1~4 Each is independently selected from the group consisting of alkyls, or R 1 and R 3 These,...

Claims

1. Compounds having formula (I'): 【Chemistry 297】 or a pharmaceutically acceptable salt or solvate thereof (in the formula, B' is, B1': 【Chemistry 298】 B2': 【Chemistry 299】 and B3': 【Chemical 300】 A fused ring selected from the group consisting of, R １ is -C １～４ alkyl, -C ３～１０ cycloalkyl, -C １～４ alkyl -C ３～１０ cycloalkyl, -C ６～１０ aryl, -C １～４ alkyl -C ６～１０ aryl, (5 - to 10 - membered)-C １～９ heteroaryl, -C １～４ alkyl-(5 - to 10 - membered)-C １～９ heteroaryl, (5 - to 10 - membered)-C ２～９ heterocyclyl and -C １～４ alkyl-(5 - to 10 - membered)-C ２～９ heterocyclyl, and is selected from the group consisting of, wherein said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ alkyl (substituted, if necessary, by one, two or three halogen atoms), optionally substituted C ６～１０ aryl, optionally substituted (5 - to 10 - membered)-C １～９ heteroaryl and (5 - to 10 - membered)-C ２～９ heterocyclyl, and are each independently optionally substituted by one, two or three substituents selected from the group consisting of, and said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to a further (second) ring. R ２ｂ is, -C ３～５ Cycloalkyl, -C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, substituted as needed (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. R ３ , R ３’ , R ４ and R ４’ This is hydrogen, halogen, and unsubstituted C. １～４ Alkyl and substituted C １～４ Each is independently selected from the group consisting of alkyl groups, R ５ｂ C １～４ Alkyl, -C ３～１０ Cycloalkyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl, -C １～４ Alkyl-(5-10 member)-C １～９ Heteroaryl, (5-10 member) -C ２～９ Heterocyclyl and -C １～４ Alkyl-(5-10 member)-C ２～９ Selected from the group consisting of heterocyclyls, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, substituted as needed (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring, or R １ and R ２ｂ These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as needed, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as needed by heteroatoms selected from the group consisting of N, S, and O, R ５ｂ is, -C ３～１０ Cycloalkyl, -C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ Selected from the group consisting of heterocyclyl groups, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, substituted as needed (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring, or R １ and R ３ These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or R １ and R ４ These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or R ２ｂ and R ５ｂ These, together with the nitrogen atom to which they are bonded, form halogens, hydroxyls, CN, -ORa, -SRa, and -N(Ra). ２ , (=O), -C １～４ Alkyl (halogen, CN, -ORa and -N(Ra)) ２ (Each of which is independently selected from the group consisting of, and as necessary, is substituted by one, two, or three substituents), -C ６～１０ Ariel, - (5 to 10 members) - C １～９ Heteroaryl, -(5- to 10-membered)-C ２～９ Heterocyclyl and -C ３～１０ A five- or six-membered heterocyclic ring is formed, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of cycloalkyl groups, wherein one, two, or three carbon atoms of the heterocyclic ring are optionally replaced by heteroatoms selected from the group consisting of N, S, and O, and the heterocyclic ring is optionally condensed to a phenyl ring, provided that B' is B1' or B3', the heterocyclic ring is 1) Halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra) ２ , (=O), -C １～４ Alkyl (halogen, CN, -ORa and -N(Ra)) ２ (Substituted as necessary by one, two, or three substituents independently selected from the group consisting of , -C) ６～１０ Ariel, - (5 to 10 members) - C １～９ Heteroaryl, -(5- to 10-membered)-C ２～９ Heterocyclyl and -C ３～１０ It is substituted with at least one substituent selected from the group consisting of cycloalkyls (Ra is as defined above), or 2) Condensed to a phenyl ring On the condition that, R ６’ 、 R ７’ and R ８’ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, -ORa, -SRa, -N(Ra) ２ , (=O), -C １～４ alkyl (substituted, if necessary, with one, two or three substituents each independently selected from the group consisting of halogen, CN, -ORa and -N(Ra) ２ ), optionally substituted -C ６～１０ aryl, optionally substituted -(5- to 10-membered)-C １～９ heteroaryl, -(5- to 10-membered)-C ２～９ heterocyclyl and -C ３～１０ cycloalkyl, and the aryl, heteroaryl and heterocyclyl are optionally fused to a further (second) ring, provided that at least one of R ６’ , R ７’ and R ８’ is other than hydrogen R ９’ and R １０’ These are halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra) ２ , (=O), -C １～４ Alkyl (halogen, CN, -ORa and -N(Ra)) ２ (Optionally substituted by one, two, or three substituents independently selected from the group consisting of) optionally substituted -C ６～１０ Aryl, substituted as needed - (5 to 10 members) - C １～９ Heteroaryl, -(5- to 10-membered)-C ２～９ Heterocyclyl and -C ３～１０ Each is independently selected from the group consisting of cycloalkyls, and the aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. Each Ra independently contains hydrogen and -C. １～４ Alkyl, -C ３～１０ Cycloalkyl or -(5- to 10-membered)-C ２～９ It is a heterocycline, and the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms. However, the aforementioned compound is 【Chemical 301】 (Provided that it is not the case.)

2. B' is, B1': 【Chemical 302】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. B' is, B2': 【Chemical 303】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

4. B' is, B3': 【Chemical 304】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

5. B' is, 【Chemical 305】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is B3' selected from the group consisting of the above.

6. R １ However, -C １～４ Alkyl, -C ３～１０ Cycloalkyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C ６～１０ Ariel, -C １～４ Alkyl-C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl, -C １～４ Alkyl-(5-10 member)-C １～９ Heteroaryl, (5-10 member) -C ２～９ Heterocyclyl and -C １～４ Alkyl-(5-10 member)-C ２～９ Selected from the group consisting of heterocyclyls, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, substituted as needed (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring. R ３ , R ３’ , R ４ and R ４’ However, hydrogen, halogens, and unsubstituted carbon １～４ Alkyl and substituted C １～４ A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, independently selected from the group consisting of alkyls.

7. R ３ and R ４ However, it is hydrogen, R ３’ and R ４’ However, hydrogen, halogens, and unsubstituted carbon １～４ Alkyl and substituted C １～４ A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, independently selected from the group consisting of alkyls.

8. R ３ , R ３’ , R ４ and R ４’ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein each of these is hydrogen.

9. R １ and R ２ｂ However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is substituted as needed, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as needed by heteroatoms selected from the group consisting of N, S, and O, R ５ｂ However, -C ３～１０ Cycloalkyl, -C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ Selected from the group consisting of heterocyclyls, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, substituted as needed (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ The compound is optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring, provided that the compound is, 【Chemical 306】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, provided that it is not the compound described above.

10. R １ and R ３ However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is substituted as needed, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as needed by heteroatoms selected from the group consisting of N, S, and O, R ３’ , R ４ and R ４’ However, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 1.

11. R １ and R ４ However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is substituted as needed, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as needed by heteroatoms selected from the group consisting of N, S, and O, R ３ , R ３’ and R ４’ However, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 1.

12. R １ and R ４ However, together with the nitrogen and carbon atoms to which they are bonded, they form a 5- to 10-membered heterocyclic ring which is substituted as needed, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as needed by heteroatoms selected from the group consisting of N, S, and O, R ３ , R ３’ and R ４’ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein each of these is hydrogen.

13. R ２ｂ However, -C ３～５ Cycloalkyl, -C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ Selected from the group consisting of heterocyclyls, the cycloalkyl, aryl, heteroaryl and heterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, substituted as needed (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, aryl, heteroaryl, and heterocyclyl are optionally condensed to a further (second) ring. R ５ｂ However, C １～４ Alkyl, -C ３～１０ Cycloalkyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl, -C １～４ Alkyl-(5-10 member)-C １～９ Heteroaryl, (5-10 member) -C ２～９ Heterocyclyl and -C １～４ Alkyl-(5-10 member)-C ２～９ Selected from the group consisting of heterocyclyls, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, substituted as needed (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclies, and the cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, alkylheteroaryl, heterocyclil, and alkylheterocyclil are optionally condensed to a further (second) ring. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

14. R ２ｂ but, 【Chemical 307】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above.

15. R ５ｂ However, non-substituted C １～６ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is alkyl.

16. R ５ｂ However, non-substituted C ２～６ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is alkyl.

17. Ra is hydrogen or -C １～４ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is alkyl (as may be substituted as necessary with one, two, or three fluorine atoms).

18. Ra is -C ３～１０ Cycloalkyl or -(5- to 10-membered)-C ２～９ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the cycloalkyl or heterocyclyl group is optionally substituted with one, two, or three fluorine atoms.

19. The aforementioned compound is as follows: 【Chemical 308】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above.

20. The aforementioned compound is as follows: 【Chemical 309】 【Chemical 310】 【Chemical 311】 【Chemical 312】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of the above.

21. An effective amount of 1) the compound according to claim 1, 2) the following: 【Chemical Industry 315】 【Chemistry 342】 A pharmaceutical composition comprising a compound selected from the group consisting of, or a pharmaceutically acceptable salt or solvate thereof, or 3) a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) has the following structure: 【Chemistry 313】 or a pharmaceutically acceptable salt or solvate thereof (in the formula, B is a substituted condensed benzene ring or a 5-membered or 6-membered condensed heteroaromatic ring, wherein the benzene ring is optionally substituted with halogen, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C1-4 alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, -ORa, and -N(Ra)2), optionally substituted -C6-10 aryl, optionally substituted -(5-10 membered)-C1-9 heteroaryl, -(5-10 membered)-C2-9 heterocyclyl, and -C3-10 The aryl, heteroaryl, and heterocyclyl are optionally fused to a further (second) ring, and the 5-membered or 6-membered heteroaromatic ring is optionally substituted with one or two substituents independently selected from the group consisting of halogens, hydroxyl, CN, -ORa, -SRa, -N(Ra)2, (=O), -C1-4 alkyl (optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, CN, -ORa, and -N(Ra)2), optionally substituted -C6-10 aryl, optionally substituted -(5-10 member)-C1-9 heteroaryl, -(5-10 member)-C2-9 heterocyclyl, and -C3-10 cycloalkyl, and the aryl, heteroaryl, and heterocyclyl are optionally fused to a further (second) ring. R １ is, -C １～４ Alkyl, -C ３～１０ Cycloalkyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C ６～１０ Ariel, -C １～４ Alkyl-C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl, -C １～４ Alkyl-(5-10 member)-C １～９ Heteroaryl, (5-10 member) -C ２～９ Heterocyclyl and -C １～４ Alkyl-(5-10 member)-C ２～９ Selected from the group consisting of heterocyclyls, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, substituted as needed (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring. R ２ C １～４ Alkyl, -C ３～１０ Cycloalkyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C ６～１０ Ariel, -C １～４ Alkyl-C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl, -C １～４ Alkyl-(5-10 member)-C １～９ Heteroaryl, (5-10 member) -C ２～９ Heterocyclyl and -C １～４ Alkyl-(5-10 member)-C ２～９ Selected from the group consisting of heterocyclyls, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, and substituted as needed (5-10 member) - C １～９ They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heteroaryls, and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring. R ３ , R ３’ , R ４ and R ４’ This is hydrogen, halogen, and unsubstituted C. １～４ Alkyl and substituted C １～４ Each is independently selected from the group consisting of alkyls, R ５ is hydrogen, C １～４ Alkyl, -C ３～１０ Cycloalkyl, -C １～４ Alkyl-C ３～１０ Cycloalkyl, -C ６～１０ Ariel, -C １～４ Alkyl-C ６～１０ Ariel, (5-10 members) - C １～９ Heteroaryl, -C １～４ Alkyl-(5-10 member)-C １～９ Heteroaryl, (5-10 member) -C ２～９ Heterocyclyl and -C １～４ Alkyl-(5-10 member)-C ２～９ Selected from the group consisting of heterocyclyls, the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORa, -SRa, -N(Ra) ２ , -C １～４ Alkyl (substituted as necessary with one, two, or three halogen atoms), optionally substituted C ６～１０ Aryl, substituted as needed (5-10 members) - C １～９ Heteroaryl and (5- to 10-membered)-C ２～９ They are optionally substituted with one, two, or three substituents independently selected from the group consisting of heterocyclyls, wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are optionally condensed to a further (second) ring, or R １ and R ２ These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or R １ and R ３ These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or R １ and R ４ These, together with the nitrogen and carbon atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as necessary, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as necessary by heteroatoms selected from the group consisting of N, S, and O, or R ２ and R ５ These, together with the nitrogen atoms to which they are bonded, form a 5- to 10-membered heterocyclic ring which is substituted as needed, and one, two, or three of the carbon atoms of the heterocyclic ring are replaced as needed by heteroatoms selected from the group consisting of N, S, and O, and the heterocyclic ring is condensed as needed with a phenyl ring. Each Ra independently contains hydrogen and -C. １～４ Alkyl, -C ３～１０ Cycloalkyl or -(5- to 10-membered)-C ２～９ (The heterocycline is a heterocycline, and the alkyl, cycloalkyl, or heterocycline group is optionally substituted with one, two, or three fluorine atoms.) A pharmaceutical composition having the following characteristics.

22. The aforementioned compound, 【Chemical 314】 The pharmaceutical composition according to claim 21, which is selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

23. The aforementioned compound, 【Chemical 317】 【Chemical 318】 The pharmaceutical composition according to claim 21, which is selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

24. A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

25. The aforementioned compound, 【Chemical 323】 The pharmaceutical composition according to claim 24, which is selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

26. The aforementioned compound, 【Chemical 324】 【Chemical 325】 【Chemistry 326】 【Chemistry 327】 The pharmaceutical composition according to claim 24, which is selected from the group consisting of or a pharmaceutically acceptable salt or solvate thereof.

27. A composition for pharmacokinetic use in the treatment of MPS1, comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, characterized in that the composition is administered in combination with α-L-iduronidase or a recombinant variant thereof as necessary.

28. The composition according to claim 27, wherein the α-L-idulonidase or its recombinant variant comprises laronidase.

29. The composition according to claim 27, wherein MPS1 is Hurler disease, Hurler-Scheie syndrome, or Schie syndrome.

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