Heteroaryl compounds in conditions associated with altered beta-glucocerebrosidase activity and their therapeutic use

Abstract

This application relates to compounds of formula (IA) and (IB), and salts and solvates thereof, wherein R 1a , R 2a , R 3a , A 1 , A 2 , A 3 , R 1b , R 2b , R 3b , B 1 and B 2 as described herein), as well as methods for their preparation, pharmaceutical compositions containing them, and their use for treating and / or preventing lysosomal storage diseases, such as Gaucher's disease, and alpha-synucleinopathies, such as Parkinson's disease. TIFF2023503465000485.tif34101

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to European Patent Application No. EP19383037.9, filed on November 25, 2019, which is incorporated herein by reference in its entirety.

[0002] Field of disclosure The present disclosure relates to heteroaryl compounds, and in particular pyridyl, pyrimidinyl and triazinyl compounds, novel methods for their preparation, and the use of heteroaryl compounds in the treatment and / or prevention of conditions related to altered activity of β - glucocerebrosidase in patients, such as lysosomal storage diseases and α - synucleinopathies. The present disclosure also relates to the use of the heteroaryl compounds described herein in the treatment and / or prevention of medical disorders in patients, such as Gaucher disease, Parkinson's disease, Lewy body dementia, diffuse Lewy body disease, multiple system atrophy (MSA), epilepsy, bipolar disorder, schizophrenia, anxiety disorders, major depression, polycystic kidney disease, type 2 diabetes, open - angle glaucoma, multiple sclerosis (MS), multiple myeloma, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), corticobasal degeneration, frontotemporal dementia, GBA1 Parkinson's, neurological Gaucher disease, neuroaxonal dystrophy, neurodegenerative diseases with Parkinsonian syndromes, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt - Jakob disease or normal aging without impairment.

Background Art

[0003] Background of the disclosure Gaucher disease, which is proposed to result from β - glucocerebrosidase enzyme deficiency, is a very rare lysosomal storage disease. Conditions related to β - glucocerebrosidase are known to be caused by mutations in the gene resulting in a deficiency of the enzyme β - glucocerebrosidase.

[0004] β-Glucocerebrosidase cleaves β-glucocerebroside from various substrates, and due to the lack of its activity, in patients suffering from conditions related to β-glucocerebrosidase activity, such as Gaucher's disease, accumulation of substrates (i.e., gangliosides, and oligosaccharides having a β-linked glucocerebroside at the terminus) is caused. Beutler et al. (Mol Med. 1(1):82-92 (1994)) reported that the deficiency of glucocerebrosidase results in the accumulation of insoluble glucocerebroside in tissues, leading to the clinical manifestations of Gaucher's disease.

[0005] In many lysosomal disorders such as Gaucher's disease, the mutant enzyme often retains catalytic activity but misfolds in the endoplasmic reticulum ("ER"). This triggers the accumulation of the mutant protein in the ER, and this mutant protein is ultimately tagged for proteasomal degradation by ubiquitination, avoiding the transport of the enzyme to the lysosome. See, for example, Patniak et al., Journal of Medicinal Chemistry 55(12):5734-5748 (2012).

[0006] Gaucher's disease (or Gaucher disease) is a heterogeneous disorder with three subtypes. The majority of patients, i.e., those without neurological signs of the disease, are classified as type I. In type I, clinical signs include splenomegaly and hepatomegaly, thrombocytopenia, anemia, and bone disease. Types II and III are neuropathic forms that are classified with respect to severity and onset of neurological disease. Type II has the most severe symptoms at or near birth. Patients with type II have a median lifespan of 9 months. Type III has a later onset. See, for example, Patniak et al., Journal of Medicinal Chemistry 55(12):5734-5748 (2012). Patients with Gaucher disease exhibit hematological signs such as anemia and thrombocytopenia, as well as hepatosplenomegaly, skeletal deformities, and in some cases, neurological damage. See, for example, Boyd et al., Journal of Medicinal Chemistry 56 (7):2705-2725 (2013).

[0007] Enzyme replacement therapy ("ERT") and substrate reduction therapy ("SRT") are the two current treatments for type I Gaucher disease. ERT involves long-term treatment by injection of recombinant enzyme (imiglucerase) to patients. ERT can be effective in reducing and reversing the clinical signs of the disease, but it is very costly. SRT is generally applied for the treatment of adult patients with mild to moderate type I Gaucher disease, and in such patients, ERT is not a treatment option. The prescription drug, i.e., miglustat, an iminosugar, inhibits glucosylceramide synthase and reduces the production of glucocerebroside in lysosomes. SRT can be effective in some patients, but it is accompanied by side effects including weight loss, diarrhea, tremors, and peripheral nerve damage. Neither ERT nor SRT is effective for the neuropathic types II and III of Gaucher disease. See, for example, Patniak et al., Journal of Medicinal Chemistry 55(12):5734-5748 (2012).

[0008] Mutations in the gene encoding glucocerebrosidase are also risk factors for α-synucleinopathies such as Parkinson's disease and diffuse Lewy body disease. Parkinson's disease is a neurodegenerative disorder associated with the death of dopamine-containing cells in the midbrain region. Diffuse Lewy body disease is a dementia that is sometimes confused with Alzheimer's disease.

[0009] Small molecules (chaperones) that bind allosterically or competitively to the mutant β-glucocerebrosidase enzyme and thereby can stabilize the enzyme from degradation constitute important therapeutic targets in conditions associated with altered β-glucocerebrosidase activity. These chemical chaperones promote protein folding by binding to and stabilizing the mutant protein, ultimately increasing its transport to the lysosome. Improvement in the trafficking of the mutant protein from the ER to the lysosome results in a decrease in lysosome size and correction of the accumulation. These chaperones may also increase the stability of the mutant enzyme against degradation in the lysosome. See, for example, Patniak et al., Journal of Medicinal Chemistry 55(12):5734-5748 (2012). It has surprisingly been found that the compounds of formulas (IA) and (IB) can bind to β-glucocerebrosidase and thereby stabilize the enzyme against denaturation.

Prior Art Documents

Non-Patent Documents

[0010]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

[0011] Summary of the Disclosure The present disclosure relates to the discovery that heteroaryl compounds represented by formulas (IA) and (IB) can bind to β-glucocerebrosidase (mutant or non-mutant), and thus, for example, lysosomal storage diseases such as Gaucher disease, or α-synucleinopathies such as Parkinson's disease, or other conditions related to alteration of the activity of β-glucocerebrosidase are useful for the treatment or prevention.

[0012] In one aspect, the present disclosure provides compounds represented by the following formulas (IA) and (IB), collectively referred to herein as "the compounds of the present disclosure", and pharmaceutically acceptable salts and solvates thereof (each individually, hereinafter referred to as "the compounds of the present disclosure").

[0013] In another aspect, the present disclosure provides a method for treating or preventing a condition related to alteration of the activity of β-glucocerebrosidase in a patient in need thereof. The method includes administering to the patient in need thereof an effective amount of the compound of the present disclosure.

[0014] In another aspect, the present disclosure provides a method for treating or preventing a lysosomal storage disease such as Gaucher disease in a patient in need thereof by administering an effective amount of the compound of the present disclosure.

[0015] In another aspect, the present disclosure provides a method for treating or preventing an α-synucleinopathy such as Parkinson's disease in a patient in need thereof by administering an effective amount of the compound of the present disclosure.

[0016] In another aspect, the present disclosure relates to a method for treating or preventing a disease or disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body dementia, diffuse Lewy body disease, multiple system atrophy (MSA), epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis (MS), multiple myeloma, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), corticobasal degeneration, frontotemporal dementia, GBA1 Parkinson's, neurological Gaucher disease, neuroaxonal dystrophy, neurodegenerative diseases with Parkinsonism, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and normal aging without impairment.

[0017] In another aspect, the method described herein further comprises the step of administering to the patient at least one other therapeutic agent. In another aspect, the therapeutic agent is an effective amount of an enzyme for enzyme replacement therapy. In another aspect (asoect), the enzyme is β-glucocerebrosidase or an analog thereof. In another aspect, the enzyme is imiglucerase. In another aspect, the therapeutic agent is an effective amount of a small molecule chaperone. In another aspect, the small molecule chaperone binds competitively to the enzyme. In another aspect, the small molecule chaperone is selected from the group consisting of iminoalditols, iminosugars, amino sugars, thiophenyl glycosides, glycosidases, sulfatases, glycosyltransferases, phosphatases, and peptidase inhibitors. In another aspect, the small molecule chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol, and miglustat. In another aspect, the small molecule chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), and ambroxol. In another aspect, the small molecule chaperone is miglustat.

[0018] In another aspect, the therapeutic agent is an effective amount of a substrate reducing agent for substrate reduction therapy. In another aspect, the substrate reducing agent is miglustat.

[0019] In another aspect, the present disclosure provides a compound of the present disclosure described herein for use in preventing or treating a condition associated with an alteration in the activity of β-glucocerebrosidase in a patient in need thereof.

[0020] In another aspect, the present disclosure provides a compound of the present disclosure described herein for use in preventing or treating a lysosomal storage disorder such as Gaucher disease.

[0021] In another aspect, the present disclosure provides a compound of the present disclosure described herein for use in preventing or treating an α-synucleinopathy such as Parkinson's disease.

[0022] In another aspect, the present disclosure provides a compound of the present disclosure described herein for use in preventing or treating a disease or disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body dementia, diffuse Lewy body disease, multiple system atrophy (MSA), epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis (MS), multiple myeloma, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), corticobasal degeneration, frontotemporal dementia, GBA1 Parkinson's, neuronal Gaucher disease, neuroaxonal dystrophy, neurodegenerative diseases with Parkinsonism, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and normal aging without impairment.

[0023] In another aspect, the present disclosure also encompasses the use of a compound of the present disclosure described herein for treating or preventing a condition associated with an alteration in the activity of β-glucocerebrosidase, such as lysosomal storage disorders and α-synucleinopathies, in a patient in need thereof.

[0024] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure described herein and at least one pharmaceutically acceptable excipient.

[0025] In another aspect, the disclosure provides a compound of the disclosure described herein for use as a medicament.

[0026] In another aspect, the disclosure provides the use of a compound of the disclosure described herein in the preparation of a medicament for preventing or treating a condition associated with an alteration in the activity of β-glucocerebrosidase, such as lysosomal storage diseases and α-synucleinopathies, in a patient in need thereof.

[0027] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure described herein and at least one pharmaceutically acceptable excipient for use in treating or preventing a condition associated with an alteration in the activity of β-glucocerebrosidase, such as lysosomal storage diseases and α-synucleinopathies, in a patient in need thereof.

[0028] Other aspects and advantages of the disclosure will become apparent from the following detailed description of the disclosure. Embodiments and advantages of the disclosure will be recognized and achieved particularly by the elements and combinations pointed out in the appended claims.

[0029] It should be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the claimed disclosure. **DETAILED DESCRIPTION OF THE INVENTION**

[0030] **Detailed Description of the Disclosure** One aspect of the disclosure is based on the use of a compound of the disclosure for binding to β-glucocerebrosidase. In view of this property, the compounds of the disclosure are expected to be useful, for example, in treating or preventing Gaucher disease and other diseases or conditions described herein.

[0031] Compounds of the disclosure useful in this aspect of the disclosure are compounds of formula (IA) and formula (IB): [Chemical formula] and its pharmaceutically acceptable salts and solvates (wherein A 1 , A 2 , A 3 , R 1a , R 2a , R 3a , B 1 , B 2 , R 1b , R 2b and R 3b are as defined below). is as follows.

[0032] In another aspect, the compounds of the present disclosure are compounds of formula (IA): [Chemical formula] and its pharmaceutically acceptable salts and solvates (wherein A 1 , A 2 and A 3 are each independently selected from the group consisting of N, CH, and C(R 4a ), provided that at least one of A 1 , A 2 or A 3 is N, R 4a are each independently selected from the group consisting of halogen, -C 1~4 alkyl, -C 1~4 alkoxy, and -CN, R 1a 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)-C2~9 heterocyclyl, -C 1~4 alkyl-(5- to 10-membered)-C 2~9 heterocyclyl and -C(=O)Ra a selected from the group consisting of, wherein said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 alkyl (optionally substituted by one, two or three halogen atoms), 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 optionally substituted -O-(C 6~10 aryl) are each independently selected from the group consisting of one, two or three substituents optionally substituted by, and said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to a further (second) ring, R 2a is hydrogen, -C 1~4 alkyl and C 3~6 cycloalkyl selected from the group consisting of, said -C 1~4 alkyl is optionally substituted; or R 1a and R 2a together with the nitrogen atom to which they are attached form an optionally substituted 5- to 10-membered heterocyclic ring, said heterocyclic ring optionally contains one, two or three additional heteroatoms selected from the group consisting of N, S or O, and said heterocyclic ring is optionally fused to a phenyl ring, Ra a is -C 1~4 alkyl, -C3~10 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 said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 Alkyl (optionally substituted 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 Optionally substituted by one, two or three substituents each independently selected from the group consisting of heterocyclyl, wherein said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to a further (second) ring, Rb a Each is independently hydrogen, -C 1~4 Alkyl, -C 3~10 Cycloalkyl or -(5 - to 10 - membered)-C 2~9 Heterocyclyl, wherein said alkyl, cycloalkyl or heterocyclyl group is optionally substituted by one, two or three fluorine atoms, R 3a is, -C6~10 Aryl, -(5 - to 10 - membered)-C 1~9 Heteroaryl, -C 3~10 Cycloalkyl and -(5 - to 10 - membered)-C 2~9 selected from the group consisting of heteroaryl, cycloalkyl and heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each independently selected from the group consisting of halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 alkyl (halogen, -CN, -ORb a and -N(Rb a ) 2 and are each independently selected from the group consisting of one, two or three substituents, and are optionally substituted), 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 selected from the group consisting of one, two or three substituents and are optionally substituted, and said -C 6~10 aryl is optionally fused to a 5 - or 6 - membered heterocyclic ring) is.

[0033] In some embodiments, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts and solvates thereof (wherein, A 1 , A 2 and A 3 are each independently selected from the group consisting of N, CH and C(R 4a ), provided that at least one of A 1 , A 2 or A 3 is N, R 4a are each independently selected from the group consisting of halogen, -C 1~4 alkyl, -C 1~4 alkoxy and -CN, R 1a is -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, -C 1~4 Alkyl-(5 - to 10 - membered)-C 2~9 Heterocyclyl and -C(=O)Ra a Selected from the group consisting of, wherein said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 Alkyl (optionally substituted by one, two or three halogen atoms), 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 optionally substituted -O-(C 6~10 Aryl) are each independently selected from one, two or three substituents selected from the group consisting of and are optionally substituted by; said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally further fused to a further (second) ring, R 2a is hydrogen, -C 1~4 Alkyl and C 3~6 Cycloalkyl selected from the group consisting of, said -C 1~4 Alkyl is optionally substituted; or R 1a and R 2a together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclic ring which is optionally substituted, said heterocyclic ring optionally containing one, two or three additional heteroatoms selected from the group consisting of N, S or O, and said heterocyclic ring being optionally fused to a phenyl ring, Ra a 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, selected from the group consisting of, and said alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 alkyl (optionally substituted 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 2~9Optionally substituted with one, two or three substituents each independently selected from the group consisting of heterocyclyl, wherein said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to a further (second) ring, Rb a each independently is hydrogen, -C 1~4 alkyl, -C 3~10 cycloalkyl or -(5- to 10-membered)-C 2~9 heterocyclyl, wherein said alkyl, cycloalkyl or heterocyclyl group is optionally substituted with one, two or three fluorine atoms, R 3a is -C 6~10 aryl, -(5- to 10-membered)-C 1~9 heteroaryl, -C 3~10 cycloalkyl and -(5- to 10-membered)-C 2~9 heterocyclyl selected from the group consisting of, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 alkyl (optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, -CN, -ORb a and -N(Rb a ) 2 ), 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 with one, two or three substituents each independently selected from the group consisting of) is.

[0034] In another aspect, the compounds of the present disclosure are A 1 , A2 and A 3 A compound of formula (IA) wherein one of them is N, and pharmaceutically acceptable salts and solvates thereof.

[0035] In another aspect, the compounds of the present disclosure are A 1 , A 2 and A 3 A compound of formula (IA) wherein two of them are N, and pharmaceutically acceptable salts and solvates thereof.

[0036] In another aspect, the compounds of the present disclosure are A 1 , A 2 and A 3 are N, a compound of formula (IA), and pharmaceutically acceptable salts and solvates thereof. In some embodiments of this aspect, the compound of formula (IA) is

Chemical Formula

[0037] In some aspects, the compounds of the present disclosure are A 1 , A 2 and A 3 A compound of formula (IA) and pharmaceutically acceptable salts thereof, wherein two or less of them are N.

[0038] In another aspect, the compounds of the present disclosure are A 1 is N, A 2 and A 3 are each independently selected from the group consisting of CH and C(R 4a ), a compound of formula (IA), and pharmaceutically acceptable salts and solvates thereof. In another embodiment, A 2 and A 3 are both CH.

[0039] In another aspect, the compounds of the present disclosure are A 2 is N, A 1 and A 3 are each independently selected from the group consisting of CH and C(R 4aCompounds of formula (IA), and their pharmaceutically acceptable salts and solvates, each independently selected from the group consisting of 1 and A 3 are both CH.

[0040] In another aspect, the compounds of the present disclosure are such that A 3 is N, and A 1 and A 2 are each independently selected from the group consisting of CH and C(R 4a ), compounds of formula (IA), and their pharmaceutically acceptable salts and solvates. In another embodiment, A 1 and A 2 are both CH.

[0041] In another aspect, the compounds of the present disclosure are such that A 1 and A 2 are both N, and A 3 is CH or C(R 4a ), compounds of formula (IA), and their pharmaceutically acceptable salts and solvates. In another embodiment, A 3 is CH.

[0042] In another aspect, the compounds of the present disclosure are such that A 1 and A 3 are both N, and A 2 is CH or C(R 4a ), compounds of formula (IA), and their pharmaceutically acceptable salts and solvates. In another embodiment, A 2 is CH.

[0043] In another aspect, the compounds of the present disclosure are such that A 2 and A 3 are both N, and A 1 is CH or C(R 4a ), compounds of formula (IA), and their pharmaceutically acceptable salts and solvates. In another embodiment, A 1 is CH. In another aspect, the compounds of the present disclosure are such that R 3ais halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 alkyl (halogen, -CN, -ORb a and -N(Rb a ) 2 selected independently from the group consisting of one, two or three substituents, optionally substituted), 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 selected independently from the group consisting of -C 6~10 aryl, and pharmaceutically acceptable salts and solvates thereof. In another embodiment, R 3a is unsubstituted -C 6~10 aryl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl (halogen, CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl), optionally substituted by one, two or three substituents selected independently from the group consisting of -C 6~10 aryl. In another aspect, R 3a is unsubstituted -C 6~10 aryl, preferably unsubstituted phenyl. In another aspect, R 3a is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C1~4 (alkyl) 2 、 -NH(C 1~4 (alkyl) and -C 1~4 (alkyl)(halogen, -CN, -O(C 1~4 ))alkyl, -N(C 1~4 (alkyl) 2 and -NH(C 1~4 (alkyl) and is optionally substituted by one, two or three substituents each independently selected from the group consisting of) and is substituted by one or two substituents each independently selected from the group consisting of -C 6~10 is aryl. In another aspect, R 3a is -C 6~10 is aryl, preferably phenyl optionally substituted by one or two substituents each independently selected from the group consisting of halogen, hydroxy, -CN, methoxy, ethoxy, methylthio, ethylthio, dimethylamino, diethylamino, methylamino, ethylamino, halomethyl (such as fluoromethyl), di(halo)methyl (such as difluoromethyl), tri(halo)methyl (such as trifluoromethyl), cyanomethyl, methoxymethyl, methoxyethyl, dimethylaminomethyl, dimethylaminoethyl, methylaminomethyl and methylaminoethyl. In another aspect, R 3a is phenyl substituted by halogen, hydroxy, -CN, methyl, ethyl, methoxy or ethoxy. In another aspect, the substituent is attached to the meta-position of the phenyl group. In another aspect, the substituent is attached to the ortho-position of the phenyl group. In another aspect, the substituent is attached to the para-position of the phenyl group.

[0044] In some aspects, the compounds of the present disclosure are those of formula (IA) wherein R 3a is phenyl substituted by one or two substituents each independently selected from the group consisting of F, Cl, Br, I, hydroxy, methyl, methoxy and -CN, and pharmaceutically acceptable salts and solvates thereof. In some aspects, R 3ais phenyl substituted by F or hydroxy at the ortho or meta position of the phenyl group. In some embodiments, R 3a is phenyl substituted by F or hydroxy at the ortho position of the phenyl group. In some embodiments, R 3a is phenyl substituted by F or hydroxy at the meta position of the phenyl group.

[0045] In some embodiments, the compounds of the present disclosure have R 3a being unsubstituted -C 6~10 aryl fused to a 5- or 6-membered heterocyclic ring, and pharmaceutically acceptable salts and solvates thereof. In some embodiments, R 3a is unsubstituted phenyl fused to a 5- or 6-membered heterocyclic ring. In some embodiments, the 5- or 6-membered heterocyclic ring contains one, two or three heteroatoms selected from the group consisting of N, S and O, and the remaining atoms are carbon atoms. In some embodiments, the fused heterocyclic ring is a 5-membered ring having one or two oxygen atoms. In some embodiments, the fused heterocyclic ring is a 6-membered ring having one or two oxygen atoms. In some embodiments, R 3a is [Chemical formula] is.

[0046] In another embodiment, the compounds of the present disclosure have R 3a being halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, -CN, -ORb a and -N(Rb a ) 2 ), optionally substituted -C 6~10 aryl, optionally substituted -(5- to 10-membered)-C1~9 Heteroaryl and -(5- to 10-membered)-C 2~9 -(5- or 10-membered)-C optionally substituted with one, two or three substituents each independently selected from the group consisting of heteroaryl and heterocyclyl 1~9 A compound of formula (IA) which is heteroaryl, and pharmaceutically acceptable salts and solvates thereof. In another aspect, R 3a is unsubstituted -(5- to 10-membered)-C 1~9 heteroaryl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) each independently selected from the group consisting of one, two or three substituents optionally substituted with one or two substituents each independently selected from the group consisting of) 1~9 heteroaryl. In another aspect, R 3a is unsubstituted -(5- to 10-membered)-C 1~9 heteroaryl. In another aspect, R 3a is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4optionally substituted with one, two or three substituents each independently selected from the group consisting of (alkyl)), and is substituted with one or two substituents each independently selected from the group consisting of (-(5-membered to 10-membered)-C 1~9 is heteroaryl. In some embodiments, -(5-membered to 10-membered)-C 1~9 heteroaryl is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

[0047] In another embodiment, R 3a is halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 alkyl (optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, -CN, -ORb a and -N(Rb a ) 2 ), optionally substituted -C 6~10 aryl, optionally substituted -(5-membered to 10-membered)-C 1~9 heteroaryl and -(5-membered to 10-membered)-C 2~9 heterocyclyl, each optionally substituted with one, two or three substituents each independently selected from the group consisting of -C 3~10 cycloalkyl. In another embodiment, R 3a is unsubstituted -C 3~10 cycloalkyl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl (halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4Optionally substituted with one, two or three substituents each independently selected from the group consisting of alkyl), optionally substituted with one or two substituents each independently selected from the group consisting of -C 3~10 is cycloalkyl. In another aspect, R 3a is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl), optionally substituted with one, two or three substituents each independently selected from the group consisting of, optionally substituted with one or two substituents each independently selected from the group consisting of C 4~6 is cyclohexyl. In another aspect, R 3a is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl), optionally substituted with one, two or three substituents each independently selected from the group consisting of, optionally substituted with one or two substituents each independently selected from the group consisting of cyclohexyl which is optionally substituted.

[0048] In another aspect, R 3a is halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rba ) 2 、 -C 1~4 alkyl (halogen, -CN, -ORb a and -N(Rb a ) 2 independently selected from one, two or three substituents each selected from the group consisting of, and optionally substituted by) an optionally substituted -C 6~10 aryl, an optionally substituted -(5 - to 10 - membered)-C 1~9 heteroaryl and -(5 - to 10 - membered)-C 2~9 heterocyclyl independently selected from one, two or three substituents each selected from the group consisting of, and optionally substituted by) an optionally substituted -(5 - to 10 - membered)-C 2~9 heterocyclyl.

[0049] In another aspect, the compounds of the present disclosure are those wherein R 2a is H and R 1a is as defined above, compounds of formula (IA), and their pharmaceutically acceptable salts and solvates.

[0050] In another aspect, the compounds of the present disclosure are those wherein R 2a is -C 1~4 alkyl and R 1a is as defined above, compounds of formula (IA), and their pharmaceutically acceptable salts and solvates. In another aspect, R 2a is methyl or ethyl. In another aspect, R 2a is methyl.

[0051] In another aspect, the compounds of the present disclosure are those wherein R 1a is -C 6~10 aryl or -C 1~4 alkyl - C 6~10 aryl, wherein said aryl or alkylaryl is halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4Alkyl (optionally substituted 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 Optionally substituted by one, two or three substituents independently selected from the group consisting of heterocyclyl, where Rb a Is as defined above, and the aryl is optionally fused to a further (second) ring, a compound of formula (IA), and pharmaceutically acceptable salts and solvates thereof.

[0052] In another aspect, R 1a Is unsubstituted C 6~10 Aryl, or halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 Alkyl (optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, -CN, -ORb a And -N(Rb a ) 2 ), 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, substituted by one, two or three substituents independently selected from the group consisting of -C 6~10 Aryl, where Rb a Is as defined above, and the aryl is optionally fused to a further (second) ring. In another aspect, R 1a Is unsubstituted -C 6~10 Aryl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C1~4 (alkyl) and -C 1~4 alkyl (halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) independently selected from the group consisting of one, two or three substituents each independently selected from the group consisting of) optionally substituted by one or two substituents independently selected from the group consisting of -C 6~10 is aryl. In another embodiment, R 1a is unsubstituted -C 6~10 is aryl. In another embodiment, R 1a is unsubstituted phenyl. In another embodiment, R 1a is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl (halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) independently selected from the group consisting of one, two or three substituents each independently selected from the group consisting of) optionally substituted by one or two substituents independently selected from the group consisting of -C 6~10 is aryl. In some embodiments, R 1a is unsubstituted C 6~10 aryl fused to a 5- or 6-membered heterocyclic ring. In some embodiments, the 5- or 6-membered heterocyclic ring contains one, two or three heteroatoms selected from the group consisting of N, S and O, and the remaining atoms are carbon atoms. In some embodiments, the fused heterocyclic ring is a 5-membered ring having one or two oxygen atoms. In some embodiments, the fused heterocyclic ring is a 6-membered ring having one or two oxygen atoms. In some embodiments, R 1a is

Chemical formula

[0053] In another embodiment, R 1a is unsubstituted -C 1~4 alkyl -C 6~10 aryl, or halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 alkyl (halogen, -CN, -ORb a and -N(Rb a ) 2 is optionally substituted by one, two or three substituents independently selected from the group consisting of), 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 is optionally substituted by one, two or three substituents independently selected from the group consisting of)-C 1~4 alkyl -C 6~10 aryl, where Rb a is as defined above, and said aryl is optionally fused to a further (second) ring. In another embodiment, R 1a is unsubstituted -C 1~4 alkyl -C 6~10 aryl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl (halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4Optionally substituted with one, two or three substituents each independently selected from the group consisting of (alkyl)) and substituted with one or two substituents each independently selected from the group consisting of -C 1~4 alkyl-C 6~10 is aryl. In another aspect, R 1a is unsubstituted -C 1~4 alkyl-C 6~10 is aryl. In another aspect, R 1a is unsubstituted benzyl or phenethyl. In another aspect, R 1a is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) and optionally substituted with one, two or three substituents each independently selected from the group consisting of) and substituted with one or two substituents each independently selected from the group consisting of -C 1~4 alkyl-C 6~10 is aryl.

[0054] In another aspect, for the compounds of the present disclosure, R 1a is -C 3~10 cycloalkyl or -C 1~4 alkyl-C 3~10 cycloalkyl, wherein the cycloalkyl or alkylcycloalkyl is halogen, hydroxy, -CN, -ORb a , -SRb a , -N(Rb a ) 2 , -C 1~4 alkyl(optionally substituted with one, two or three halogen atoms) and optionally substituted -C 6~10Aryl, optionally substituted -(5- to 10-membered)-C 1~9 Heteroaryl and -(5- to 10-membered)-C 2~9 Optionally substituted by one, two or three substituents each independently selected from the group consisting of heterocyclyl, where Rb a Is as defined above, and the cycloalkyl is optionally fused to a further (second) ring, a compound of formula (IA), and pharmaceutically acceptable salts and solvates thereof. In another aspect, R 1a Is unsubstituted -C fused to a phenyl ring 3~10 Cycloalkyl. In another aspect, R 1a Is -C fused to a phenyl ring 4~7 Cycloalkyl.

[0055] In another aspect, R 1a Is an unsubstituted pentyl ring or an unsubstituted hexyl ring fused to a phenyl ring.

[0056] In another aspect, the compounds of the present disclosure are those wherein Rb a Is hydrogen or -C 1~4 Alkyl, a compound of formula (IA), and pharmaceutically acceptable salts and solvates thereof.

[0057] In another aspect, the compounds of the present disclosure are those wherein R 1a And R 2a Together with the nitrogen atom to which they are attached form an optionally substituted 5- to 10-membered heterocyclic ring, said heterocyclic ring optionally containing one, two or three additional heteroatoms selected from the group consisting of N, S or O, said heterocyclic ring optionally fused to a phenyl ring, a compound of formula (IA), and pharmaceutically acceptable salts and solvates thereof. In another aspect, R 1a And R 2a Together with the nitrogen atom form, at nitrogen, -C 1~4 Alkyl (such as methyl or ethyl), C 1~4 Alkyl or -O(C 1~4-C optionally substituted by (alkyl) 6~10 aryl (such as phenyl) or -C(=O)O(C 1~4 forms a pipererazinyl ring optionally substituted by (alkyl).

[0058] In another aspect, a compound of the present disclosure is R 1a and R 2a which, together with the nitrogen atom to which they are attached, form a 5- or 6-membered ring optionally fused to a phenyl ring, a compound of formula (IA), and pharmaceutically acceptable salts and solvates thereof. In another aspect, R 1a and R 2a form a 5- or 6-membered ring fused to a phenyl ring together with the nitrogen atom to which they are attached. In some aspects, R 1a and R 2a together with the nitrogen atom to which they are attached,

Chemical formula

[0059] In another aspect, the present disclosure provides

Chemical formula

Chemical formula

[0060] In another aspect, the present disclosure provides

Chemical formula

[0061] In another aspect, the present disclosure provides [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] The present disclosure provides a compound of formula (IA) selected from the group consisting of, and a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride (HCl salt).

[0062] In another aspect, the present disclosure [Chemical formula] [Chemical formula] The present disclosure provides a compound of formula (IA) selected from the group consisting of.

[0063] In another aspect, the compound of the present disclosure is a compound of formula (IB): [Chemical formula] as well as pharmaceutically acceptable salts and solvates thereof (wherein, B 1 and B 2 are each independently selected from the group consisting of N, CH, and C(R 4b ), provided that at least one of B 1 or B 2 is N, R 4b are each independently selected from the group consisting of halogen, -C 1~4 alkyl, -C 1~4 alkoxy, and -CN, X and Y are independently selected from the group consisting of a bond (i.e., absent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 alkylene-C(=O), and are independently selected from the group consisting of: R 1b 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, -C 1~4 alkyl-(5- to 10-membered)-C 1~9 heteroaryl, -(5- to 10-membered)-C 2~9 heterocyclyl, -C 1~4 alkyl-(5- to 10-membered)-C 2~9 heterocyclyl and -C(=O)Ra b and is selected from the group consisting of: the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl groups are each independently optionally substituted with one, two, or three substituents selected from the group consisting of halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl (optionally substituted with one, two, or three halogen atoms), 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 optionally substituted -O-(C 6~10 aryl), and the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl, and alkylheterocyclyl are each optionally fused to an additional (second) ring, Rab 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 selected from the group consisting of heterocyclyl, and the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl (optionally substituted 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 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, Rb b each is independently hydrogen, -C 1~4 alkyl, -C 3~10 cycloalkyl or -(5 - to 10 - membered)-C 2~9It is heterocyclic, and the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one, two or three fluorine atoms, R 2b and R 3b are each independently selected from the group consisting of hydrogen, -C 1~4 alkyl, -C 6~10 aryl, -(5- to 10-membered)-C 1~9 heteroaryl, -C 3~10 cycloalkyl and -(5- to 10-membered)-C 2~9 heterocyclic, and the aryl, heteroaryl, cycloalkyl and heterocyclic groups are halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl (optionally substituted by one or two substituents each independently selected from the group consisting of halogen, -CN, -ORb b and -N(Rb b ) 2 ), optionally substituted -C 6~10 aryl, optionally substituted -(5- to 10-membered)-C 1~9 heteroaryl and -(5- to 10-membered)-C 2~9 heterocyclic, optionally substituted by one, two or three substituents each independently selected from the group consisting of) is.

[0064] In another aspect, the compounds of the present disclosure are B 1 and B 2 are N, compounds of formula (IB), and pharmaceutically acceptable salts and solvates thereof.

[0065] In another aspect, the compounds of the present disclosure are B 1 is N, B 2 is selected from the group consisting of CH and C(R 4b ), compounds of formula (IB), and pharmaceutically acceptable salts and solvates thereof. In another aspect, B2 is CH.

[0066] In another aspect, the compounds of the present disclosure are B 2 is N, and B 1 is selected from the group consisting of CH and C(R 4b ), compounds of formula (IB), as well as their pharmaceutically acceptable salts and their solvates. In another aspect, B 1 is CH.

[0067] In another aspect, the compounds of the present disclosure are R 2b is hydrogen or -C 1~4 alkyl, R 3b is -C 6~10 aryl, -(5- to 10-membered)-C 1~9 heteroaryl, -C 3~10 cycloalkyl and -(5- to 10-membered)-C 2~9 heterocyclyl, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl (optionally substituted by one or two substituents independently selected from the group consisting of halogen, -CN, -ORb b and -N(Rb b ) 2 ), 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 independently selected from the group consisting of, compounds of formula (IB), as well as their pharmaceutically acceptable salts and solvates.

[0068] In another aspect, the compounds of the present disclosure are R 3b is hydrogen or -C 1~4 alkyl, R2b is -C 6~10 aryl, -(5 - to 10 - membered)-C 1~9 heteroaryl, -C 3~10 cycloalkyl and -(5 - to 10 - membered)-C 2~9 heterocyclyl, selected from the group consisting of, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are each independently selected from halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl(halogen, -CN, -ORb b and -N(Rb b ) 2 independently selected from the group consisting of, and are optionally substituted by one or two substituents), 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 independently selected from the group consisting of, a compound of formula (IB), and pharmaceutically acceptable salts and solvates thereof.

[0069] In another aspect, for the compounds of the present disclosure, R 2b is hydrogen or -C 1~4 alkyl, and R 3b is halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl(halogen, -CN, -ORb b and -N(Rb b ) 2 independently selected from the group consisting of, and are optionally substituted by one or two substituents), optionally substituted -C 6~10 aryl, optionally substituted -(5 - to 10 - membered)-C 1~9 heteroaryl and -(5 - to 10 - membered)-C2~9 -C optionally substituted with one, two or three substituents each independently selected from the group consisting of heterocyclyl 6~10 A compound of formula (IB), which is aryl, and pharmaceutically acceptable salts and solvates thereof. In another aspect, R 3b is unsubstituted -C 6~10 aryl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, CN, -O(C 1~4 alkyl), -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) and is optionally substituted with one or two substituents each independently selected from the group consisting of) and is substituted with one or two substituents each independently selected from the group consisting of -C 6~10 aryl. In another aspect, R 3b is unsubstituted -C 6~10 aryl, preferably unsubstituted phenyl. In another aspect, R 3b is halogen, hydroxy, -CN, -O(C 1~4 alkyl), -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 alkyl), -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) and is optionally substituted with one or two substituents each independently selected from the group consisting of) and is substituted with one or two substituents each independently selected from the group consisting of -C 6~10 aryl. In another aspect, R 3b is -C 6~10Aryl, preferably phenyl substituted with one or two substituents each independently selected from the group consisting of halogen, hydroxy, -CN, methoxy, ethoxy, methylthio, ethylthio, dimethylamino, diethylamino, methylamino, ethylamino, halomethyl (such as fluoromethyl), di(halo)methyl (such as difluoromethyl), cyanomethyl, methoxymethyl, methoxyethyl, dimethylaminomethyl, dimethylaminoethyl, methylaminomethyl and methylaminoethyl. In another embodiment, R 3b is phenyl substituted with halogen, hydroxy, -CN, methyl, ethyl, methoxy or ethoxy. In another embodiment, the substituent is attached to the meta-position of the phenyl group. In another embodiment, the substituent is attached to the ortho-position of the phenyl group. In another embodiment, the substituent is attached to the para-position of the phenyl group.

[0070] In another embodiment, the compound of the present disclosure is such that R 2b is hydrogen or -C 1~4 alkyl, and R 3b is halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl (optionally substituted with one or two substituents each independently selected from the group consisting of halogen, -CN, -ORb b and -N(Rb b ) 2 ), 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 with one, two or three substituents each independently selected from the group consisting of -(5- to 10-membered)-C 1~9 heteroaryl, and pharmaceutically acceptable salts and solvates thereof. In another embodiment, R 3b is unsubstituted -(5- to 10-membered)-C1~9 heteroaryl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) independently selected from the group consisting of one or two substituents each independently selected from the group consisting of) and is optionally substituted by one or two substituents each independently selected from the group consisting of)-(5 - to 10 - membered)-C 1~9 heteroaryl. In another embodiment, R 3b is unsubstituted-(5 - or 10 - membered)-C 1~9 heteroaryl. In another embodiment, R 3b is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) independently selected from the group consisting of one or two substituents each independently selected from the group consisting of) and is optionally substituted by one or two substituents each independently selected from the group consisting of)-(5 - or 10 - membered)-C 1~9 heteroaryl.

[0071] In another embodiment, the compound of the present disclosure has R 2b being hydrogen or -C 1~4 alkyl, and R 3b being -C 3~10 cycloalkyl or -(5 - to 10 - membered)-C 2~9heterocyclic, and the cycloalkyl and heterocyclic groups are halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl (halogen, -CN, -ORb b and -N(Rb b ) 2 optionally substituted by one or two substituents each independently selected from the group consisting of), optionally substituted -C 6~10 aryl, optionally substituted -(5 - to 10 - membered)-C 1~9 heteroaryl and -(5 - to 10 - membered)-C 2~9 heterocyclic, optionally substituted by one, two or three substituents each independently selected from the group consisting of, a compound of formula (IB), and pharmaceutically acceptable salts and solvates thereof.

[0072] In another aspect, for the compounds of the present disclosure, R 3b is hydrogen or -C 1~4 alkyl, and R 2b is halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl (halogen, -CN, -ORb b and -N(Rb b ) 2 optionally substituted by one or two substituents each independently selected from the group consisting of), optionally substituted -C 6~10 aryl, optionally substituted -(5 - to 10 - membered)-C 1~9 heteroaryl and -(5 - to 10 - membered)-C 2~9 heterocyclic, optionally substituted by one, two or three substituents each independently selected from the group consisting of -C 6~10A compound of formula (IB) which is aryl, and its pharmaceutically acceptable salts and solvates. In another aspect, R 2b is unsubstituted -C 6~10 aryl, or -C 1~4 aryl which is substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 2 alkyl) 1~4 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, CN, -O(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl)) as required. In another aspect, R 6~10 is unsubstituted -C 2b aryl, preferably unsubstituted phenyl. In another aspect, R 6~10 is -C 2b aryl which is substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy, -CN, -O(C 1~4 alkyl), -S(C 1~4 )alkyl, -N(C 1~4 )alkyl 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 alkyl), -N(C 1~4 )alkyl 2 and -NH(C 1~4 alkyl)) as required. In another aspect, R 6~10 is -C 2b is -C 6~10Aryl, preferably phenyl substituted by one or two substituents independently selected from the group consisting of halogen, hydroxy, -CN, methoxy, ethoxy, methylthio, ethylthio, dimethylamino, diethylamino, methylamino, ethylamino, halomethyl (such as fluoromethyl), di(halo)methyl (such as difluoromethyl), cyanomethyl, methoxymethyl, methoxyethyl, dimethylaminomethyl, dimethylaminoethyl, methylaminomethyl and methylaminoethyl. In another embodiment, R 2b is phenyl substituted by halogen, hydroxy, -CN, methyl, ethyl, methoxy or ethoxy. In another embodiment, the substituent is attached to the meta-position of the phenyl group. In another embodiment, the substituent is attached to the ortho-position of the phenyl group. In another embodiment, the substituent is attached to the para-position of the phenyl group.

[0073] In another embodiment, the compound of the present disclosure has R 3b being hydrogen or -C 1~4 alkyl, and R 2b being halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl (optionally substituted by one or two substituents independently selected from the group consisting of halogen, -CN, -ORb b and -N(Rb b ) 2 ), optionally substituted -C 6~10 aryl, optionally substituted -(5-membered to 10-membered)-C 1~9 heteroaryl and -(5-membered to 10-membered)-C 2~9 heterocyclyl, optionally substituted by one, two or three substituents independently selected from the group consisting of -(5-membered to 10-membered)-C 1~9 heteroaryl, and pharmaceutically acceptable salts and solvates thereof. In another embodiment, R 2b is unsubstituted -(5-membered or 10-membered)-C1~9 heteroaryl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) independently selected from the group consisting of one or two substituents each independently selected from the group consisting of) is optionally substituted by one or two substituents independently selected from the group consisting of)-(5 - to 10 - membered)-C 1~9 heteroaryl. In another embodiment, R 3b is unsubstituted-(5 - to 10 - membered)-C 1~9 heteroaryl. In another embodiment, R 2b is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl) independently selected from the group consisting of one or two substituents each independently selected from the group consisting of) is optionally substituted by one or two substituents independently selected from the group consisting of)-(5 - or 10 - membered)-C 1~9 heteroaryl.

[0074] In another embodiment, the compound of the present disclosure is such that R 3b is hydrogen or -C 1~4 alkyl, and R 2b is -C 3~10 cycloalkyl or -(5 - to 10 - membered)-C 2~9heterocyclic, wherein the cycloalkyl and heterocyclic groups are each independently selected from the group consisting of halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl(halogen, -CN, -ORb b and -N(Rb b ) 2 and are optionally substituted by one or two substituents independently selected from the group consisting of), optionally substituted -C 6~10 aryl, optionally substituted -(5- to 10-membered)-C 1~9 heteroaryl and -(5- to 10-membered)-C 2~9 heterocyclic, optionally substituted by one, two or three substituents independently selected from the group consisting of, a compound of formula (IB), and pharmaceutically acceptable salts and solvates thereof.

[0075] In another aspect, the compounds of the present disclosure are those wherein R 2b is hydrogen and R 3b is as defined above, a compound of formula (IB), and pharmaceutically acceptable salts and solvates thereof.

[0076] In another aspect, the compounds of the present disclosure are those wherein R 3b is hydrogen and R 2b is as defined above, a compound of formula (IB), and pharmaceutically acceptable salts and solvates thereof.

[0077] In another aspect, the compounds of the present disclosure are those wherein R 1b is -C 6~10 aryl or -C 1~4 alkyl-C 6~10 aryl, wherein the aryl or alkylaryl is halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4Alkyl (optionally substituted 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 independently selected from the group consisting of, Rb b is as defined above, a compound of formula (IB), and pharmaceutically acceptable salts and solvates thereof.

[0078] In another aspect, R 1b is unsubstituted C 6~10 Aryl, or halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 Alkyl (halogen, -CN, -ORb b and -N(Rb b ) 2 , optionally substituted by one, two or three substituents independently selected from the group consisting of), 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, substituted by one, two or three substituents independently selected from the group consisting of C 6~10 Aryl. In another aspect, R 1b is unsubstituted -C 6~10 Aryl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl) and -C 1~4 alkyl (halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl)2 and -NH(C 1~4 optionally substituted with one, two or three substituents independently selected from the group consisting of alkyl), and is substituted with one or two substituents independently selected from the group consisting of -C 6~10 is aryl. In another embodiment, R 1b is unsubstituted -C 6~10 is aryl. In another embodiment, R 1b is unsubstituted phenyl. In another embodiment, R 1b is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl)and -C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and -NH(C 1~4 alkyl)optionally substituted with one, two or three substituents independently selected from the group consisting of), and is substituted with one or two substituents independently selected from the group consisting of -C 6~10 is aryl.

[0079] In another embodiment, R 1b is unsubstituted -C 1~4 alkyl -C 6~10 aryl, or halogen, hydroxy, -CN, -ORb b , -SRb b , -N(Rb b ) 2 , -C 1~4 alkyl(halogen, -CN, -ORb b and -N(Rb b ) 2 optionally substituted with one, two or three substituents independently selected from the group consisting of), optionally substituted -C 6~10 aryl, optionally substituted -(5 - to 10 - membered)-C 1~9Heteroaryl and -(5 - to 10 - membered)-C 2~9 Optionally substituted by one, two or three substituents independently selected from the group consisting of heterocyclyl-C 1~4 Alkyl-C 6~10 Is aryl. In another aspect, R 1b Is unsubstituted-C 1~4 Alkyl-C 6~10 Aryl, or halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl)and-C 1~4 alkyl(halogen, -CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and-NH(C 1~4 alkyl)optionally substituted by one, two or three substituents independently selected from the group consisting of-C 1~4 Alkyl-C 6~10 Is aryl. In another aspect, R 1 Is unsubstituted-C 1~4 Alkyl-C 6~10 Is aryl. In another aspect, R 1b Is unsubstituted benzyl or unsubstituted phenethyl. In another aspect, R 1b Is halogen, hydroxy, -CN, -O(C 1~4 )alkyl, -S(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 , -NH(C 1~4 alkyl)and-C 1~4 alkyl(halogen, CN, -O(C 1~4 )alkyl, -N(C 1~4 alkyl) 2 and-NH(C 1~4Optionally substituted with one, two or three substituents each independently selected from the group consisting of (alkyl)) and substituted with one or two substituents each independently selected from the group consisting of -C 1~4 alkyl-C 6~10 is aryl.

[0080] In another embodiment, the compounds of the present disclosure are Rb b is hydrogen or -C 1~4 alkyl, the compounds of formula (IB), and their pharmaceutically acceptable salts and solvates.

[0081] In another aspect, the compounds of the present disclosure are such that X is absent and Y is a bond (i.e., absent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 alkylene-C(=O), the compounds of formula (IB), and their pharmaceutically acceptable salts and solvates.

[0082] In another aspect, the compounds of the present disclosure are such that X is C 1~4 alkylene and Y is a bond (i.e., absent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 alkylene-C(=O), the compounds of formula (IB), and their pharmaceutically acceptable salts and solvates.

[0083] In another aspect, the compounds of the present disclosure are such that X is C(=O) and Y is a bond (i.e., absent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 alkylene-C(=O), the compounds of formula (IB), and their pharmaceutically acceptable salts and solvates.

[0084] In another aspect, the compounds of the present disclosure are such that X is C(=O)-C1~2 is alkylene, and Y is a bond (i.e., non-existent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 a compound of formula (IB) selected from the group consisting of alkylene-C(=O), and its pharmaceutically acceptable salts and solvates.

[0085] In another aspect, for the compounds of the present disclosure, X is C 1~2 is alkylene-C(=O), and Y is a bond (i.e., non-existent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 a compound of formula (IB) selected from the group consisting of alkylene-C(=O), and its pharmaceutically acceptable salts and solvates.

[0086] In another aspect, for the compounds of the present disclosure, Y is absent and X is a bond (i.e., non-existent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 a compound of formula (IB) selected from the group consisting of alkylene-C(=O), and its pharmaceutically acceptable salts and solvates.

[0087] In another aspect, for the compounds of the present disclosure, Y is C 1~4 is alkylene, and X is a bond (i.e., non-existent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 a compound of formula (IB) selected from the group consisting of alkylene-C(=O), and its pharmaceutically acceptable salts and solvates.

[0088] In another aspect, for the compounds of the present disclosure, Y is C(=O), and X is a bond (i.e., non-existent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2Compounds of formula (IB) selected from the group consisting of alkylene-C(=O), and pharmaceutically acceptable salts and solvates thereof.

[0089] In another aspect, for the compounds of the present disclosure, Y is C(=O)-C 1~2 wherein alkylene, X is a bond (i.e., absent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 Compounds of formula (IB) selected from the group consisting of alkylene-C(=O), and pharmaceutically acceptable salts and solvates thereof.

[0090] In another aspect, for the compounds of the present disclosure, Y is C 1~2 alkylene-C(=O), and X is a bond (i.e., absent), C 1~4 alkylene, C(=O), C(=O)-C 1~2 alkylene and C 1~2 Compounds of formula (IB) selected from the group consisting of alkylene-C(=O), and pharmaceutically acceptable salts and solvates thereof.

[0091] In another aspect, for the compounds of the present disclosure, X and Y are each independently C 1~4 alkylene, compounds of formula (IB), and pharmaceutically acceptable salts thereof. In another aspect, X is a methylene group and Y is an ethylene group. In another aspect, X is an ethylene group and Y is a methylene group.

[0092] In another embodiment, the present disclosure provides

Chemical formula

Chemical formula

[0093] As used herein, the term "halogen" or "halo" refers to -F, -Cl, -Br or -I.

[0094] As used herein, the term "hydroxy" or "hydroxyl" refers to an -OH group.

[0095] As used herein, the term "alkyl" is a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms that does not contain unsaturation and is bonded to the rest of the molecule by a single bond. Unless otherwise specified, an alkyl radical typically has 1 to 4 carbon atoms, i.e., C 1~4 alkyl. Exemplary C 1~4 alkyl groups can be methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, i-butyl and sec-butyl. In another embodiment, alkyl is C 1~2 alkyl (methyl or ethyl).

[0096] As used herein, the term "C 1~4 alkoxy" refers to oxygen substituted by one of the above C 1~4 alkyl groups, e.g., oxygen substituted by one of the C 1~2 alkyl groups (e.g., methoxy, ethoxy, propoxy, iso-propoxy, butoxy, tert-butoxy, iso-butoxy and sec-butoxy).

[0097] As used herein, the term "cycloalkyl" encompasses saturated carbocyclic radicals. Unless otherwise specified, a cycloalkyl radical typically has 3 to 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group is, for example, cyclopropyl, cyclopentyl and cyclohexyl. In another embodiment, the cycloalkyl group is C 3~10 cycloalkyl.

[0098] As used herein, the term "alkylcycloalkyl", when used in the definition of a substituent, is a cycloalkyl group as defined above, which is linked to the core structure it replaces via an alkylene radical such as C 1~4 an alkylene radical such as ethylene, and refers to a cycloalkyl group that is linked to the core structure it replaces. As an example, a cyclopentylethyl substituent is a substituent consisting of a cyclopentyl group linked to the core structure it replaces via an ethylene group.

[0099] As used herein, the term "heterocyclyl" or "heterocyclic group" generally refers to a monocyclic or polycyclic, non-aromatic, saturated or unsaturated C 2~10 carbon ring containing, in which case one or more, 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 heterocyclyl, i.e., a heterocycle having 3 to 7 carbon atoms and at least one heteroatom. In another embodiment, the heterocyclyl is a (5- to 10-membered)-C 2~9 heterocyclyl, i.e., a heterocycle having 5 to 10 members, of which 2 to 9 members are carbon. In another embodiment, the heteroatom is N. In another embodiment, the heteroatom is O.

[0100] In another embodiment, the heterocyclyl radical is saturated. The heterocyclic radical can be a monocyclic or bicyclic or more fused ring, and at least one ring contains a heteroatom. When the heterocyclyl radical has one or more substituents, these substituents can be the same or different.

[0101] The heterocyclyl which is optionally substituted as described above is usually unsubstituted or can be the same or different and is substituted with one, two or three substituents. Examples of heterocyclic radicals include piperidyl, pyrrolidyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, pyrazolidinyl, quinuclidinyl, tetrazolyl, chromanyl, isochromanyl, imidazolidinyl, oxiranyl, aziridinyl, 4,5-dihydro-oxazolyl and 3-aza-tetrahydrofuranyl. The substituents are selected from, for example, a halogen atom such as a fluorine atom or a chlorine atom, a hydroxy group, an alkoxycarbonyl group, in which case the alkyl moiety has 1 to 4 carbon atoms, a hydroxycarbonyl group, a carbamoyl group, a nitro group, a cyano group, C 1~4 an alkyl group (optionally substituted by one or more halogen atoms), C 1~4 an alkoxy group (optionally substituted by one or more halogen atoms), and C 1~4 having a hydroxyalkyl group.

[0102] As used herein, the term "alkylheterocyclyl", when used in the definition of a substituent, refers to a heterocyclyl group as defined above which is linked to the core structure to which it is attached via an alkylene radical. In one embodiment, the alkylheterocyclyl is -C 1~4 alkyl-(5- to 10-membered)-C 2~9 heterocyclyl.

[0103] As used herein, the term "aryl" usually refers to C such as phenyl and naphthyl 6~10Represents a monocyclic or polycyclic aryl radical. In another embodiment, the aryl is phenyl. The optionally substituted aryl radical is usually unsubstituted or can be the same or different and is substituted by one, two or three substituents. The substituents are selected, for example, from halogen atoms such as fluorine or chlorine atoms, hydroxy groups, alkoxycarbonyl groups where the alkyl moiety has 1 to 4 carbon atoms, hydroxycarbonyl groups, carbamoyl groups, nitro groups, cyano groups, C 1~4 alkyl groups (optionally substituted by one or more halogen atoms), C 1~4 alkoxy groups (optionally substituted by one or more halogen atoms), and C 1~4 hydroxyalkyl groups. When the aryldical has two or more substituents, the substituents can be the same or different. Unless otherwise specified, the substituents on the aryl group are usually themselves unsubstituted.

[0104] As used herein, the term "alkylaryl", when used in the definition of a substituent, refers to an aryl group as defined above that is linked to the core structure it substitutes via an alkylene radical such as C 1~4 alkylene.

[0105] As used herein, the term "heteroaryl" usually represents a 5- to 10-membered ring system containing at least one heteroaromatic ring and at least one heteroatom selected from O, S and N, usually containing 1, 2, 3 or 4 heteroatoms.

[0106] The heteroaryl group can contain a monocyclic or bicyclic or more fused rings, in which case at least one ring contains a heteroatom. The optionally substituted heteroaryl group is usually unsubstituted or can be the same or different and is substituted by one, two or three substituents. The substituents are selected from, for example, a halogen atom, for example, a fluorine, chlorine or bromine atom, an alkoxycarbonyl group, in which case the alkyl moiety has 1 to 4 carbon atoms, a carbamoyl group, a nitro group, a hydroxy group, C 1~4 an alkyl group (optionally substituted by one or more halogen atoms), and C 1~4 an alkoxy group (optionally substituted by one or more halogen atoms). When the heteroaryl radical has two or more substituents, the substituents can be the same or different. Unless otherwise specified, the substituents on the heteroaryl radical are usually unsubstituted themselves.

[0107] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, tetrazolyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridinyl, benzothiazolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, 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.

[0108] In another embodiment, the heteroaryl is a (5- to 10-membered)-C 2~9It is heteroaryl. In another embodiment, the heteroaryl is halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb) 2 , -C 1~4 alkyl (optionally substituted 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 is optionally substituted by one, two or three groups 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.

[0109] When referring to optionally substituted heteroaryl radicals or the remainder within the present disclosure, when they contain an N atom, it is intended to include N-oxides obtainable from these radicals.

[0110] As used herein, the term "alkylheteroaryl", when used in the definition of a substituent, refers to a heteroaryl group as defined above that is linked to the core structure to which it is attached via an alkylene radical. In another embodiment, the alkylheteroaryl is -C 1~4 alkyl-(5- to 10-membered) -C 1~9 heteroaryl.

[0111] The term "pharmaceutically acceptable" refers to compositions and molecular entities that are physiologically tolerable and that do not ordinarily produce allergic reactions or similar adverse reactions such as gastric disturbances, dizziness and the like when administered to humans or animals. For example, the term "pharmaceutically acceptable" means that it has been approved by a state or central government regulatory agency or is included in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals and, more particularly, in humans.

[0112] The term "treatment" or "treating" refers to performing a therapy in an effective amount, manner or mode to improve a condition, symptom, or parameter associated with the condition or to prevent the progression of the condition to either a statistically significant degree or to a degree detectable by one of ordinary skill in the art. The effective amount, manner or mode can vary depending on the subject and can be adjusted according to the patient.

[0113] An "effective" amount or "therapeutically effective amount" of a drug or pharmacologically active agent means an amount of the drug or agent that is non-toxic but sufficient to achieve the desired effect. The "effective" amount can vary for each subject depending on, for example, the age and general condition of the individual, the particular active agent or agent. Thus, it is not always possible to specify an exact "effective amount". However, in any individual case, the appropriate "effective" amount can be determined by one of ordinary skill in the art using routine experimentation.

[0114] The term "prevention" or "preventing" refers to reducing the risk of acquiring or developing a given disease or disorder or to inhibiting or reducing the recurrence of a disease or disorder.

[0115] The term "about", as used herein in connection with a measured quantity, refers to the normal variations in such a measured quantity that would be predicted by a person of ordinary skill in the art making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring device. Typically, the term "about" includes the recited number ±10%. Thus, "about 10" means 9 - 11.

[0116] As used herein, the term "optionally substituted" refers to a group that may or may not be substituted.

[0117] As is clear from the context, the term "up to" before a number or series of numbers is understood to include the number adjacent to the term "up to" and all previous numbers or integers that can logically be included. When "up to" is present before a series of numbers or a range, it is understood that "up to" can modify each number within the series or range.

[0118] As used herein, the term "patient" refers to a human. 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 who has started walking. In some embodiments, the patient is pre - pubescent. In some embodiments, the patient is an adolescent.

[0119] As used herein, the term "child" is a human being between birth and the onset of puberty.

[0120] The term "puberty" is a physical change process by which a child's body matures into an adult body capable of sexual reproduction. On average, puberty begins in girls at about 10 - 11 years of age and ends at about 15 - 17 years of age. In boys, puberty begins at about 11 - 12 years of age and ends at about 16 - 17 years of age.

[0121] As used herein, the term "infant" is synonymous with "baby" and is a very young human child. The term "infant" typically refers to a young child under 1 year of age.

[0122] As used herein, the term "toddler who has started walking" refers to a child between 12 and 36 months of age.

[0123] As used herein, the term "preadolescent" refers to humans aged 10 to 13 years old.

[0124] As used herein, the term "adolescent" refers to humans between 10 and 19 years old.

[0125] The term "solvate" means any form of the active compound of the present disclosure that has another molecule (e.g., a polar solvent such as water or ethanol, cyclodextrin or dendrimer) bonded to this compound via non-covalent bonds. Methods of solvation are known in the art.

[0126] The present disclosure also provides salts of the compounds of the present disclosure. Non-limiting examples include sulfates, hydrogen halides, phosphates, lower alkanesulfonates, arylsulfonates, C which may contain one or more double bonds, an aryl nucleus, or other functional groups such as hydroxy, amino or keto 1~20 Salts of aliphatic monobasic acids, dibasic acids or tribasic acids, salts of aromatic acids, wherein the aromatic nucleus may or may not be substituted by groups such as hydroxyl, lower alkoxyl, amino, lower monoalkyl or dialkylaminosulfonamide. Similarly, included within the scope of the present disclosure are quaternary salts of tertiary nitrogen atoms with lower alkyl halides or alkyl sulfates, and oxygenated derivatives of tertiary nitrogen atoms such as N-oxides. In preparing dosage forms, those skilled in the art will select pharmaceutically acceptable salts.

[0127] Solvates and salts can be prepared by methods known in the art. It should be noted that pharmaceutically unacceptable solvates are also within the scope of the present disclosure as they can be useful in preparing pharmaceutically acceptable salts and solvates.

[0128] The compounds of the present disclosure are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen with deuterium or tritium, carbon 11 C,13 C or 14 replacement with carbon-rich carbon, or replacement of nitrogen with 15 nitrogen-rich nitrogen, excepted, the compounds having this structure are within the scope of the present disclosure.

[0129] Some of the compounds disclosed herein may contain one or more asymmetric centers, and thus, other stereoisomers such as enantiomers, diastereomers, and epimers can occur. The present disclosure is intended to encompass all such contemplated forms, as well as their racemic and resolved forms, and all uses of their mixtures. Individual enantiomers can be separated according to methods known to those skilled in the art in view of the present disclosure. When the compounds described herein contain an olefinic double bond or other centers of geometric asymmetry, 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 the present disclosure.

[0130] 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. It includes enantiomers and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereomers).

[0131] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0132] The term "epimer" refers to a diastereomer having an opposite configuration at only one of two or more tetrahedral stereogenic centers present in an individual molecular entity.

[0133] The term "stereogenic center" is an atom having groups such that interchanging any two groups results in a stereoisomer.

[0134] The terms "enantiomer" and "enantiomerism" refer to molecules that cannot be superimposed on their mirror images and are therefore optically active. In this case, an enantiomer rotates the plane of polarization in one direction, and its mirror-image compound rotates the plane of polarization in the opposite direction.

[0135] The term "racemic" refers to a mixture of equimolar amounts of enantiomers, which is optically inactive.

[0136] The term "resolution" refers to the separation, enrichment, or removal of one of the two enantiomers of a molecule.

[0137] The terms "a" and "an" refer to one or more.

[0138] Some of the reactions for preparing the compounds of the present 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) the amine functionality while the reaction is taking place on other functional groups or moieties of the molecule. Those skilled in the art are familiar with the selection, attachment, and cleavage of amine protecting groups and recognize that numerous and diverse protecting groups are known in the art, and which protecting group is suitable depends on the particular synthetic scheme being planned. Treatises on this subject, such as Wuts, P. G. M. & Greene, T. W., Greene's Protective Groups in Organic Synthesis, 4rd Ed. (J. Wiley & Sons, 2007), which is hereby incorporated by reference in its entirety, are available. Suitable amine protecting groups include methyl carbamate, tert-butyloxycarbonyl (tert-butyl carbamate; BOC), 9-fluorenylmethyl carbamate, benzyl carbamate, 2-(trimethylsilyl)ethyl carbamate, trifluoroacetamide, benzylamine, allylamine, tritylamine, trichloroacetyl, trifluoroacetyl, p-toluenesulfonyl, and allyl carbamate. In another embodiment, the protected amino group can be a phthalimide protected amino group (NPhth).

[0139] As used herein, the term "enzyme replacement therapy" or "ERT" refers to the administration of a naturally occurring or recombinant enzyme, or an analog thereof, that is produced exogenously to a patient in need thereof. In the case of lysosomal storage diseases, for example, a patient accumulates harmful levels of a substrate (i.e., a stored substance) in lysosomes due to a deficiency or defect in an enzyme responsible for substrate metabolism, or due to a deficiency in an enzyme activator required for proper enzyme function. Enzyme replacement therapy results in a reduction (i.e., a decrease) in the level of the substrate accumulated in the affected tissue in the patient. Enzyme replacement therapy for treating lysosomal storage diseases is known in the art. According to the combination therapy of the present disclosure, in a patient having a lysosomal storage disease such as Gaucher disease, a lysosomal enzyme, such as β-glucocerebrosidase, can be used in enzyme replacement therapy to reduce the level of a corresponding substrate, such as β-glucocerebroside.

[0140] As used herein, the term "substrate reduction therapy" or "SRT" is a therapeutic approach used to treat certain metabolic disorders, such as lysosomal storage disorders, where the accumulation of a substrate, such as a glycolipid, is attenuated not by replacing the defective enzyme, but by reducing the level of the substrate to a favorable balance with the residual activity of the defective enzyme. See, for example, Coutinho et al., Int. J. Mol. Sci. 17:1065 (2016). Substrate reduction therapy and enzyme replacement therapy (see above) can have distinct, independent, and potentially complementary mechanisms of action in the treatment of lysosomal storage diseases and other disorders.

[0141] The general principle of SRT is that a substrate reducing agent is administered to a patient to partially inhibit the biosynthesis of a substrate, which accumulates in the absence of specific lysosomal enzymes. As used herein, the term "substrate reducing agent" is a small molecule that reduces the number of substrate molecules that require catabolism within the lysosome, thus contributing to balancing the rate of synthesis and the rate of impaired catabolism. Substrate reducing agents are known in the art.

[0142] As used herein, an "effective amount" of an enzyme is an amount sufficient to improve the clinical course of a lysosomal storage disorder when administered to a subject in the combination therapies of the present disclosure, where clinical improvement is measured by any of a variety of well-defined parameters known to those of skill in the art.

[0143] As used herein, the term "small molecule chaperone" refers to a compound other than the compounds of the present disclosure that binds allosterically or competitively to a mutant enzyme, such as β-galactosidase, thereby stabilizing the enzyme against degradation. In some embodiments, the small molecule chaperone promotes proper folding of the enzyme and transport of the enzyme to its active site. Small molecule chaperones for treating lysosomal storage disorders are known in the art. See, for example, US2016 / 0207933(A1) and WO2011 / 049737(A1).

[0144] α-Synucleinopathy is a neurodegenerative disease characterized by abnormal accumulation of aggregates of α-synuclein protein in neurons, nerve fibers, or glial cells. There is a well-established clinical association between mutations in the glucocerebrosidase gene and the development of more frequently occurring multifactorial disorders, including Parkinson's disease and other synucleinopathies. See Siebert, M., et al., Brain 137:1304-1322 (2014). According to Siebert et al., there is an interrelationship between glucocerebrosidase activity (wild-type and mutant) and α-synuclein in synucleinopathies such as Parkinson's disease and Lewy body dementia. This interrelationship suggests that therapies for Gaucher disease that target enhancement of glucocerebrosidase activity or reduction of glucocerebroside accumulation have been found to provide strategies for modulating α-synuclein protein synthesis and subsequent aggregation and oligomerization.

[0145] Synthesis of the Compounds of the Present Disclosure

[0146] The compounds of the present disclosure can be prepared using methods known to those skilled in the art in view of the present disclosure or by the exemplary methods shown in the following schemes. For example, the compounds of the present disclosure having formula (IA) can be prepared as shown in Schemes 1-8 below, and the compounds of the present disclosure having formula (IB) can be prepared as shown in Schemes 9-12 below. Further methods of synthesis are described and exemplified in the examples below.

Chemical formula

[0147] Method 1 Step 1 (Reaction A)

[0148] In the first method according to the present disclosure, as illustrated in reaction A of the above scheme (Scheme 1), R 3a reacts a compound of formula (IIA) as defined above with dicyandiamide (IIIA) to obtain a biguanide compound of formula (IVA).

[0149] Using reaction A, a compound of formula (IVA) is prepared by reacting a compound of formula (IIA) with a compound of formula (IIIA). The reaction can be carried out under standard conditions in the presence of a suitable acid or base (e.g., copper sulfate, sodium carbonate, ammonia, sodium methoxide in methanol, hydrogen chloride, hydrogen sulfide or mixtures thereof) and a suitable solvent (e.g., butanol, water, tetrahydrofuran, xylene, acetone, methanol, ethanol, acetonitrile, 2-propanol, dichloromethane, dimethylformamide, dimethyl sulfoxide or mixtures thereof), and at reaction conditions such as approximately room temperature, reflux temperature or microwave irradiation, for example.

[0150] This reaction can also be carried out in the presence of a suitable catalyst (or its salt) such as iron(III) chloride or copper(II) chloride, and also, if necessary, in the presence of an additive or protecting group such as chlorotrimethylsilane or trimethylsilyl trifluoromethanesulfonate.

[0151] 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 T. W. Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999).

[0152] Step 2 (Reaction B)

[0153] Subsequently, as illustrated in reaction B of the above scheme (Scheme 1), a biguanide (hydrochloride or not hydrochloride) compound of formula (IVA) is reacted with a compound of formula (VA) (R 4react with (which can be methyl or ethyl) to obtain a compound of formula (VIA).

[0154] Reaction B is carried out under standard condensation conditions, for example, in the presence of a suitable base (such as sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, 1,8-diazabicyclo(5.4.0)undec-7-ene or potassium carbonate) and a suitable solvent (such as ethanol, methanol, dimethylformamide or a mixture thereof), and at, for example, approximately room temperature or reflux temperature.

[0155] This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999).

Chemical formula

[0156] Method 2 (Reaction C)

[0157] Compound (IA) can be prepared by reacting a compound of formula (VIA) with a compound of formula (XIIA) using Reaction C. Subsequently, as illustrated in Reaction C of Scheme 2, the carboxylic acid or acid chloride of the compound of formula (VIA) is converted to a substituted amide group to obtain the compound of formula (IA) according to the present disclosure. Reaction C is carried out under standard amide coupling conditions, for example, in the presence of a suitable coupling agent (such as 1,1'-carbonyldiimidazole, N,N'-cyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or its hydrochloride), N,N'-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (i.e., O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetra-fluorocarbonate, 1-cyclohexylcarbodiimide-3-propyloxymethylpolystyrene, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluoroborate), optionally in the presence of a suitable base (such as sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and / or lithium diisopropylamide (or their variants)) and an appropriate solvent (such as 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.

[0158] The reaction mixture is stirred at low or room temperature or heated until the starting materials are consumed. This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999).

[0159] The compound of formula (IA) can be provided as the free base or converted to the salt form (e.g., HCl salt) by standard salt formation procedures. [Chemical formula] A 1 、A 2 、A 3 、R 1a 、R 2a and R 3a are as defined above with respect to formula (IA), and PG is a protecting group.

[0160] Method 3 Step 1 (Reaction D)

[0161] In another method according to the present disclosure, as illustrated in reaction D of the above scheme (Scheme 3), a compound of formula (VIIA) (Z 2 is -NR 1a R 2a 、-OPG, where PG is a protecting group, and R 1a and R 2a are each as defined above) is reacted with an amine source (e.g., tert-octylamine) to obtain a compound of formula (VIIIA).

[0162] Subsequently, as exemplified in reaction D of the above scheme (Scheme 3), one of the chlorines of the compound of formula (VIIIA) is replaced by reaction with an amine to form the corresponding amino group, thereby obtaining the compound of formula (XA) according to the present disclosure.

[0163] Reaction D can be carried out under standard conditions in the presence of a suitable palladium catalyst such as Pd(dba) 2 , palladium acetate or Pd 2 (dba) 3 etc., a suitable base (especially cesium carbonate or triethylamine) and a suitable ligand such as 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino) ferrocene, Xantphos or XPhos, and at, for example, approximately room temperature or reflux temperature, in a suitable solvent (such as butanol, toluene, dioxane or a mixture thereof).

[0164] Alternatively, this conversion can be carried out in the presence of a suitable base (such as N,N-diisopropylethylamine or triethylamine) and a suitable solvent such as dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol or a mixture thereof.

[0165] This reaction can be carried out using the protecting groups present, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3 rd Edition, New York, 1999).

[0166] Step 2 (Reaction E)

[0167] Subsequently, as exemplified in reaction E of the above scheme (Scheme 3), for the compound of formula (VIIIA) (Z 1 is -NR 1a R 2a , -OPG, where PG is a protecting group and R1a and R 2a react the remaining chlorine of each, as defined above, with the amine group (IXA) (R 3a , as defined above) to obtain a compound of formula (XA).

[0168] The compound of formula (XA) can be used as its free base or converted to its (iys) salt form (e.g., HCl salt) by standard salt formation procedures. Reaction E is carried out, for example, in the presence of a suitable base (e.g., triethylamine, pyridine, potassium carbonate or N,N-diisopropylethylamine) or acid (e.g., sulfuric acid, hydrogen chloride or acetic acid), or in the absence of a base or acid, optionally in the presence of a suitable catalyst, ligand and base (e.g., Pd(dba) 2 , Xantphos and cesium carbonate or 1,1'-bis(diphenylphosphino)ferrocene (Dppf), Pd(OAc) 2 and K 3 PO 4 ) and a suitable solvent (e.g., ethanol, water, acetonitrile, N,N-dimethylacetamide, propanol, N-methylpyrrolidine, 1-methylpiperidine, dimethylformamide, dioxane, butanol or mixtures thereof) under standard nucleophilic substitution conditions.

[0169] Stir this reaction mixture at low temperature, room temperature or heat it until the starting materials are consumed. This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T.W. Greene, "Protective Groups in Organic Synthesis," 3 rd rd Edition, New York, 1999).

Chemical formula

[0170] Method 4 (Reaction F)

[0171] In a fourth method according to the present disclosure, as illustrated in Reaction F of the above scheme (Scheme 4), a compound of formula (XIA) in which R 3a is as defined above reacts with an amine compound (XIIA) (R 1a and R 2a are each as defined above) to obtain an amide compound of formula (XIIA).

[0172] Reaction F is carried out under standard amide formation conditions. For example, a carboxylic acid or acid chloride of a compound of formula (XIA) is converted to a substituted amide group in the presence of a suitable coupling agent (e.g., propylphosphonic anhydride, (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate), 1,1'-carbonyldiimidazole, N,N'-cyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or its hydrochloride), N,N'-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (i.e., O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetra-fluorocarbonate, 1-cyclohexylcarbodiimide-3-propyloxymethylpolystyrene, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluoroborate), optionally in the presence of a suitable base (e.g., sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, sodium hydroxide, potassium tert-butoxide and / or lithium diisopropylamide (or its variant)) and an appropriate solvent (e.g., tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine) to obtain a compound of formula (XIIA) according to the present invention.Such a reaction may be carried out in the presence of further additives such as 1-hydroxybenzotriazole hydrate.

[0173] If the acid chloride of Compound XIA is used, it can be prepared from the corresponding carboxylic acid under standard acid chloride formation conditions, for example, in the presence of thionyl chloride or oxalyl chloride.

[0174] The reaction mixture is stirred at low temperature or room temperature or heated until the starting materials are consumed. This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis", 3rd Edition, New York, 1999). [Chemical formula] R 1a 、R 2a and R 3a are as defined above with respect to formula (IA).

[0175] Method 5 (Reaction G)

[0176] In another method according to the present disclosure, as exemplified in Reaction G of the above scheme (Scheme 5), an aryl chloride compound of formula (XIIIA) (M can be -NH 2 or -Cl, N can be -CONR 1a R 2a , -COOPG or -SO 2 Me, PG is a protecting group, and R 1a and R 2a are each as defined above) is reacted with an amine compound of formula (IXA) (R 3a is as defined above) to obtain a compound of formula (XIVA).

[0177] As exemplified in Reaction G of the above scheme (Scheme 5), the aryl chloride of the compound of formula (XIIIA) is reacted with an amine (IXA) to replace it to form the corresponding amino group, thereby obtaining a compound of formula (XIVA) according to the present disclosure.

[0178] Reaction G is carried out, for example, in the presence of a suitable base (e.g., sodium hydride, triethylamine, pyridine, potassium carbonate or N,N-diisopropylethylamine) or an acid (e.g., sulfuric acid, hydrogen chloride or acetic acid), or in the absence of a base or an acid, and if necessary, in the presence of a suitable catalyst (e.g., Pd(dba) 2 or Pd(OAc) 2 ), a ligand (e.g., xanthphos, BINAP or 1,1'-bis(diphenylphosphino)ferrocene (Dppf)) and a base (e.g., cesium carbonate or K 3 PO 4 ) and an appropriate solvent (e.g., ethanol, water, acetonitrile, N,N-dimethylacetamide, propanol, N-methylpyrrolidine, 1-methylpiperidine, dioxane, dimethylformamide, butanol or a mixture thereof) under standard nucleophilic substitution conditions.

[0179] This reaction mixture is stirred at low temperature, room temperature or heated until the starting materials are consumed. This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3 rd rd Edition, New York, 1999).

Chemical Formula

[0180] Method 6 (Reaction H)

[0181] In another method according to the present disclosure, as illustrated in reaction H of the above scheme (Scheme 6), a compound of formula (XVA) (Y 1 can be -Cl or -HNR 3a , and Z 2 can be -NR 1a R 2a or -OPG, where PG is a protecting group, and R 1a , R 2a and R 3a are each as defined above) is reacted with an amine source (e.g., tert-octylamine, tert-butyl carbamate or diphenylmethanimine) to obtain a compound of formula (XVIA).

[0182] As illustrated in reaction H of the above scheme (Scheme 6), the aryl chloride of the compound of formula (XVA) is substituted by reaction with an amine to form the corresponding protected amino group, thereby obtaining a compound of formula (XVIA) according to the present disclosure.

[0183] Reaction H can be carried out under standard conditions in the presence of a suitable palladium catalyst such as Pd(dba) 2 , palladium acetate or Pd 2 (dba) 3 , a suitable base (especially cesium carbonate, sodium tert-butoxide or triethylamine) and a suitable ligand (e.g., 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, BINAP, xantphos or XPhos) in a suitable solvent (e.g., butanol, toluene, dioxane or a mixture thereof), and at, for example, approximately room temperature or reflux temperature.

[0184] Alternatively, the conversion can be carried out in the presence of a suitable base (e.g., N,N-diisopropylethylamine or triethylamine) and a suitable solvent such as dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol or a mixture thereof.

[0185] This reaction can be carried out using the protecting groups present, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3 rd rd Edition, New York, 1999).

Chemical formula

[0186] Method 7 (Reaction I)

[0187] Alternatively, as illustrated in Reaction I of the above scheme (Scheme 7), a compound of formula (XVIA) (where Y 1 can be -Cl or -HNR 3a , Z 2 can be -NR 1a R 2a or -OPG, where PG is a protecting group, and R 1a , R 2a and R 3a are each as defined above) is reacted to obtain a compound of formula (XVIIA).

[0188] As illustrated in Reaction I of the above scheme (Scheme 7), the protecting group on the amine moiety of the compound of formula (XVIA) (e.g., tert-octylamine, tert-butyl carbamate or diphenylmethanimine) is treated to form the corresponding primary amino group of the compound of formula (XVIIA) according to the present disclosure.

[0189] Compound (XVIIA) can be provided as its free base or converted to its salt form (e.g., HCl salt) by standard salt-forming procedures.

[0190] Reaction I can be carried out under standard deprotection conditions, for example, in the presence of HCl, trifluoroacetic acid or boron tribromide. Such reactions can be carried out in the presence of a suitable solvent (e.g., tetrahydrofuran, dioxane, dichloromethane or mixtures thereof).

[0191] The reaction mixture is stirred at low temperature, room temperature or heated until the starting material is consumed. This reaction can be carried out using the protecting groups present, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T.W. Greene, "Protective Groups in Organic Synthesis," 3 rd rd Edition, New York, 1999).

Chemical formula

[0192] Method 8 (Reaction J)

[0193] In another method according to the present disclosure, as illustrated in Reaction J of the above scheme (Scheme 8), a compound of formula (XVA) (Y 1 can be -Cl or -HNR 3a , Z 2 can be -NR 1a R 2a , -OPG, where PG is a protecting group, and R 1a , R 2a and R 3a are each as defined above) is reacted with an amine precursor (e.g., sodium azide) to obtain a compound of formula (XVIIA).

[0194] As exemplified in reaction J of the above scheme (Scheme 8), the aryl chloride of the compound of formula (XVA) is substituted by reaction with an azide, and then reduced with a reducing agent to form the corresponding amino group, to obtain a compound of formula (XVIIA) according to the present disclosure.

[0195] Compound (XVIIA) can be provided as its free base or can be converted to its salt form (e.g., HCl salt) by standard salt formation procedures.

[0196] Reaction J can be carried out under standard conditions, for example, in the presence of sodium azide in a suitable solvent (e.g., dimethylformamide) at approximately room temperature or reflux temperature. Subsequently, this reaction mixture is treated with a reducing agent (e.g., sodium borohydride) in a suitable solvent (e.g., methanol).

[0197] This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3 rd Edition, New York, 1999).

Chemical formula

[0198] Step 1 (Reaction A)

[0199] In another method according to the present disclosure, as exemplified in reaction A of the above scheme (Scheme 9), a compound of formula (IIB) (where R 1b is as defined above) is reacted with an amine source to obtain a compound of formula (IIIB).

[0200] Subsequently, as illustrated in reaction A of the above scheme (Scheme 9), one of the chlorines of the compound of formula (IIB) is replaced by reaction with an amine to form the corresponding amino group, thereby obtaining a compound of formula (IIIB) according to the present disclosure.

[0201] Reaction A is carried out under standard conditions in the presence of a suitable palladium catalyst such as Pd(dba), palladium acetate or Pd 2 , palladium acetate or Pd 2 (dba) 3 in a suitable solvent (e.g., butanol, toluene, dioxane or a mixture thereof), a suitable base (especially cesium carbonate or triethylamine) and a suitable ligand such as 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Xantphos or XPhos, and at, for example, approximately room temperature or reflux temperature.

[0202] Alternatively, the conversion can be carried out in the presence of a suitable base (e.g., N,N-diisopropylethylamine or triethylamine) and a suitable solvent such as dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol or a mixture thereof.

[0203] This reaction can be carried out using the protecting groups present, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3 rd rd Edition, New York, 1999).

[0204] Step 2 (Reaction B)

[0205] Subsequently, as illustrated in reaction B of the above scheme (Scheme 9), a compound of formula (IIIB) (PG is a protecting group and R 1b is as defined above) is reacted with an aniline group (R 3bReact as defined above) to obtain a compound of formula (VB).

[0206] Subsequently, as illustrated in reaction B of the above scheme (Scheme 9), the remaining chlorine of the compound of formula (IIIB) is substituted by reaction with an amine (IVB) to form the corresponding amino group, thereby obtaining a compound of formula (VB) according to the present disclosure.

[0207] Reaction B is carried out, for example, in the presence of a suitable base (e.g., triethylamine, pyridine, potassium carbonate or N,N-diisopropylethylamine) or acid (e.g., sulfuric acid, hydrogen chloride or acetic acid), or in the absence of a base or acid, and optionally in the presence of a suitable catalyst, ligand and base (e.g., Pd(dba) 2 , Xantphos and cesium carbonate) and a suitable solvent (e.g., ethanol, water, acetonitrile, N,N-dimethylacetamide, propanol, N-methylpyrrolidine, 1-methylpiperidine, dioxane, butanol or mixtures thereof) under standard nucleophilic substitution conditions.

[0208] The reaction mixture is stirred at low temperature, room temperature or heated until the starting materials are consumed. This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3 rd Edition, New York, 1999).

Chemical formula

[0209] Step 1 (Reaction C)

[0210] In another method according to the present disclosure, as illustrated in reaction C of the above scheme (Scheme 10), a compound of formula (IIB) (R 1b is as defined above) is reacted with an aniline group (R 2b is as defined in (VIB) above) to obtain a compound of formula (VIIB).

[0211] Subsequently, as illustrated in reaction C of the above scheme (Scheme 10), one of the chlorines of the compound of formula (IIB) is replaced by reacting with aniline (VIB) to form the corresponding amino group, thereby obtaining a compound of formula (VIIB) according to the present disclosure.

[0212] Reaction C is carried out, for example, in the presence of a suitable base (e.g., triethylamine, pyridine, potassium carbonate or N,N-diisopropylethylamine) or acid (e.g., sulfuric acid, hydrogen chloride or acetic acid), or in the absence of a base or acid, and optionally in the presence of a suitable catalyst, ligand and base (e.g., Pd(dba) 2 , xanthphos and cesium carbonate) and a suitable solvent (e.g., ethanol, water, acetonitrile, N,N-dimethylacetamide, propanol, N-methylpyrrolidine, 1-methylpiperidine, dioxane, butanol or mixtures thereof) under standard nucleophilic substitution conditions.

[0213] This reaction mixture is stirred at low temperature, room temperature or heated until the starting materials are consumed. This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3 rd rd Edition, New York, 1999).

[0214] Step 2 (Reaction D)

[0215] Subsequently, as illustrated in reaction D of the above scheme (Scheme 10), a compound of formula (VIIB) (R1b and R 2b react with an amine source as defined above to obtain a compound of formula (VIIIB).

[0216] Subsequently, as exemplified in reaction D of the above scheme (Scheme 10), the remaining chlorine of the compound of formula (VIIB) is replaced by reaction with an amine to form the corresponding amino group, and a compound of formula (VIIIB) is obtained according to the present disclosure.

[0217] Reaction D can be carried out under standard conditions in the presence of a suitable palladium catalyst such as Pd(dba) 2 , palladium acetate or Pd 2 (dba) 3 etc., a suitable base (especially cesium carbonate or triethylamine) and a suitable ligand such as 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Xantphos or XPhos, and at, for example, approximately room temperature or reflux temperature, in a suitable solvent (e.g., butanol, toluene, dioxane or a mixture thereof).

[0218] Alternatively, the conversion can be carried out in the presence of a suitable base (e.g., N,N-diisopropylethylamine or triethylamine) and a suitable solvent such as dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol or a mixture thereof.

[0219] This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3 rd rd Edition, New York, 1999).

Chemical formula

[0220] Step 1 (Reaction E)

[0221] Subsequently, as illustrated in Reaction E of Scheme 11 above, the hydroxyl group of the compound of formula (IXB) is converted to a chloride to obtain the compound of formula (IIB) according to the present disclosure.

[0222] Reaction E is carried out under standard chlorination conditions in the presence of a suitable chlorinated agent such as phosphoryl chloride, phosphorus pentachloride, cobalt chloride or bis(trichloromethyl) carbonate, and a suitable base (e.g., triethylamine, N,N-diethylaniline, N,N-diisopropylethylamine or 4-(dimethylamino)pyridine), and a suitable solvent such as dimethylformamide, dichloromethane, tetrahydrofuran or a mixture thereof.

[0223] This reaction mixture is stirred at low temperature, room temperature or heated until the starting materials are consumed. This reaction can be carried out using the protecting groups present, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999). [Chemical formula] R 1b is as defined above, and n is each independently 1, 2, 3 or 4.

[0224] Step 1 (Reaction F)

[0225] In another method according to the present disclosure, as illustrated in Reaction F of the above scheme (Scheme 12), the compound of formula (XB) (R1b react with urea or guanidine as defined above to obtain a compound of formula (XIB).

[0226] Reaction F is carried out under standard cyclocondensation conditions, for example, in the presence of a suitable base (such as sodium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, 1,8-diazabicyclo(5.4.0)undec-7-ene or potassium carbonate) and a suitable solvent (such as ethanol, methanol, dimethylformamide or mixtures thereof), and at approximately room temperature or reflux temperature, for example.

[0227] This reaction can be carried out using the protecting groups present, and those protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see T. W. Greene, "Protective Groups in Organic Synthesis," 3rd Edition, New York, 1999).

[0228] Use of the Compounds of the Present Disclosure

[0229] In this method, the utility of the compounds of the present disclosure, including pharmaceutically acceptable salts or solvates, can be demonstrated in appropriate in vitro or in vivo assays. The compounds of the present disclosure have the ability to increase β-glucocerebrosidase. Accordingly, the compounds of the present disclosure can be used / administered in a patient to treat and / or prevent conditions associated with altered β-glucocerebrosidase activity, such as lysosomal storage diseases and α-synucleinopathies. In one aspect, the lysosomal storage disease is Gaucher's disease. In another aspect, the α-synucleinopathy is Parkinson's disease. In another aspect, the condition associated with altered β-glucocerebrosidase activity is a disease or disorder selected from the group consisting of Gaucher's disease, Parkinson's disease, Lewy body dementia, diffuse Lewy body disease, multiple system atrophy (MSA), epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis (MS), multiple myeloma, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), corticobasal degeneration, frontotemporal dementia, GBA1 Parkinson's, neuronal Gaucher's disease, neuroaxonal dystrophy, neurodegenerative diseases with Parkinsonism, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and normal aging without impairment.See, for example, Maegawa G. H. B. et al., The Journal of Biological Chemistry 284(35):23502-23516 (2009); Jung O. et al., Expert Rev. Proteomics. 13(5):471-479 (2016); Mazzulli J. R. et al., The Journal of Neuroscience 36(29):7693-7706 (2016); Khanna R. et al., FEBS Journal 277:1618-1638 (2010); Parenti G. et al., Molecular Therapy 23(7):1138-1148 (2015); and Sun Y. et al., The Journal of Biological Chemistry 287(6):4275-4287 (2012).

[0230] In another aspect, the present disclosure is directed to a method of treating or preventing a condition associated with an alteration in the activity of β-glucocerebrosidase in a patient in need thereof, the method comprising administering to the patient in need thereof an effective amount of a compound of the present disclosure. In another aspect, the compound of the present disclosure is a compound of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compound of the present disclosure is a compound of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0231] In another aspect, the present disclosure is directed to a method of treating or preventing a lysosomal storage disorder, such as Gaucher disease, in a patient in need thereof, the method comprising administering to the patient in need thereof an effective amount of a compound of the present disclosure. In another aspect, the compound of the present disclosure is a compound of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compound of the present disclosure is a compound of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0232] In another aspect, the present disclosure is directed to a method of treating or preventing an α-synucleinopathy such as Parkinson's disease in a patient in need thereof, comprising the step of administering an effective amount of a compound of the present disclosure. In another aspect, the compound of the present disclosure is a compound of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compound of the present disclosure is a compound of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0233] In another aspect, the present disclosure is a method of treating or preventing a disease or disorder selected from the group consisting of Gaucher's disease, Parkinson's disease, Lewy body dementia, diffuse Lewy body disease, multiple system atrophy (MSA), epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis (MS), multiple myeloma, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), corticobasal degeneration, frontotemporal dementia, GBA1 Parkinson's, neuronal Gaucher's disease, axonal dystrophy, neurodegenerative disease with Parkinsonism, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and normal aging in a patient in need thereof, comprising the step of administering an effective amount of a compound of the present disclosure to the patient. In another aspect, the compound of the present disclosure is a compound of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compound of the present disclosure is a compound of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0234] In another aspect, any of the methods described herein can further include the step of administering to the patient at least one other therapeutic agent. In another aspect, the therapeutic agent is an effective amount of an enzyme for enzyme replacement therapy. In another aspect, the enzyme is β-glucocerebrosidase or an analog thereof. In another aspect, the enzyme is imiglucerase. In another aspect, the therapeutic agent is an effective amount of a small molecule chaperone. In another aspect, the small molecule chaperone binds competitively to the enzyme. In another aspect, the small molecule chaperone is selected from the group consisting of iminoalditols, iminosugars, amino sugars, thiophenyl glycosides, glycosidases, sulfatases, glycosyltransferases, phosphatases, and peptidase inhibitors. In another aspect, the small molecule chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol, and miglustat. In another aspect, the small molecule chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), and ambroxol. In another aspect, the small molecule chaperone is miglustat.

[0235] In another aspect, the therapeutic agent is an effective amount of a substrate reducing agent for substrate reduction therapy. In another aspect, the substrate reducing agent is miglustat.

[0236] In another aspect, the present disclosure is directed to the compounds of the present disclosure described herein for use in the prevention or treatment of a condition associated with an alteration in the activity of β-glucocerebrosidase in a patient in need thereof. In another aspect, the compound of the present disclosure is a compound of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compound of the present disclosure is a compound of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0237] In another aspect, the present disclosure is directed to the compounds of the present disclosure described herein for use in preventing or treating lysosomal storage diseases such as Gaucher disease. In another aspect, the compounds of the present disclosure are the compounds of formula (IA) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compounds of the present disclosure are the compounds of formula (IB) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0238] In another aspect, the present disclosure is directed to the compounds of the present disclosure described herein for use in preventing or treating α-synucleinopathies such as Parkinson's disease. In another aspect, the compounds of the present disclosure are the compounds of formula (IA) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compounds of the present disclosure are the compounds of formula (IB) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0239] In another aspect, the present disclosure is directed to the compounds of the present disclosure described herein for use in preventing or treating a disease or disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body dementia, diffuse Lewy body disease, multiple system atrophy (MSA), epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis (MS), multiple myeloma, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), corticobasal degeneration, frontotemporal dementia, GBA1 Parkinson's, neuronal Gaucher disease, neuroaxonal dystrophy, neurodegenerative diseases with Parkinsonism, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and normal aging. In another aspect, the compounds of the present disclosure are the compounds of formula (IA) described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compounds of the present disclosure are the compounds of formula (IB) described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0240] In another aspect, the present disclosure also relates to the use of the compounds of the present disclosure described herein, such as those described herein, for treating or preventing conditions associated with altered β-glucosylceramidase activity in a patient in need thereof. In another aspect, the compounds of the present disclosure are compounds of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compounds of the present disclosure are compounds of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0241] In another aspect, the present disclosure relates to the compounds of the present disclosure described herein for use as a medicament. In another aspect, the compounds of the present disclosure are compounds of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compounds of the present disclosure are compounds of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0242] In another aspect, the present disclosure relates to the use of the compounds of the present disclosure described herein in the preparation of a medicament for preventing or treating conditions associated with altered β-glucosylceramidase activity, such as lysosomal storage diseases and α-synucleinopathies as described herein, in a patient in need thereof. In another aspect, the compounds of the present disclosure are compounds of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compounds of the present disclosure are compounds of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0243] In another aspect, the present disclosure is directed to a pharmaceutical composition for use in treating or preventing conditions associated with altered β-glucocerebrosidase activity, such as lysosomal storage diseases and α-synucleinopathies described herein, in patients in need thereof, comprising a compound of the present disclosure described herein and at least one pharmaceutically acceptable excipient. In another aspect, the compound of the present disclosure is a compound of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the compound of the present disclosure is a compound of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0244] Pharmaceutical composition

[0245] The present disclosure also relates to a pharmaceutical composition comprising an effective amount of a compound of the present disclosure and at least one pharmaceutically acceptable excipient. In another aspect, the composition comprises an effective amount of a compound of formula (IA) as described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In another aspect, the composition comprises an effective amount of a compound of formula (IB) as described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0246] The compounds of the present disclosure can be used in human medicine by virtue of their activity. As noted above, the compounds of the present disclosure are useful, for example, for treating or preventing lysosomal storage diseases such as Gaucher's disease and α-synucleinopathies such as Parkinson's disease. The compounds of the present disclosure can be administered to any patient suffering from any of the foregoing conditions. The term "patient" as used herein refers to any human who can receive the beneficial effects of the compounds of the present disclosure.

[0247] When administered to a patient, the compounds of the present disclosure can be administered as a component of a composition comprising a pharmaceutically acceptable excipient or carrier.

[0248] The compounds of the present disclosure can be administered in combination with at least one other therapeutic agent. Administration of the compounds of the present disclosure with at least one other therapeutic agent can be sequential or simultaneous. In another aspect, the compounds of the invention and at least one other therapeutic agent are administered in separate dosage forms. In another aspect, the compounds of the invention and at least one other therapeutic agent are administered simultaneously in the same dosage form.

[0249] The term "excipient" refers to a vehicle, diluent or adjuvant administered with the active ingredient. Such pharmaceutical excipients can be sterile liquids such as water and oils, including those of petroleum origin, animal origin, plant origin or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. For example, aqueous solutions of water or physiological saline for injection, as well as aqueous solutions of dextrose and glycerol can be used as vehicles. Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" (by E.W. Martin), 21 st Edition, 2005; or "Handbook of Pharmaceutical Excipients," Rowe C.R.; Paul J.S.; Marian E.Q., sixth Edition, which are incorporated herein by reference.

[0250] Examples of pharmaceutical compositions include either solid compositions (tablets, pills, capsules, granules, etc.) or liquid compositions (solutions, suspensions or emulsions) for oral, topical or parenteral administration.

[0251] In another embodiment, the pharmaceutical composition is in an oral delivery form. Pharmaceutical forms suitable for oral administration can be tablets and capsules, and can contain conventional excipients known in the art such as binders, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for preparing tablets, for example, magnesium stearate; disintegrants, for example, starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose, or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

[0252] Solid oral compositions can be prepared by conventional methods such as blending, filling, and tablet preparation. Repeated blending operations can be used to distribute the active ingredient in all compositions using a large amount of filler. Such operations are conventional in the art. Tablets can be prepared, for example, by dry granulation or wet granulation, and can be coated by well-known methods in normal pharmaceutical practice using enteric coating if necessary.

[0253] The pharmaceutical composition can also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products, in suitable unit dosage forms. Suitable excipients such as fillers, buffering agents or surfactants can be used.

[0254] The specified formulations can be prepared using standard methods, such as those described or referred to in the Spanish and US Pharmacopoeias, and similar reference books.

[0255] Generally, the effective amount of the compounds of the present disclosure administered will depend on the relative effectiveness of the selected compound, the severity of the condition or disorder being treated, and the weight of the patient. The active compounds can be administered once or multiple times a day, for example, once, twice, three times, or four times a day, 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 dosage of the compounds of the present disclosure is about 500 mg / kg body weight / day or less. In another embodiment, the effective dosage of the compounds of the present disclosure is about 100 mg / kg body weight / day or less. In another embodiment, the effective dosage is such that the compounds of the present disclosure are in the range of about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day; in another embodiment, the compounds of the present disclosure are in the range of about 0.02 mg / kg body weight / day to about 50 mg / kg body weight / day, and in another embodiment, the compounds of the present disclosure are in the range of about 0.025 mg / kg body weight / day to about 20 mg / kg body weight / day.

[0256] The compositions of the present disclosure can be prepared by a method comprising the step of mixing a compound of the present disclosure with a pharmaceutically acceptable excipient or carrier. The mixing can be carried out using known methods for mixing a compound with a pharmaceutically acceptable excipient or carrier. In another embodiment, the compounds of the present disclosure are present in the composition in an effective amount.

[0257] The following examples illustrate, but are not limited to, the compounds, compositions, and methods of the present disclosure. In view of the present disclosure, suitable modifications and adaptations of the various conditions and parameters that are commonly encountered in clinical therapy and are apparent to those skilled in the art are within the spirit and scope of the present disclosure.

Examples

[0258] General experimental conditions

[0259] Hereinafter, 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, "CDCl 3 " means deuterated chloroform, "DMSO-d 6 " means deuterated dimethyl sulfoxide, "DCM" means dichloromethane, "MeOH" means methanol, "ACN" means acetonitrile, "THF" means tetrahydrofuran, "DMF" means dimethylformamide, "EtOAc" means ethyl acetate, "NaHCO 3 " means sodium bicarbonate, "DIPE" means diisopropyl ether, "DIPEA" means N,N-diisopropylethylamine, "HATU" means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, "Pd2(dba)3" means tris(dibenzylideneacetone)-dipalladium(0), "Pd(PPh3)4" means palladium-tetrakis(triphenylphosphine), "DavePhos" means 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, "XPhos" means 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, "Zn(CN)2" means zinc(II) cyanide, "Pd2(dba)3" means tris(dibenzylideneacetone)-dipalladium(0), "XantPhos" means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, "SnCl2" means tin(II) chloride, "TBTU" means O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate.

[0260] The IUPAC names of the compounds given in this specification were created using ChemBioDraw Ultra 12.0 or 12.0.2. 11H NMR spectra were recorded on a Bruker (400 MHz).

[0261] HPLC spectra were recorded on Waters 2695, Agilent 1260 Infinity-2 & Waters UPLC-H class.

[0262] LC-MS analysis of the compounds was performed according to one of the following methods:

[0263] Method-A1: 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).

[0264] Method-B1: 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).

[0265] Method - C1: Aquity UPLC BEH C18 (50 mm × 2.1 mm, 1.7 μm); wavelength: 215 nm; flow rate: 0.6 mL / min; run time: 3.0 min; mobile phase A: 0.1% formic acid in water and B: 0.1% formic acid in acetonitrile; time and mobile phase - gradient (time in minutes / %B): 0 / 95, 0.3 / 95, 2.0 / 5, 3.5 / 5, 3.6 / 95, MASS: Agilent 1290 infinity, Mass: 6150 SQD (ESI / APCI).

[0266] Method - D1: XSelect C18 (50 mm × 4.6 mm, 3.5 μm); wavelength: PDA MaxPlot 210.0 - 400 nm; flow rate: 1.6 ml / min; column temperature: 50 °C; run time: 5 min; mobile phase A: H 2 O 0.1% formic acid, B: acetonitrile 0.1% formic acid; gradient of B: 5 - 95% B in 3.5 min; chromatography system: Waters Alliance HT 2795 and PDA 2996; mass spectrometer: 3100 detector single quadrupole (ESI).

[0267] Method - E1: Sunfire C18 (150 mm × 19 mm, 10 μm); wavelength: the wavelength is selected considering the UV maximum absorption of the target; flow rate: 9 - 14 mL / min; column temperature: 30 - 35 °C; run time: 30 min; mobile phase, A: ACN (in some cases, MeOH:ACN (1:1) was used to enhance the separation between the target and impurities); B: ammonium bicarbonate solution (pH 7); gradient: adjusted for each sample to enhance the separation between the target and impurities; chromatography system: Dionex 3000 (PLCP001) equipped with a foxy R1 fraction collector.

[0268] Method - F1: BEH C18 (50 mm × 2.1 mm, 1.7 μm); wavelength: PDA MaxPlot 210.0 - 400 nm; flow rate: 0.50 mL / min; column temperature: 35 °C; run time: 20 min; mobile phase A: 50 mM ammonium formate solution adjusted to pH 4 with formic acid, B: water, C: ACN; gradient: A:B:C 5:80:15 for 0.5 min + from 5:80:15 to 10:85:5 in 4.5 min + 10:85:5 for 4 min; chromatography system: Acquity H class UPLC; mass spectrometer: Acquity QDa.

[0269] Method - A2: Aquity UPLC BEH C18 (50 mm × 2.1 mm, 1.7 μm); wavelength: 215 nm; flow rate: 0.6 mL / min; run time: 4.0 min; mobile phase A: 0.1% formic acid in water and B: 0.1% formic acid in acetonitrile; time and mobile phase - gradient (time in minutes / %A): 0.0 / 95, 0.3 / 95, 2.0 / 5, 3.5 / 5, 3.6 / 95, 4.2 / 95; MASS: Waters Acquity UPLC equipped with SQD (ESI / APCI).

[0270] Method - B2: 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 + from 10:5:85 to 95:5:0 in 4 min + 95:5:0 for 4.5 min; chromatography system: Waters Alliance HT 2795 and PDA 2996; mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0271] Method - C2: SunFire C18 (100mm×2.1mm, 3.5μm); Wavelength: PDA MaxPlot 210.0~400nm; Flow rate: 0.30mL / min; Column temperature: 35°C; Run time: 30 minutes; Mobile phase A: ACN / MeOH (50:50), B: 100mM ammonium acetate solution, C: water; Gradient: A:B:C 10:5:85 for 5 minutes + from 10:5:85 to 95:5:0 in 15 minutes + 95:5:0 for 10 minutes; Chromatography system: Waters Alliance HT 2795 and PDA 2996; Mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0272] General procedure A [Chemical formula] Step 1

[0273] To a stirred solution of 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid (1.0eq), appropriate amine (1.5eq) (e.g., 1-phenylpiperazine) and HATU (0.7eq) in DMF (15mL / mmol), DIPEA (1.3eq) was added. The resulting mixture was stirred at room temperature for 14 - 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (×3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by flash column chromatography (15% - 30% EtOAc / hexane) to give the desired amide product (e.g., ((2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone). Step 2

[0274] A stirred solution of the appropriate aryl chloride (e.g., (2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone) (1.0 eq) in n-butanol (7.0 mL / mmol) was added with the appropriate aniline (e.g., 2-aminophenol) (1.1 eq) and sulfuric acid (catalyst, 1 drop) at room temperature. The reaction mixture was stirred at 100 - 115 °C for 18 h. Then, the reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (15% - 30% EtOAc / hexane) to obtain the desired amine product (e.g., (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone). Step 3

[0275] A stirred solution of the appropriate protected amine (e.g., (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone) (1.0 eq) in TFA (15.0 mL / mmol) was stirred at 60 °C or room temperature for 2 - 16 h. Then, the reaction mixture was evaporated completely to give a residue, which was neutralized with saturated NaHCO 3 . The aqueous mixture was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (0% - 10% MeOH / DCM) and / or by semi-preparative HPLC (method - D) to obtain the desired amine product (e.g., (6-amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone).

[0276] General procedure A1 for the synthesis of Example 1

Chemical Structure

[0277] Step 11: Preparation of Intermediate 1 Methyl 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate

Chemical formula

[0278] To a stirred mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (10 g, 48.3 mmol, 1.0 eq) and tert-octylamine (11.6 mL, 72.46 mmol, 1.5 eq) in THF (10 mL) was added DIPEA (12.6 mL, 72.46 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 16 h. Complete conversion was shown by TLC analysis (10% EtOAc / Hex). The mixture was diluted with water, extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by flash column chromatography (EtOAc / heptane, 50 - 100) to give methyl 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate as a white solid. Yield: (10.4 g, 72%). ES-MS [M + H] + : 300.0, Rt = 6.76 min (Method - A1).

[0279] Step 21: Preparation of Intermediate 2 2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid

Chemical formula

[0280] THF:H 2To a stirred mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (2.0 g, 6.6 mmol, 1.0 eq.) in O(1:1, 50 mL), lithium hydroxide (0.86 g, 35.9 mmol, 5.5 eq) was added. The resulting mixture was stirred at room temperature for 2 h. Complete conversion was indicated by TLC analysis (10% EtOAc / Hex). The mixture was acidified by adding concentrated HCl, extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid as a white solid, which was used without further purification. Yield: (1.02 g, 54% yield). ES-MS [M+H] + : 286.0, Rt = 5.59 min (Method - A1).

[0281] Step 31: Preparation of Intermediate 3 (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone [Chemical Structure]

[0282] A stirred solution of 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid (0.40 g, 1.40 mmol, 1.0 eq), 1-phenylpiperazine (0.32 mL, 2.09 mmol, 1.5 eq) and HATU (0.40 g, 1.00 mmol, 0.7 eq) in DMF (20 mL) was treated with DIPEA (0.32 mL, 1.84 mmol, 1.3 eq). The resulting mixture was stirred at room temperature for 14 h. Complete conversion was indicated by TLC analysis (50% EtOAc / Hex). The reaction mixture was quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude was purified by flash column chromatography (EtOAc / heptane, 50 - 100) to afford (2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone as a brown solid. Yield: (0.206 g, 35% yield). ES-MS [M+H] + : 430.0, Rt = 7.146 min (Method - A1).

[0283] Step 41: Intermediate 4 (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)

Chemical Structure

[0284] A stirred solution of (2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone (0.206 g, 0.48 mmol, 1.0 eq) in 1-butanol (3 mL) was added with 2-aminophenol (0.060 g, 0.55 mmol, 1.1 eq) and sulfuric acid (catalyst, 1 drop) at room temperature. The reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by flash column chromatography (EtOAc / heptane, 50 - 100) to give (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone as a white solid. Yield: (0.155 g, 65%). ES-MS [M+H] + : 503.1, Rt = 7.052 min (Method-A1).

[0285] (Example 1) (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

Chem.

[0286] A stirred solution of (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone (0.155 g, 0.30 mmol, 1.0 eq) in TFA (2.0 mL) was stirred at 60 °C for 2 h. Then, the reaction mixture was evaporated completely to give a residue, which was basified with saturated NaHCO 3 The aqueous mixture was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by flash column chromatography (10% MeOH / CH2 Cl 2 ) was purified to obtain the title compound (6-amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone as a white solid. Yield: (0.069 g, 58%). ES-MS [M-H] - : 389.1, Rt = 16.93 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.14 (brs, 1H), 8.09 - 7.78 (m, 2H), 7.47 - 7.11 (m, 2H), 7.08 - 6.92 (m, 4H), 6.82 (td, J = 3.8, 1.2 Hz, 3H), 6.76 - 6.62 (m, 1H), 6.00 (s, 1H), 3.72 (t, J = 5.3 Hz, 2H), 3.59 (t, J = 5.1 Hz, 2H), 3.19 (t, J = 5.3 Hz, 2H), 3.11 (t, J = 5.2 Hz, 2H).

[0287] Intermediate 5 (2-((3-methoxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

Chemical Structure

[0288] (Example 2) (6-Amino-2-((3-methoxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone [Chemical formula]

[0289] The title compound was synthesized according to the procedure described for the preparation of Example 1 using (2-((3-methoxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone and isolated as a white powder. Yield: (0.039 g, 43%). ES-MS [M+H] + : 405.0, Rt = 17.96 min (Method - B1). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (s, 1H), 7.53 (t, J = 2.3 Hz, 1H), 7.27 (ddd, J = 8.2, 2.0, 0.9 Hz, 1H), 7.23 (dd, J = 8.8, 7.2 Hz, 2H), 7.10 (t, J = 8.1 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.87 - 6.78 (m, 3H), 6.46 (ddd, J = 8.2, 2.5, 0.9 Hz, 1H), 5.99 (s, 1H), 3.72 (q, J = 3.8 Hz, 2H), 3.69 (s, 3H), 3.59 (t, J = 5.1 Hz, 2H), 3.19 (t, J = 5.3 Hz, 2H), 3.14 (d, J = 5.1 Hz, 2H).

[0290] Intermediate 6 (4-Phenylpiperazin-1-yl)(2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)methanone [Chemical formula]

[0291] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using p-toluidine and isolated as a light brown powder. Yield: (0.094 g, 67%). ES-MS [M+H] + : 501.2, Rt = 7.458 min (Method-A1).

[0292] (Example 3) (6-Amino-2-(p-tolylamino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

Chemical Structure

[0293] The title compound was synthesized according to the procedure described for the preparation of Example 1 using (4-phenylpiperazin-1-yl)(2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)methanone and isolated as a white powder. Yield: (0.034 g, 48%). ES-MS [M+H] + : 389.0, Rt = 18.640 min (Method-B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (s, 1H), 7.70 - 7.58 (m, 2H), 7.23 (dd, J = 8.6, 7.2 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 7.01 - 6.91 (m, 2H), 6.88 - 6.78 (m, 3H), 5.96 (s, 1H), 3.75 - 3.68 (m, 2H), 3.59 (t, J = 5.1 Hz, 2H), 3.20 (d, J = 5.4 Hz, 2H), 3.16 - 3.08 (m, 2H), 2.22 (s, 3H).

[0294] Intermediate 7 N-Benzyl-2-chloro-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chem.

[0295] The title compound was synthesized according to the procedure described for the preparation of Intermediate 3 using N-methyl-1-phenylmethanamine and isolated as a pale brown powder. Yield: (0.310 g, 46%). ES-MS [M+H] + : 389.0, Rt = 7.09 min (Method - A1).

[0296] Intermediate 8 N-Benzyl-2-((2-hydroxyphenyl)amino)-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chem.

[0297] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using 2-aminophenol and isolated as a pale brown powder. Yield: (0.220 g, 60%). ES-MS [M+H] + : 462.1, Rt = 6.95 min (Method - A1).

[0298] (Example 4) 6-Amino-N-benzyl-2-((2-hydroxyphenyl)amino)-N-methylpyrimidine-4-carboxamide

Chem.

[0299] The title compound was synthesized according to the procedure described for the preparation of Example 1 using N-benzyl-2-((2-hydroxyphenyl)amino)-N-methyl-6-((2,4,4-trimethyl-pentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a white powder. Yield: (0.135 g, 81%). ES-MS [M-H] - : 350.1, Rt = 16.50 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.12 (d, J = 39.7 Hz, 1H), 8.43 - 7.70 (m, 2H), 7.48 - 7.35 (m, 1H), 7.35 - 7.23 (m, 4H), 6.98 (d, J = 8.2 Hz, 2H), 6.87 - 6.80 (m, 2H), 6.79 - 6.68 (m, 1H), 5.99 (d, J = 6.9 Hz, 1H), 4.60 (d, J = 29.1 Hz, 2H), 2.84 (d, J = 28.8 Hz, 3H).

[0300] Intermediate 9 2-chloro-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chemical Structure

[0301] The title compound was synthesized according to the procedure described for the preparation of Intermediate 3 using N-methylaniline and isolated as a light brown powder. Yield: (0.196 g, 60%). ES-MS [M+H] + : 375.0, Rt = 6.823 min (Method - A1).

[0302] Intermediate 10 2-((2-Hydroxyphenyl)amino)-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chemical formula

[0303] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using 2-chloro-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)-pyrimidine-4-carboxamide and 2-aminophenol, and isolated as a pale brown powder. Yield: (0.085 g, 36%). ES-MS [M+H] + : 448.1, Rt = 6.824 min (Method-A1).

[0304] (Example 5) 6-Amino-2-((2-hydroxyphenyl)amino)-N-methyl-N-phenylpyrimidine-4-carboxamide

Chemical formula

[0305] The title compound was synthesized according to the procedure described for the preparation of Example 1 using 2-((2-hydroxyphenyl)amino)-N-methyl-N-phenyl-6-((2,4,4-trimethyl-pentan-2-yl)amino)pyrimidine-4-carboxamide, and isolated as a white powder. Yield: (0.046 g, 73%). ES-MS [M-H] - : 336.0, Rt = 15.46 min (Method-B1). 1 H NMR (400 MHz, DMSO-d 6) δ 10.10 (s, 1H), 7.63 (brs, 2H), 7.44 - 7.00 (m, 5H), 6.85 - 6.76 (m, 4H), 6.76 - 6.66 (m, 1H), 5.91 (s, 1H), 3.33 (d, J = 6.4 Hz, 3H).

[0306] Intermediate 11 N-Methyl-N-phenyl-2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chemical Structure

[0307] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using 2-chloro-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)-pyrimidine-4-carboxamide and p-toluidine, and isolated as a pale brown powder. Yield: (0.106 g, 71%). ES-MS [M+H] + : 446.1, Rt = 7.189 min (Method - A1).

[0308] (Example 6) 6-Amino-N-methyl-N-phenyl-2-(p-tolylamino)pyrimidine-4-carboxamide

Chemical Structure

[0309] The title compound was synthesized according to the procedure described for the preparation of Example 1 using N-methyl-N-phenyl-2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)-amino)pyrimidine-4-carboxamide, and isolated as a white powder. Yield: (0.033 g, 50%). ES-MS [M+H] +: 334.1, Rt = 17.108 min (Method - B1). 1 H NMR (400 MHz, DMSO - d 6 ) δ 8.73 (bs, 1H), 7.42 - 7.05 (m, 7H), 6.96 (d, J = 8.2 Hz, 2H), 6.68 - 6.49 (m, 2H), 5.90 (s, 1H), 3.34 (d, J = 0.4 Hz, 3H), 2.21 (s, 3H).

[0310] Intermediate 12 2 - ((3 - Methoxyphenyl)amino)-N - methyl - N - phenyl - 6 - ((2,4,4 - trimethylpentan - 2 - yl)amino)pyrimidine - 4 - carboxamide

Chemical Structure

[0311] This compound was synthesized according to the procedure described for the preparation of Intermediate 4 using 2 - chloro - N - methyl - N - phenyl - 6 - ((2,4,4 - trimethylpentan - 2 - yl)amino)pyrimidine - 4 - carboxamide and m - anisidine, and isolated as a light brown powder. Yield: (0.120 g, 68%). ES - MS [M + H] + : 462.1, Rt = 6.975 min (Method - A1).

[0312] (Example 7) 6 - Amino - 2 - ((3 - methoxyphenyl)amino)-N - methyl - N - phenylpyrimidine - 4 - carboxamide

Chemical Structure

[0313] The title compound was synthesized according to the procedure described for the preparation of Example 1 using 2-((3-methoxyphenyl)amino)-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a white powder. Yield: (0.053 g, 59%). ES-MS [M+H] + : 350.0, Rt = 16.374 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.87 (s, 1H), 7.41 - 7.14 (m, 6H), 7.13 - 6.99 (m, 2H), 6.66 (brs, 2H), 6.47 - 6.40 (m, 1H), 5.87 (s, 1H), 3.71 (s, 3H), 3.34 (s, 3H).

[0314] Intermediate 13 (2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

Chemical Structure

[0315] The title compound was synthesized according to the procedure described for the preparation of Intermediate 3 using isoindoline hydrochloride and isolated as a white powder. Yield: (0.029 g, 71% yield). ES-MS [M+H] + : 387.0, Rt = 7.657 min (Method - A1).

[0316] Intermediate 14 (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

Chemical Structure

[0317] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using (2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)-(isoindolin-2-yl)methanone and isolated as a white powder. Yield: (0.240 g, 70%). ES-MS [M+H] + : 460.1, Rt = 7.398 min (Method-A1).

[0318] (Example 8) (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone [Chemical formula]

[0319] The title compound was synthesized according to the procedure described for the preparation of Example 1 using (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)-pyrimidin-4-yl)(isoindolin-2-yl)methanone and isolated as a pink powder. Yield: (0.029 g, 16%). ES-MS [M+H] + : 348.0, Rt = 16.891 min (Method-B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 8.06 - 7.76 (m, 2H), 7.49 - 7.36 (m, 1H), 7.36 - 7.21 (m, 3H), 6.99 (brs, 2H), 6.94 - 6.82 (m, 2H), 6.81 - 6.67 (m, 1H), 6.21 (s, 1H), 4.98 (s, 2H), 4.82 (s, 2H).

[0320] Intermediate 15 2-Chloro-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chem.

[0321] The title compound was synthesized according to the procedure described for the preparation of Intermediate 3 using N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine and isolated as a yellow powder. Yield: (0.326 g, 55%). ES-MS [M-H] - : 429.0, Rt = 7.592 min (Method-A1).

[0322] Intermediate 16 2-((2-Hydroxyphenyl)amino)-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chem.

[0323] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using 2-chloro-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a yellow powder. Yield: (0.334 g, 87%). ES-MS [M-H] - : 500.1, Rt = 7.452 min (Method-A1).

[0324] (Example 9) 6-Amino-2-((2-hydroxyphenyl)amino)-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine-4-carboxamide [Chemical formula]

[0325] The title compound was synthesized according to the procedure described for the preparation of Example 1 using 2-((2-hydroxyphenyl)amino)-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a yellow powder. Yield: (0.048 g, 19%). ES-MS [M+H] + : 388.0, Rt = 18.006 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.17 (brs, 1H), 8.05 - 7.83 (m, 3H), 7.12 (s, 1H), 7.08 - 6.97 (m, 2H), 6.96 - 6.90 (m, 2H), 6.89 - 6.80 (m, 2H), 6.80 - 6.67 (m, 1H), 5.96 - 5.91 (m, 1H), 4.71 - 4.55 (m, 0.3H), 3.97 - 3.88 (m, 0.7H), 3.21 - 2.96 (m, 1H), 2.96 - 2.85 (m, 3H), 2.85 - 2.71 (m, 2H), 2.71 - 2.57 (m, 1H), 2.02 - 1.85 (m, 2H).

[0326] Intermediate 17 2-chloro-N-(2,3-dihydro-1H-inden-2-yl)-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide [Chemical formula]

[0327] The title compound was synthesized according to the procedure described for the preparation of Intermediate 3 using N-methyl-2,3-dihydro-1H-inden-2-amine and isolated as a yellow powder. Yield: (0.531 g, 98%). ES-MS [M+H] + : 415.0, Rt = 7.590 min (Method - A1).

[0328] Intermediate 18 N-(2,3-Dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chemical formula

[0329] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using 2-chloro-N-(2,3-dihydro-1H-inden-2-yl)-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a yellow powder. Yield: (0.475 g, 76%). ES-MS [M+H] + : 488.1, Rt = 7.464 min (Method - A1).

[0330] (Example 10) 6-Amino-N-(2,3-dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)-N-methylpyrimidine-4-carboxamide

Chemical formula

[0331] The title compound was synthesized according to the procedure described for the preparation of Example 1 using N-(2,3-dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a yellow powder. Yield: (0.239 g, 64%). ES-MS [M+H] + : 376.0, Rt = 17.717 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (brs, 1H), 7.97 - 7.80 (m, 2H), 7.26 (dd, J = 5.4, 3.4 Hz, 1H), 7.21 - 7.07 (m, 3H), 7.02 - 6.93 (m, 2H), 6.87 - 6.80 (m, 2H), 6.77 (ddd, J = 8.7, 6.3, 2.4 Hz, 1H), 5.94 (d, J = 14.9 Hz, 1H), 5.41 - 5.28 (m, 1H), 4.70 (p, J = 7.7 Hz, 1H), 3.17 (dd, J = 16.3, 8.4 Hz, 1H), 3.05 (h, J = 7.5 Hz, 3H), 2.77 (d, J = 16.1 Hz, 3H).

[0332] Intermediate 19 2-Chloro-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chemical Structure

[0333] The title compound was synthesized according to the procedure described for the preparation of Intermediate 3 using aniline and isolated as a yellow powder. Yield: (0.307 g, 81%). ES-MS [M+H] + : 361.0, Rt = 7.526 min (Method - A1).

[0334] Intermediate 20 2 - ((2 - hydroxyphenyl)amino)-N - phenyl - 6 - ((2,4,4 - trimethylpentan - 2 - yl)amino)pyrimidine - 4 - carboxamide

Chemical Structure

[0335] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using 2 - chloro - N - phenyl - 6 - ((2,4,4 - trimethylpentan - 2 - yl)amino)pyrimidine - 4 - carboxamide and isolated as a yellow powder. Yield: (0.220 g, 60%). ES - MS [M + H] + : 434.1, Rt = 7.571 min (Method - A1).

[0336] (Example 11) 6 - amino - 2 - ((2 - hydroxyphenyl)amino)-N - phenylpyrimidine - 4 - carboxamide

Chemical Structure

[0337] The title compound was synthesized according to the procedure described for the preparation of Example 1 using 2 - ((2 - hydroxyphenyl)amino)-N - phenyl - 6 - ((2,4,4 - trimethylpentan - 2 - yl)amino)-pyrimidine - 4 - carboxamide and isolated as a yellow powder. Yield: (0.028 g, 17%). ES - MS [M + H] + : 322.0, Rt = 17.818 min (Method - B1). 1 H NMR (400 MHz, DMSO - d 6) δ 10.26 (s, 1H), 9.98 (s, 1H), 8.24 (dd, J = 7.5, 2.0 Hz, 1H), 7.92 (s, 1H), 7.81 (dd, J = 8.7, 1.2 Hz, 2H), 7.38 (dd, J = 8.5, 7.4 Hz, 2H), 7.24 - 7.05 (m, 3H), 6.97 - 6.74 (m, 3H), 6.61 (s, 1H).

[0338] Intermediate 21 2-Chloro-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chemical Structure

[0339] The title compound was synthesized according to the procedure described for the preparation of Intermediate 3 using 1,2,3,4-tetrahydronaphthalen-2-amine and isolated as a yellow powder. Yield: (0.111 g, 15%). ES-MS [M+H] + : 415.0, Rt = 8.074 min (Method - A1).

[0340] Intermediate 22 2-((2-Hydroxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chemical Structure

[0341] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using 2-chloro-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a yellow powder. Yield: (0.038 g, 29%). ES-MS [M+H] + : 488.1, Rt = 7.614 min (Method - A1).

[0342] (Example 12) 6 - Amino - 2 - ((2 - hydroxyphenyl)amino)-N-(1,2,3,4 - tetrahydronaphthalen - 2 - yl)pyrimidine - 4 - carboxamide [Chemical formula]

[0343] The title compound was synthesized according to the procedure described for the preparation of Example 1 using 2 - ((2 - hydroxyphenyl)amino)-N-(1,2,3,4 - tetrahydronaphthalen - 2 - yl)-6 - ((2,4,4 - trimethylpentan - 2 - yl)amino)pyrimidine - 4 - carboxamide and isolated as a brown powder. Yield: (0.012 g, 44%). ES-MS [M - H] - : 374.0, Rt = 18.723 min (Method - B1). 1 H NMR (400 MHz, DMSO - d 6 ) δ 9.95 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.09 (dd, J = 8.0, 1.5 Hz, 1H), 7.78 (s, 1H), 7.25 - 6.98 (m, 6H), 6.93 - 6.77 (m, 2H), 6.71 (ddd, J = 8.8, 6.9, 2.0 Hz, 1H), 6.55 (s, 1H), 4.40 - 3.92 (m, 1H), 3.01 (dd, J = 16.2, 5.2 Hz, 1H), 2.90 - 2.82 (m, 3H), 2.17 - 1.95 (m, 1H), 1.93 - 1.72 (m, 1H).

[0344] Intermediate 23 2-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chem.

[0345] The title compound was synthesized according to the procedure described for the preparation of Intermediate 3 using 2,3-dihydro-1H-inden-2-amine and isolated as a brown solid. Yield: (0.169 g, 40%). ES-MS [M+H] + : 401.0, Rt = 7.634 min (Method-A1).

[0346] Intermediate 24 N-(2,3-Dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chem.

[0347] The title compound was synthesized according to the procedure described for the preparation of Intermediate 4 using 2-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a yellow solid. Yield: (0.100 g, 50%). ES-MS [M+H] + : 474.1, Rt = 7.296 min (Method-A1).

[0348] (Example 13) 6-Amino-N-(2,3-dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)pyrimidine-4-carboxamide

Chem.

[0349] The title compound was synthesized according to the procedure described for the preparation of Example 1, N-(2,3-dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide, and isolated as an orange powder. Yield: (0.021 g, 33%). ES-MS [M+H] + : 362.0, Rt = 18.309 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.08 (dd, J = 8.0, 1.5 Hz, 1H), 7.79 (s, 1H), 7.25 (dd, J = 5.4, 3.3 Hz, 2H), 7.19 - 7.13 (m, 2H), 7.09 (brs, 2H), 6.90 - 6.76 (m, 2H), 6.70 (ddd, J = 8.0, 6.9, 2.1 Hz, 1H), 6.53 (s, 1H), 4.67 (qt, J = 7.7, 6.5 Hz, 1H), 3.22 (dd, J = 15.8, 7.5 Hz, 2H), 2.96 (dd, J = 15.8, 6.4 Hz, 2H).

[0350] Intermediate 25 (2-(((1S,2S)-2-Hydroxycyclohexyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

Chemical Structure

[0351] A stirred solution of (2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone (0.148 g, 0.345 mmol, 1.0 eq) in DMF (1 mL) was added to (1S,2S)-2-aminocyclohexan-1-ol (0.119 g, 1.03 mmol, 3.0 eq) and K 2 CO 3 (96 mg, 0.69 mmol, 2.0 eq). The reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 2-(((1S,2S)-2-hydroxycyclohexyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone as a brown oil, which was used without further purification. Yield: (0.180 g, crude). ES-MS [M+H] + : 509.2, Rt = 7.112 min (Method - A1).

[0352] (Example 14) (6-Amino-2-(((1S,2S)-2-hydroxycyclohexyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

Chem.

[0353] The title compound was synthesized according to the procedure described for the preparation of Example 1 using 2-(((1S,2S)-2-hydroxycyclohexyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)-pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone and isolated as a pale brown powder. Yield: (0.007 g, 6%). ES-MS [M+H] + : 397.0, Rt = 16.59 min (Method - B1). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.23 (dd, J = 8.7, 7.2 Hz, 2H), 6.98 - 6.92 (m, 2H), 6.81 (t, J = 7.3 Hz, 2H), 6.52 (brs, 2H), 6.26 (brs, 1H), 5.77 (s, 1H), 4.65 (s, 1H), 4.08 - 3.45 (m, 6H), 3.22 - 2.90 (m, 4H), 2.06 - 1.78 (m, 2H), 1.65 - 1.54 (s, 2H), 1.27 - 1.09 (m, 4H).

[0354] Intermediate 26 N-Benzyl-2-(((1S,2S)-2-hydroxycyclohexyl)amino)-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chem.

[0355] The title compound was synthesized according to the procedure described for the preparation of Intermediate 24 using N-benzyl-2-chloro-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a white powder. Yield: (0.10 g, 31%). ES-MS [M+H] + : 468.1, Rt = 7.046 min (Method - A1).

[0356] (Example 15) 6-Amino-N-benzyl-2-(((1S,2S)-2-hydroxycyclohexyl)amino)-N-methylpyrimidine-4-carboxamide

Chem.

[0357] The title compound was synthesized according to the procedure described for the preparation of Example 1 using N-benzyl-2-(((1S,2S)-2-hydroxycyclohexyl)amino)-N-methyl-6-((2,4,4-trimethyl-pentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a white powder. Yield: (0.013 g, 5%). ES-MS [M+H] + : 356.1, Rt = 16.109 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.69 - 7.11 (m, 5H), 6.67 - 6.44 (m, 2H), 6.39 - 6.07 (m, 1H), 5.92 - 5.65 (m, 1H), 4.59 (s, 2H), 3.61 - 3.42 (m, 1H), 2.81 (d, J = 41.4 Hz, 3H), 2.18 - 1.72 (m, 2H), 1.68 - 1.36 (m, 2H), 1.34 - 0.92 (m, 6H).

[0358] General Procedure B

Chemical Structure

[0359] To a mixture of the appropriate amine (e.g., 3-bromoaniline) (1.0 eq) and dicyandiamide (1.0 eq), 3M HCl (0.33 mL / mmol) was added at room temperature. The reaction mixture was heated to 90 °C for 18 h. After the reaction was complete, the reaction mixture was cooled to room temperature, evaporated under reduced pressure, and co-distilled twice with toluene. The crude product was washed with diethyl ether or triturated with EtOAc and dried to obtain the desired biguanide product (e.g., 3-bromophenylbiguanide hydrochloride). Step 2

[0360] To a stirred solution of the appropriate biguanide compound (e.g., 3-bromophenylbiguanide hydrochloride) (1.0 eq) and diethyl oxalate (3.0 eq) in methanol (5.12 mL / mmol), 25% sodium methoxide in methanol (1.0 - 5 eq) was added. The resulting mixture was stirred under reflux for 16 h. The reaction mixture was then cooled to room temperature and concentrated to dryness. The resulting solid was poured into water, filtered off to give a white solid, which was treated with LiOH (5 eq) in THF:H 2 O (1:1, 12 mL / mmol) and stirred at room temperature for 3 h. The mixture was then acidified with concentrated HCl and the resulting suspension was filtered to give the desired carboxylic acid derivative (e.g., 4-amino-6-((3-bromophenyl)amino)-1,3,5-triazine-2-carboxylic acid). Step 3

[0361] Follow General Procedure A, Step 1.

[0362] General Procedure B1-1 for the synthesis of Example 16

Chemical Structure

[0363] Step 11: Preparation of Intermediate 27 3-Bromophenylbiguanide hydrochloride

Chemical Structure

[0364] To a mixture of 3-bromoaniline (2.0 g, 11.63 mmol, 1.0 eq) and dicyandiamide (0.978 g, 11.63 mmol, 1.0 eq), 3M HCl (3.84 mL) was added at room temperature. The reaction mixture was heated to 90 °C for 18 h. After the reaction was complete, the reaction mixture was cooled to room temperature and evaporated completely under reduced pressure and co-distilled twice with toluene. The crude product was washed with diethyl ether and dried to give the desired product as a white solid. Yield: (1.79 g, 53%). ES-MS [M+H] + : 255.9, Rt = 7.149 minutes (Method - A1).

[0365] Step 21: Preparation of Intermediate 28 4 - Amino - 6 - ((3 - bromophenyl)amino)-1,3,5 - triazine - 2 - carboxylic acid [Chemical Structure]

[0366] To a stirred solution of 3 - bromophenylbiguanide hydrochloride (0.30 g, 1.17 mmol, 1.0 eq) and diethyl oxalate (0.48 mL, 3.51 mmol, 3.0 eq) in MeOH (6 mL), 25% NaOMe in MeOH (0.32 mL, 1.17 mmol, 1.0 eq) was added. The resulting mixture was stirred under reflux for 16 hours. Then, the reaction mixture was cooled to room temperature and concentrated to dryness. The obtained solid was poured into water and filtered off to give a white solid, which was treated with LiOH (0.127 g, 5.3 mmol, 5 eq) in THF:H 2 O (1:1, 14 mL) and stirred at room temperature for 3 hours. Then, the mixture was acidified with concentrated HCl and the resulting suspension was filtered to give 4 - amino - 6 - ((3 - bromophenyl)amino)-1,3,5 - triazine - 2 - carboxylic acid as a white solid. Yield: (0.298 g, 82%, over 2 steps). ES-MS [M+H] + : 311.9, Rt = 0.648 minutes (Method - A1).

[0367] Step 31: Preparation of Example 16 (4 - Amino - 6 - ((3 - bromophenyl)amino)-1,3,5 - triazin - 2 - yl)(4 - phenylpiperazin - 1 - yl)methanone [Chemical Structure]

[0368] The title compound was synthesized according to the procedure described for Intermediate 3 using 4-amino-6-((3-bromophenyl)amino)-1,3,5-triazine-2-carboxylic acid and isolated as a white powder. Yield: (0.040 g, 18%). ES-MS [M+H] + : 455.9, Rt = 18.585 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (brs, 1H), 8.02 (t, J = 2.0 Hz, 1H), 7.80 - 7.72 (m, 1H), 7.53 - 7.45 (m, 2H), 7.31 - 7.20 (m, 3H), 7.20 - 7.12 (m, 1H), 6.96 (d, J = 7.8 Hz, 2H), 6.82 (t, J = 7.2 Hz, 1H), 3.80 - 3.65 (m, 2H), 3.47 (t, J = 5.0 Hz, 2H), 3.18 (t, J = 5.3 Hz, 2H), 3.13 (t, J = 5.1 Hz, 2H).

[0369] (Example 17) 4-Amino-N-benzyl-6-((3-bromophenyl)amino)-N-methyl-1,3,5-triazine-2-carboxamide

Chemical Structure

[0370] This compound was synthesized according to the procedure described for Intermediate 3 using 4-amino-6-((3-bromophenyl)amino)-1,3,5-triazine-2-carboxylic acid and N-methyl-1-phenylmethanamine and isolated as a white powder. Yield: (0.068 g, 34% yield). ES-MS [M+H] + : 414.9, Rt = 18.216 min (Method - B1). 1 H NMR (400 MHz, DMSO-d6 ) δ 9.99 - 9.85 (m, 1H), 8.00 (dt, J = 9.3, 2.0 Hz, 1H), 7.82 - 7.70 (m, 1H), 7.55 - 7.40 (m, 2H), 7.42 - 7.34 (m, 3H), 7.31 (dq, J = 7.6, 1.5 Hz, 2H), 7.24 (td, J = 8.0, 0.9 Hz, 1H), 7.17 (ddt, J = 7.9, 2.0, 1.0 Hz, 1H), 4.52 (d, J = 68.5 Hz, 2H), 2.80 (d, J = 24.2 Hz, 3H).

[0371] (Example 18) 4-Amino-6-((3-bromophenyl)amino)-N-methyl-N-phenyl-1,3,5-triazine-2-carboxamide [Chemical formula]

[0372] The title compound was synthesized according to the procedure described for Intermediate 3 using 4-amino-6-((3-bromophenyl)amino)-1,3,5-triazine-2-carboxylic acid and N-methylaniline and isolated as a white powder. Yield: (0.029 g, 29%). ES-MS [M+H] + : 398.9, Rt = 17.847 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.41 - 6.89 (m, 12H), 3.32 (s, 3H).

[0373] (Example 19) 4-Amino-6-((3-bromophenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3,5-triazine-2-carboxamide [Chemical formula]

[0374] The title compound was synthesized according to the procedure described for Intermediate 3 using 4-amino-6-((3-bromophenyl)amino)-1,3,5-triazine-2-carboxylic acid and 1,2,3,4-tetrahydronaphthalen-2-amine, and isolated as a white powder. Yield: (0.008 g, 3%). ES-MS [M+H] + : 438.9, Rt = 19.904 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.04 (brs, 1H), 8.31 (d, J = 7.9 Hz, 1H), 8.06 (t, J = 2.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.54 - 7.43 (m, 2H), 7.41 - 7.13 (m, 2H), 7.12 - 7.05 (m, 4H), 4.30 - 3.99 (m, 1H), 3.03 (dd, J = 16.5, 4.6 Hz, 1H), 2.92 - 2.71 (m, 3H), 2.08 - 1.93 (m, 1H), 1.78 (ddt, J = 12.4, 10.3, 8.0 Hz, 1H).

[0375] General procedure B1-2 for the synthesis of Example 20

Chemical formula

[0376] Step 11: Preparation of Intermediate 29 2-Methoxyphenylbiguanide hydrochloride

Chemical formula

[0377] To a mixture of o-anisidine (1.0 g, 8.13 mmol, 1.0 eq) and dicyandiamide (0.700 g, 8.29 mmol, 0.7 eq), 3M HCl (2.84 mL) was added at room temperature. The reaction mixture was heated to 90 °C for 16 h. After the reaction was completed, the reaction mixture was cooled to room temperature and evaporated completely under reduced pressure, and co-distilled twice with toluene. The crude product was washed with diethyl ether and dried to obtain the desired product as a pink solid. Yield: (1.96 g, 99%). ES-MS [M+H] + : 208.1, Rt = 7.037 min (Method-A1).

[0378] Step 21: Preparation of Intermediate 30 4-Amino-6-((2-methoxyphenyl)amino)-1,3,5-triazine-2-carboxylic acid

Chemical formula

[0379] To a stirred solution of 2-methoxyphenylbiguanide hydrochloride (0.83 g, 3.4 mmol, 1.0 eq) and diethyl oxalate (1.46 mL, 10.8 mmol, 3.0 eq) in MeOH (18 mL), 25% NaOMe in MeOH (0.96 mL, 16.8 mmol, 5.0 eq) was added. The resulting mixture was stirred under reflux for 16 h. Then, the reaction mixture was cooled to room temperature and concentrated to dryness. The obtained solid was poured into water and removed by filtration to obtain a white solid, which was treated with LiOH (0.290 g, 12.1 mmol, 5.0 eq) in THF:H 2 O (1:1, 30 mL) and stirred at room temperature for 3 h. Then, the mixture was acidified with concentrated HCl, and the resulting suspension was filtered to obtain 4-amino-6-((2-methoxyphenyl)amino)-1,3,5-triazine-2-carboxylic acid as a yellow solid. Yield: (0.517 g, 58%, over 2 steps). ES-MS [M+H] + : 261.0, Rt = 0.567 min (Method-A1).

[0380] Step 31: Preparation of Example 20 4-Amino-6-((2-methoxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3,5-triazine-2-carboxamide [Chemical formula]

[0381] The title compound was synthesized according to the procedure described for Intermediate 3 using 4-amino-6-((2-methoxyphenyl)amino)-1,3,5-triazine-2-carboxylic acid and 1,2,3,4-tetrahydronaphthalen-2-amine, and isolated as a white powder. Yield: (0.028 g, 14%). ES-MS [M+H] + : 391.0, Rt = 19.011 min (Method - B1). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.52 - 8.35 (m, 1H), 8.33 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.346 - 7.29 (m, 2H), 7.23 - 6.99 (m, 6H), 6.92 (td, J = 7.5, 1.7 Hz, 1H), 4.22 - 4.02 (m, 1H), 3.83 (s, 3H), 3.00 (dd, J = 16.2, 5.3 Hz, 1H), 2.92 - 2.68 (m, 3H), 1.99 (td, J = 8.5, 4.6 Hz, 1H), 1.87 - 1.64 (m, 1H).

[0382] General Procedure C [Chemical formula] Step 1

[0383] To a stirred solution of the appropriate aryl chloride (Intermediate 1) (e.g., methyl 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate) (1.0 eq) in 1-butanol at room temperature (6 mL / mmol), add the appropriate amine (e.g., p-toluidine) (1.2 eq) and catalytic sulfuric acid (2 drops), and heat to 100 °C for 16 h. After the reaction is complete, cool the reaction mixture to room temperature and basify it slowly with saturated NaHCO 3 and extract the organic product into EtOAc. Dry the organic layer over anhydrous sodium sulfate and evaporate the solvent under reduced pressure to obtain the crude product. Purify the crude product by column chromatography (silica gel 230 - 400 mesh) using 1% to 3% methanol in DCM as the eluent to obtain the desired amine compound (e.g., methyl 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate). Step 2

[0384] Add sodium hydroxide (2 eq) to a stirred solution of the appropriate carboxylic acid ester (e.g., methyl 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate) (1 eq) in MeOH:water (10:1 mL) at 0 °C. Stir the reaction mixture at room temperature for 16 h. Concentrate the reaction mixture under reduced pressure. Dilute the residue with water and acidify it with 2N HCl at 0 °C. Precipitate the product, filter it, and dry it under vacuum to obtain the crude carboxylic acid product (e.g., 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid). The crude product was used in the next step without purification. Step 3

[0385] A solution of 50% propylphosphonic anhydride (T3P) (2 eq) in EtOAc was added to a suspension of the appropriate carboxylic acid (e.g., 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid) (0.25 g, 0.70 mmol, 1 eq), the appropriate amine (e.g., N-methyl-1-phenylmethanamine (2 eq) and N,N-diisopropylethylamine) (5 eq) in DCM (3 mL / mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with a minimum amount of aqueous NaHCO 3 and the organic product was extracted with DCM (3 × 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the crude compound. The crude product was purified by column chromatography (silica gel 230 - 400 mesh; eluent 2 - 4% MeOH in DCM) to give the desired amide compound (e.g., N-benzyl-N-methyl-2-(p-tolylamino)-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxamide). Step 4

[0386] Follow general procedure A, step 3.

[0387] General procedure C1 for the synthesis of Example 21

Chemical Structure

[0388] Step - 1: Preparation of Intermediate 31 Methyl 2-(p-tolylamino)-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxylate

Chemical Structure

[0389] A stirred solution of methyl 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate (0.5 g, 1.66 mmol, 1.0 eq) in 1-butanol (10 mL) at room temperature was added p-toluidine (0.21 g, 2.0 mmol, 1.2 eq), catalyst H 2 SO 4 (2 drops), and heated at 100 °C for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature, basified slowly with saturated NaHCO 3 , and the organic product was extracted into EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel 230 - 400 mesh) using 1% to 3% MeOH in DCM as the eluent to give methyl 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate as a pale yellow solid (the mass shown in LCMS was the transesterification product with BuOH). Yield: (0.35 g, 56%). ES-MS [M+H] + : 413.32; Rt = 2.40 min (Method - C1).

[0390] Step - 2: Preparation of Intermediate 32 2-(p-Tolylamino)-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxylic acid

Chemical Structure

[0391] Sodium hydroxide (0.076 g, 1.89 mmol, 2 eq) was added to a stirred solution of methyl 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate (0.35 g, 0.94 mmol, 1 eq) in MeOH:H2O (10:1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (8 mL) and acidified with 2N HCl at 0 °C. The product was precipitated, filtered and dried under vacuum to give crude 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid. The crude product was used in the next step without purification. Yield: (0.25 g, crude). ES-MS [M+H] + : 357.18; Rt = 2.07 min (Method - C1).

[0392] Step - 3: Preparation of Intermediate 33 N-Benzyl-N-methyl-2-(p-tolylamino)-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxamide [Chemical formula]

[0393] A solution of 50% propylphosphonic anhydride (T3P) (0.89 mL, 1.40 mmol, 2 eq) in EtOAc was added to a suspension of 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid (0.25 g, 0.70 mmol, 1 eq), N-methyl-1-phenylmethanamine (0.17 g, 1.40 mmol, 2 eq) and N,N-diisopropylethylamine (0.45 g, 3.51 mmol, 5 eq) in DCM (10 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with a minimum amount of NaHCO 3 aqueous solution and the organic product was extracted with DCM (3 × 25 mL). The combined organic extracts were dried over anhydrous Na 2 SO4 It was dried. The solvent was distilled off under reduced pressure to obtain the crude compound. The crude product was purified by column chromatography (silica gel 230 - 400 mesh; eluent: 2 - 4% MeOH in DCM) to obtain 0.21 g of N-benzyl-N-methyl-2-(p-tolylamino)-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxamide as an off-white solid. Yield: (0.21 g, 48%, over 2 steps). ES-MS [M+H] + : 460.82; Rt = 2.32 min (Method - C1). 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.91 - 8.87 (d, J = 14.8 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.36 - 7.26 (m, 5H), 7.02 - 7.00 (m, 2H), 6.88 (s, 1H), 6.02 - 6.00 (d, J = 8.4 Hz, 1H), 4.61 - 4.58 (m, 2H), 2.87 (s, 2H), 2.79 (s, 1H), 2.22 (s, 3H), 1.90 - 1.99 (m, 2H), 1.43 - 1.41 (m, 6H), 0.93 - 0.90 (m, 9H).

[0394] Step - 4: Preparation of Example 21 6-Amino-N-benzyl-N-methyl-2-(p-tolylamino)pyrimidine-4-carboxamide

Chemical formula

[0395] To a stirred solution of Intermediate 32 (0.21 g, 0.45 mmol, 1.0 eq) in DCM (10 mL) at room temperature, TFA (5 mL) was added and the mixture was heated at 60 °C for 16 h. The reaction mixture was evaporated completely to obtain a residue, which was basified with saturated NaHCO 3 and the organic product was extracted into DCM. The organic layer was dried over anhydrous Na 2 SO 4It was dried and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 230 - 400 mesh) using 2% to 5% MeOH in DCM as the eluent to obtain 6-amino-N-benzyl-N-methyl-2-(p-tolylamino)pyrimidine-4-carboxamide as a light brown rubbery liquid. Yield: (78 mg, 49%). ES-MS [M + H] + : 348.22; Rt = 1.87 min (Method - C1). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.01 - 8.96 (d, J = 16.4 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.38 - 7.25 (m, 5H), 7.02 - 6.98 (m, 2H), 6.77 (s, br, 2H), 5.96 - 5.94 (d, J = 8 Hz, 1H), 4.62 - 4.57 (m, 2H), 2.88 - 2.80 (m, 3H), 2.22 (s, 3H).

[0396] Intermediate 34 N-(1,2,3,4-Tetrahydronaphthalen-2-yl)-2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chemical Structure

[0397] The title compound was synthesized according to the procedure described for the preparation of Intermediate 33. Yield: (complete conversion, continued without purification). ES-MS [M + H] + : 486 (raw material).

[0398] (Example 22) 6-Amino-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-(p-tolylamino)pyrimidine-4-carboxamide [Chemical]

[0399] The title compound was synthesized according to the procedure described for the preparation of Example 21. Yield: (14 mg, 21%). ES-MS [M+H] + : 374; Rt = 3.10 min (Method-C1).

[0400] General Procedure A2 for the Synthesis of Example 23 [Chemical]

[0401] Step-1: Preparation of Intermediate 35 2-Amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol [Chemical]

[0402] In a sealed tube, NaOMe (30% in MeOH; 6.06 mL, 33.6 mmol, 5.0 eq) was added to a stirred solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (HCl salt) (2.0 g, 6.73 mmol, 1.0 eq) in EtOH (30 mL), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture, guanidine hydrochloride (0.96 g, 10.1 mmol, 1.5 eq) was added at room temperature. The reaction mixture was heated to 100 °C for 16 hours under stirring conditions. The solvent was evaporated under reduced pressure, diluted with water, and the pH was adjusted to about 6 with dilute HCl to obtain Intermediate 1 as a pure solid, which was filtered and dried under reduced pressure. Yield: (1.2 g, 61%). ES-MS [M+H] + : 257.09, Rt = 0.59 min (Method-A2). 1 H NMR (400 MHz, DMSO-d 6): δ 11.11 (broad s, 1H), 7.35 - 7.23 (m, 5H), 6.36 (s, 2H), 3.58 (s, 2H), 3.06 (s, 2H), 2.56 - 2.53 (t, J = 12 Hz, 2H), 2.25 (m, 2H).

[0403] Step - 2: Preparation of Intermediate 36 7 - Benzyl - 4 - chloro - 5,6,7,8 - tetrahydropyrido[3,4 - d]pyrimidin - 2 - amine

Chemical Structure

[0404] N,N - Dimethylaniline (0.01 mL, catalyst) was added to a solution of Compound Intermediate 1 (0.3 g, 1.1 mmol, 1.0 eq) in POCl 3 (3 mL) at room temperature, and the mixture was heated at 100 °C for 2 hours. After the reaction was complete, the solvent was evaporated under reduced pressure and co - distilled twice with toluene to obtain a crude product. The crude product was used directly in the next step without any purification. Yield: (0.3 g, crude product).

[0405] Step - 3: Preparation of Example 23 7 - Benzyl - N4-(3 - methoxyphenyl)-5,6,7,8 - tetrahydropyrido[3,4 - d]pyrimidine - 2,4 - diamine

Chemical Structure

[0406] m - Anisidine (0.27 g, 2.2 mmol, 2.0 eq) was added to a solution of Intermediate 35 (0.3 g, 1.0 mmol, 1.0 eq) in 1,4 - dioxane (5 mL) at room temperature, and the mixture was heated at 100 °C for 16 hours. The reaction mixture was quenched with a minimal amount of NaHCO 3 aqueous solution, and the organic product was extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4It was dried. The solvent was distilled off under reduced pressure to obtain a crude compound. The crude compound was purified by reverse-phase Prep HPLC to obtain the pure compound 7-benzyl-N4-(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine. Yield: (0.03 g, 7.6%). ES-MS [M+H] + : 362.26, Rt = 1.49 min (Method-A2). 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.87 (s, 1H), 7.45 (s, 1H), 7.37 - 7.27 (m, 6H), 7.16 - 7.12 (t, J = 16 Hz, 1H), 6.54 - 6.52 (d, J = 8 Hz, 1H), 5.88 (s, 2H), 3.73 (s, 3H), 3.63 (s, 2H), 3.20 (s, 2H), 2.71 - 2.68 (t, J = 12 Hz, 2H), 2.50 (m, 2H).

[0407] (Example 24) 7-benzyl-N4-(2-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

Chemical formula

[0408] To a stirred solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (Intermediate 35, 0.200 g, 0.728 mmol, 1.0 eq) in 1-butanol (3 mL) was added o-anisidine (0.179 g, 1.456 mmol, 2.0 eq) and sulfuric acid (catalyst, 2 drops) at room temperature. The reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was subjected to flash column chromatography (10% MeOH / CH2 Cl 2 ) was purified to obtain 6-benzyl-N2-(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine as a white solid. Yield: (0.131 g, 50%). ES-MS [M+H] + : 362.15, Rt = 17.26 min (Method-C2). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (dt, J = 7.9, 1.0 Hz, 1H), 7.42 - 7.28 (m, 4H), 7.32 - 7.24 (m, 1H), 7.11 (brs, 1H), 7.08 - 6.88 (m, 2H), 6.95 - 6.63 (m, 1H), 5.98 (s, 2H), 3.79 (s, 3H), 3.71 (s, 2H), 3.31 (s, 2H), 2.68 (t, J = 5.8 Hz, 2H), 2.53 (t, J = 5.4 Hz, 2H).

[0409] (Example 25) 2-((2-Amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)phenol

Chemical formula

[0410] The title compound was synthesized according to the procedure described for the preparation of Example 24, but 2-aminophenol was used instead of o-anisidine in Step-3 and isolated as a pale yellow solid. Yield: (0.102 g, 41% yield). ES-MS [M+H] + : 348.1, Rt = 15.236 min (Method-C2). 1 H NMR (400 MHz, DMSO-d 6) δ 9.96 (s, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.44 - 7.31 (m, 5H), 7.31 - 7.23 (m, 1H), 6.92 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 6.85 (dd, J = 8.0, 1.6 Hz, 1H), 6.78 (ddd, J = 8.0, 7.2, 1.7 Hz, 1H), 6.09 (s, 2H), 3.72 (s, 2H), 3.39 (s, 2H), 2.67 (t, J = 5.8 Hz, 2H), 2.53 (t, J = 5.1 Hz, 2H).

[0411] (Example 26) 7-Benzyl-N4-(4-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine [Chemical Structure]

[0412] The title compound was synthesized according to the procedure described for the preparation of Example 24, except that 4-methoxyaniline was used instead of o-anisidine in Step-3, and isolated as a pale yellow solid. Yield: (0.056 g, 22% yield). ES-MS [M+H] + : 362.1, Rt = 15.734 min (Method-C2). 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (brs, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.42 - 7.31 (m, 4H), 7.32 - 7.13 (m, 1H), 6.86 (d, J = 9.0 Hz, 2H), 6.12 (s, 2H), 3.76 - 3.79 (m, 5H), 3.41 (s, 2H), 2.66 (t, J = 5.4 Hz, 2H), 2.53 (t, J = 5.5 Hz, 2H).

[0413] General Procedure B2 for the Synthesis of Example 27 [Chemical formula]

[0414] Step 1: Preparation of Intermediate 37 7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol [Chemical formula]

[0415] 25% NaOMe in MeOH (1.92 mL, 8.4 mmol, 5.0 eq) was added to a solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (500 mg, 1.68 mmol, 1.0 eq) and urea (0.50 g, 8.4 mmol, 5.0 eq) in EtOH (10 mL). The reaction mixture was stirred at reflux for 4 h. TLC analysis (50% EtOAc / Hex) indicated completion of the reaction. The reaction mixture was concentrated to dryness and purified by flash column chromatography (10 - 20% MeOH / DCM) to afford 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol as a white solid. Yield: (0.604 g, > theoretical yield). ES-MS [M + H] + : 258.1, Rt = 8.32 min (Method - B2). 1 H NMR (400 MHz, CDCl 3 ): 10.96 (s, 1H), 10.64 (s, 1H), 7.41 - 7.21 (m, 5H), 3.20 - 3.09 (m, 4H), 2.60 (t, J = 5.8 Hz, 2H), 2.21 (t, J = 5.7 Hz, 2H).

[0416] Step 2: Preparation of Intermediate 38 7-Benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Chem.

[0417] 7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol (4.3 g, 16.79 mmol, 1.0 eq) was added portionwise to phosphoryl chloride (15 mL, 1 mL / mmol). The reaction mixture was heated at 100 °C for 21 h under stirring conditions. The reaction mixture was cooled to room temperature and evaporated under reduced pressure and co-distilled twice with toluene. The crude product was redissolved in 10% MeOH / DCM and poured into saturated NaHCO 3 and extracted with DCM (5×), 2-methyl-THF (3×), and 5% DCM / MeOH (2×). The organic layer was dried over Na 2 SO 4 and filtered and concentrated. The crude product was purified by flash column chromatography (10 - 30 - 40 - 50% EtOAc / Hex) to afford 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine as a pale yellow solid. Yield: (2.6 g, 53% yield). ES-MS [M+H] + : 296.1, 294.1, Rt = 11.14 min (Method - B2).

[0418] Step 3: Preparation of Intermediate 39 7-Benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

Chem.

[0419] NH 3(7 N in MeOH, 0.540 mL, 3.785 mmol, 5.0 eq) was added to a suspension of 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.222 g, 0.757 mmol, 1.0 eq) in THF (8 mL). The resulting yellow suspension was heated to a maximum of 60 °C and stirred at this temperature for 3 h. The reaction was not shown by TLC analysis (10% EtOAc / Hex). Additional NH 3 (7 N in MeOH, 20 eq) was added to the reaction mixture and it was stirred at 60 °C for another 1 h. The reaction was not shown by TLC analysis (10% EtOAc / Hex). Additional NH 3 (7 N in MeOH, 100 eq) was added to the reaction mixture and it was stirred under reflux for 5 h. The formation of two new spots was shown by TLC analysis (10% EtOAc / Hex). The reaction mixture was concentrated to dryness and purified by flash column chromatography (2 - 5% MeOH / DCM) to afford 7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a beige solid. Yield: (0.074 g, 27% yield). ES-MS [M + H] + : 275.0, 277.1, Rt = 9.27 min (Method - B2). 1 H NMR (400 MHz, DMSO-d 6 ): 7.40 - 7.24 (m, 5H), 3.62 (s, 2H), 3.27 (s, 2H), 2.66 (d, J = 6.6 Hz, 2H), 2.33 (s, 2H).

[0420] Step 4: Preparation of Example 27 7-Benzyl-N 2 -(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

Chemical formula

[0421] A stirred solution of 7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.070 g, 0.255 mmol, 1.0 eq) in 1-butanol (3 mL) was added with m-anisidine (0.063 g, 0.510 mmol, 2.0 eq) and sulfuric acid (catalyst, 2 drops) at room temperature. The reaction mixture was stirred at 100 °C for 21 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by flash column chromatography (3 - 5% MeOH / DCM). The obtained product was slurried using a 1:1 mixture of EtOAc / Hex to give 7-benzyl-N 2 -(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine as a white solid. Yield: (0.026 g, 30% yield). ES-MS [M + H] + : 362.1, Rt = 19.24 min (Method - C2). 1 H NMR (400 MHz, DMSO-d 6 ): 8.70 (s, 1H), 7.51 (s, 1H), 7.41 - 7.32 (m, 4H), 7.26 (d, J = 9.6 Hz, 2H), 7.06 (t, J = 8.2 Hz, 1H), 6.39 (s, 3H), 3.69 (s, 3H), 3.64 (s, 2H), 3.27 (s, 2H), 2.68 (s, 2H), 2.36 (s, 2H).

[0422] (Example 28) 7-benzyl-N2-(2-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine [Chemical formula]

[0423] The title compound was synthesized from Intermediate 36 according to the procedure described for the preparation of Example 27 using o-anisidine and isolated as a light brown solid. Yield: (0.072 g, 47% yield). ES-MS [M+H] + : 362.1, Rt = 19.32 min (Method - C2). 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.79 - 7.34 (m, 1H), 6.82 - 6.40 (m, 6H), 6.23 - 5.91 (m, 3H), 5.69 (brs, 2H), 3.00 (s, 3H), 2.80 (s, 2H), 2.41 (s, 2H), 1.84 (t, J = 5.7 Hz, 2H), 1.56 - 1.48 (m, 2H).

[0424] (Example 29) 2-((4-Amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)phenol

Chemical formula

[0425] The title compound was synthesized from Intermediate 36 according to the procedure described for the preparation of Example 27 using 2-aminophenol and isolated as a white solid. Yield: (0.029 g, 31% yield). ES-MS [M+H] + : 348.0, Rt = 18.068 min (Method - C2). 1 H NMR (400 MHz, DMSO-d 6) δ 10.74 (brs, 1H), 7.88 (s, 1H), 7.81 - 7.60 (m, 1H), 7.38 - 7.31 (m, 4H), 7.31 - 7.23 (m, 1H), 6.89 - 6.67 (m, 3H), 6.63 (brs, 2H), 3.64 (s, 2H), 3.23 (s, 2H), 2.68 (t, J = 5.8 Hz, 2H), 2.38 - 2.30 (m, 2H).

[0426] (Example 30) 7-Benzyl-N2-(4-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine [Chemical formula]

[0427] The title compound was synthesized according to the procedure described for the preparation of Example 27, but using 4-methoxyaniline instead of m-anisidine in Step 4 and isolated as a white solid. Yield: (0.032 g, 12% yield). ES-MS [M+H] + : 362.11, Rt = 16.790 min (Method - C2). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (s, 1H), 7.61 (d, J = 9.1 Hz, 2H), 7.44 - 7.23 (m, 4H), 7.30 - 7.10 (m, 1H), 6.77 (d, J = 9.1 Hz, 2H), 6.29 (brs, 2H), 3.68 (s, 3H), 3.63 (s, 2H), 3.22 (s, 2H), 2.67 (t, J = 5.8 Hz, 2H), 2.34 (t, J = 6.1 Hz, 2H).

[0428] General procedure C2 for the synthesis of Example 31 [Chemical formula]

[0429] Step 1: Preparation of Intermediate 40 6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diol

Chem.

[0430] 25% NaOMe in MeOH (0.440 mL, 1.91 mmol, 5.0 eq) was added to a solution of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate (0.10 g, 0.382 mmol, 1.0 eq) and urea (0.115 g, 1.91 mmol, 5.0 eq) in EtOH (3 mL). The reaction mixture was stirred at reflux for 18 h. TLC analysis (50% EtOAc / Hex) indicated completion of the reaction. The reaction mixture was concentrated to dryness, water was added, the resulting solid was filtered and dried to give 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diol as a pale brown solid, which was used without further purification. Yield: (0.172 g, crude). ES-MS [M+H] + : 258.19, Rt = 0.42 min (Method - B2).

[0431] Step 2: Preparation of Intermediate 41 6-Benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Chem.

[0432] 6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diol (0.172 g, 0.67 mmol, 1 eq) was added portionwise to phosphoryl chloride (1 mL / mmol). The reaction mixture was heated at 100 °C for 18 h under stirring conditions. The reaction mixture was cooled to room temperature and evaporated under reduced pressure and co-distilled twice with toluene to give 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as a brown solid, which was used without further purification. Yield: (0.097 g, crude). ES-MS [M+H] + : 296.08, 294.05, Rt = 1.88 min (Method - B2).

[0433] Step 3: Preparation of Intermediate 42 6-Benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

Chem.

[0434] NH 3 (7N in MeOH, 0.145 mL, 0.996 mmol, 5.0 eq) was added to a suspension of 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.097 g, 0.332 mmol, 1.0 eq) in THF (0.7 mL). The resulting yellow suspension was stirred at 60 °C for 16 h in a sealed tube. Partial conversion was indicated by TLC analysis (10% EtOAc / Hex). Additional NH 3 (7N in MeOH, 20 eq) was added to the reaction mixture, which was stirred at 60 °C for 3 days. Formation of the desired product was indicated by LC-MS analysis (Method - B). The reaction mixture was concentrated to dryness to give 6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine as an off-white solid, which was used without further purification. Yield: (0.092 g, crude). ES-MS [M+H] +: 277.14, 275.09, Rt = 0.92 min (Method - B2).

[0435] Step 4: Preparation of Example 31 6-Benzyl-N2-(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine hydrochloride

Chemical formula

[0436] To a stirred solution of 6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (0.092 g, 0.332 mmol, 1.0 eq) in 1-butanol (3 mL) were added m-anisidine (0.082 g, 0.664 mmol, 2.0 eq) and sulfuric acid (catalyst, 2 drops) at room temperature. The reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (EtOAc / heptane, 50 - 100) to give 6-benzyl-N2-(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine as a white solid, which was treated with HCl (6N in iPrOH) and stirred at room temperature for 1 h. The resulting solid was filtered and triturated with DIPE to give 6-benzyl-N2-(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine hydrochloride as a light brown powder. Yield: (0.032 g, 27%). ES-MS [M + H] + : 362.17, Rt = 17.08 min (Method - C2). 1 H NMR (400 MHz, DMSO-d 6) δ 12.05 (broad singlet, 1H), 10.15 (singlet, 1H), 8.35 (broad singlet, 1H), 7.76 - 7.61 (multiplet, 2H), 7.48 (septet, J = 3.9 Hz, 3H), 7.37 - 7.17 (multiplet, 2H), 7.10 (doublet of doublets, J = 7.8, 2.0 Hz, 1H), 6.72 (doublet of doublets, J = 8.2, 2.5 Hz, 1H), 4.45 (singlet, 2H), 4.05 - 3.81 (multiplet, 1H), 3.77 (singlet, 3H), 3.69 - 3.38 (multiplet, 4H), 3.28 - 3.23 - 2.88 (multiplet, 1H).

[0437] General procedure D2 for the synthesis of Example 32 [Chemical formula]

[0438] Step 1: Preparation of Intermediate 43 Ethyl 3-oxo-1-phenylpiperidine-4-carboxylate [Chemical formula]

[0439] BINAP (0.239 g, 0.38 mmol, 4 mol%) and Pd 2 (dba) 3 (0.176 g, 0.19 mmol, 2 mol%) were added to a degassed solution of ethyl 3-oxopiperidine-4-carboxylate (1.64 g, 9.58 mmol, 1.0 eq), bromobenzene (1.1 mL, 10.54 mmol, 1.1 eq) and NaOtBu (2.76 g, 28.74 mmol, 3.0 eq) in toluene (20 mL). The resulting mixture was stirred under reflux for 90 minutes. TLC analysis (5% MeOH / CH 2 Cl 2) showed complete conversion. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (10 - 20% EtOAc / Hex) to give ethyl 3-oxo-1-phenylpiperidine-4-carboxylate as a yellow oil. Yield: (1.6 g, 63%). ES-MS [M+H] + : 247.7, Rt = 11.39 min (Method - B2). 1 H NMR (400 MHz, Chloroform-d) δ 12.44 (s, 1H), 7.68 (t, J = 7.0 Hz, 2H), 7.35 - 7.22 (m, 3H), 4.65 (qd, J = 7.1, 1.9 Hz, 2H), 4.23 (s, 2H), 3.77 (d, J = 5.8 Hz, 2H), 2.85 (ddd, J = 7.7, 3.9, 1.9 Hz, 2H), 1.72 (td, J = 7.1, 1.9 Hz, 3H).

[0440] Step 2: Preparation of Intermediate 44 2-Amino-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

Chemical Structure

[0441] NaOMe (25% in MeOH, 3.7 mL, 16.2 mmol, 5.0 eq) was added to a solution of ethyl 3-oxo-1-phenylpiperidine-4-carboxylate (0.8 g, 3.24 mmol, 1.0 eq) and guanidine hydrochloride (0.464 g, 4.86 mmol, 1.5 eq) in EtOH (20 mL). The reaction mixture was stirred under reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and adsorbed onto silica gel. The resulting crude product was purified by flash column chromatography (10% MeOH / CH 2 Cl2 ) was purified to obtain 2-amino-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol as a white solid. Yield: (0.678 g, 83%). ES-MS [M+H] + : 243.0 (Method-B2). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (brs, 1H), 6.36 (q, J = 7.9 Hz, 2H), 6.16 - 6.06 (m, 2H), 5.95 - 5.85 (m, 1H), 5.56 - 5.43 (m, 2H), 3.06 - 2.97 (m, 2H), 2.60 - 2.52 (m, 2H), 1.70 - 1.61 (m, 2H), 1.58 - 1.48 (m, 2H).

[0442] Step 3: Preparation of Intermediate 45 4-Chloro-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

Chemical Structure

[0443] 2-Amino-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (0.68 g, 2.81 mmol, 1.0 eq) was added portionwise to phosphoryl chloride (1 mL / mmol). The reaction mixture was heated at 100 °C for 2 hours under stirring conditions. The reaction mixture was cooled to room temperature and evaporated under reduced pressure, and co-distilled twice with toluene. The obtained crude product was purified by flash column chromatography (10% MeOH / CH 2 Cl 2 ) to obtain 4-chloro-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine as a brown oil. Yield: (0.72 g, not pure). ES-MS [M+H] +: Mass was not detected (Method - B2).

[0444] Step 4: Preparation of Example 32 2 - ((2 - Amino - 7 - phenyl - 5,6,7,8 - tetrahydropyrido[3,4 - d]pyrimidin - 4 - yl)amino)phenol [Chemical Formula]

[0445] To a stirred solution of 4 - chloro - 7 - phenyl - 5,6,7,8 - tetrahydropyrido[3,4 - d]pyrimidin - 2 - amine (0.720 g, 2.77 mmol, 1.0 eq) in 1 - butanol (20 mL), 2 - aminophenol (0.302 g, 2.77 mmol, 1.0 eq) and sulfuric acid (catalyst, 2 drops) were added at room temperature. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by flash column chromatography (10 - 50% EtOAc / hexane) to give 2 - ((2 - amino - 7 - phenyl - 5,6,7,8 - tetrahydropyrido[3,4 - d]pyrimidin - 4 - yl)amino)phenol as a beige solid. Yield: (0.023 g, 2.5%). ES - MS [M + H] + : 334.2, Rt = 17.309 min (Method - C2). 1 H NMR (400 MHz, DMSO - d 6) δ 10.07 (brs, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.24 (t, J = 7.7 Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 6.96 - 6.85 (m, 2H), 6.78 (q, J = 6.8 Hz, 2H), 6.14 (s, 2H), 4.02 (s, 2H), 3.73 - 3.55 (m, 2H), 2.62 - 2.53 (s, 2H).

[0446] Preparation of Compounds of Formula (IA) of Examples 33 to 141

[0447] Intermediate 46 2-(((1S,2S)-2-Hydroxycyclohexyl)amino)-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

Chemical Structure

[0448] To a stirred solution of 2-chloro-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide (Intermediate 10) (0.160 g, 0.43 mmol, 1.0 eq) in DMF (1.5 mL) was added (1S,2S)-2-aminocyclohexan-1-ol (0.150 g, 1.30 mmol, 3.0 eq) and sulfuric acid (catalyst, 1 drop) at room temperature. The reaction mixture was stirred at 130 °C for 18 h. The reaction mixture was then cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (EtOAc / heptane, 50 - 100) to give 2-(((1S,2S)-2-hydroxycyclohexyl)amino)-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide as a white solid. Yield: (0.020 g, 10%). ES-MS [M+H] + : 454.2, Rt = 7.305 min (Method - A1)

[0449] (Example 33) 6 - Amino - 2 - (((1S,2S) - 2 - hydroxycyclohexyl)amino) - N - methyl - N - phenylpyrimidine - 4 - carboxamide

Chem.

[0450] Intermediate 47 Methyl 2 - chloro - 6 - ((2 - methoxyphenyl)amino)pyrimidine - 4 - carboxylate

Chem.

[0451] To a stirred mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (5.0 g, 24.14 mmol, 1.0 eq) and 2-methoxyaniline (2.73 mL, 24.14 mmol, 1.0 eq) in methanol (50 mL) was added sodium carbonate (2.81 g, 26.55 mmol, 1.1 eq). The resulting mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness and the obtained residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The obtained crude product was purified by flash column chromatography (EtOAc / heptane, 50~100) to give methyl 2-chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylate as a white solid. Yield: (5.26 g, 74%). ES-MS [M+H] + : 294.1, Rt = 6.09 min (Method-A1)

[0452] Intermediate 48 Methyl 6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate [Chemical Structure]

[0453] A stirred mixture of methyl 2-chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylate (0.40 g, 1.34 mmol, 1.0 eq) and tert-octylamine (1.1 mL, 6.72 mmol, 5.0 eq) in DMF (4 mL) was added to DIPEA (1.2 mL, 6.72 mmol, 5.0 eq). The resulting mixture was stirred at 120 °C for 16 h. The mixture was diluted with water, extracted with ethyl acetate (×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by flash column chromatography (EtOAc / heptane, 50 - 100) to give methyl 6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate as a colorless wax. Yield: (0.094 g, 20% yield). ES-MS [M+H] + : 387.2, Rt = 7.57 min (Method-A1)

[0454] Intermediate 49 6-((2-Methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid

Chemical formula

[0455] THF:H 2To a stirred mixture of methyl 6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate (0.094 g, 0.243 mmol, 1.0 eq.) in O(1:1, 3 mL) was added lithium hydroxide (0.051 g, 1.216 mmol, 5.0 eq). The resulting mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness, acidified by addition of concentrated HCl, extracted with EtOAc / MeOH (×3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford 6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid as a pale yellow solid, which was used without further purification. Yield: (0.084 g, 93% yield). ES-MS [M+H] + : 373.1, Rt = 6.790 min (Method-A1).

[0456] Intermediate 50 (6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

Chemical Structure

[0457] A stirred solution of 6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid (0.084 g, 0.225 mmol, 1.0 eq), 1-phenylpiperazine (0.045 mL, 0.293 mmol, 1.3 eq) and HATU (0.102 g, 0.270 mmol, 1.2 eq) in DMF (1 mL) was added with DIPEA (0.059 mL, 0.337 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained crude product was purified by flash column chromatography (EtOAc / heptane, 50~100) to give (6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone as a yellow wax. Yield: (0.059 g, 51% yield). ES-MS [M+H] + : 517.2 Rt = 7.707 min (Method-A1).

[0458] (Example 34) (2-Amino-6-((2-methoxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

Chemical formula

[0459] Intermediate 51 (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone [Chemical Structure] Synthesized according to General Procedure A, Step 1. Yield: (0.163 g, 39%). ES-MS [M+H] + : 401.9, Rt = 7.443 min (Method - A1).

[0460] Intermediate 52 (3,4-Dihydroisoquinolin-2(1H)-yl)(2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)methanone [Chemical Structure] Synthesized according to General Procedure A, Step 2. Yield: (0.090 g, 47%). ES-MS [M+H] + : 474.9, Rt = 7.34 min (Method - A1).

[0461] (Example 35) (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone

Chem.

[0462] Intermediate 53 (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone

Chem.

[0463] Intermediate 54 (3,4-Dihydroquinolin-1(2H)-yl)(2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)methanone

Chem.

[0464] (Example 36) (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone

Chem.

[0465] Intermediate 55 (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(indolin-1-yl)methanone [Chemical] Synthesized according to the general procedure A, step 1. Yield: (0.188 g, 46%). ES-MS [M+H] + : 387.9, Rt = 7.57 min (Method - A1).

[0466] Intermediate 56 (2 - ((2 - hydroxyphenyl)amino)-6 - ((2,4,4 - trimethylpentan - 2 - yl)amino)pyrimidin - 4 - yl)(indolin - 1 - yl)methanone [Chemical]

[0467] BINAP (0.030 g, 0.05 mmol, 10 mol%) and Pd 2 (dba) 3 (0.025 g, 0.03 mmol, 6 mol%) were added to a degassed solution of (2 - chloro - 6 - ((2,4,4 - trimethylpentan - 2 - yl)amino)pyrimidin - 4 - yl)(indolin - 1 - yl)methanone (0.142 g, 0.40 mmol, 1.0 eq), 2 - aminophenol (0.060 g, 0.55 mmol, 1.5 eq) and cesium carbonate (0.50 g, 1.4 mmol, 3.5 eq) in dioxane (2.8 mL). The resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (10 - 20% EtOAc / hexane) to give (2 - ((2 - hydroxyphenyl)amino)-6 - ((2,4,4 - trimethylpentan - 2 - yl)amino)pyrimidin - 4 - yl)(indolin - 1 - yl)methanone as a white solid. Yield: (0.105 g, 62%). ES-MS [M+H] + : 460.9, Rt = 7.214 min (Method - A1).

[0468] (Example 37) (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(indolin-1-yl)methanone [Chemical formula] Synthesized according to General Procedure A, Step 3. This product was purified by semi-preparative HPLC (Method - E1). Yield: (0.012 g, 16%). ES-MS [M + H] + : 348.1, Rt = 16.999 min (Method - B1). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.06 (d, J = 13.6 Hz, 3H), 6.85 - 6.80 (m, 2H), 6.79 - 6.65 (m, 1H), 6.14 (s, 1H), 4.15 (t, J = 8.3 Hz, 2H), 3.10 (t, J = 8.3 Hz, 2H).

[0469] Intermediate 57 (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone [Chemical formula] Synthesized according to General Procedure A, Step 1. Yield: (0.535 g, 55%). ES-MS [M + H] + : 387.9, Rt = 7.614 min (Method - A1).

[0470] Intermediate 58 Isobenzofuran-2-yl (2-((3-methoxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)-pyrimidin-4-yl)methanone

Chemical Structure

[0471] (Example 38) (6-Amino-2-((3-methoxyphenyl)amino)pyrimidin-4-yl)(isobenzofuran-2-yl)methanone

Chemical Structure

[0472] Intermediate 59 (2-((3-Hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isobenzofuran-2-yl)methanone [Chemistry] Synthesized according to General Procedure A, Step 2. Yield: (0.094 g, 40%). ES-MS [M+H] + : 460.2, Rt = 7.138 min (Method - A1).

[0473] (Example 39) (6-Amino-2-((3-hydroxyphenyl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone [Chemistry] Synthesized according to General Procedure A, Step 3. This compound was purified by semi-preparative HPLC (Method - E1). Yield: (0.022 g, 31%). ES-MS [M+H] + : 348.2, Rt = 15.841 min (Method - B1). 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (s, 1H), 8.95 (s, 1H), 7.45 - 7.36 (m, 1H), 7.36 - 7.27 (m, 3H), 7.24 - 7.12 (m, 2H), 6.99 (t, J = 8.0 Hz, 1H), 6.79 (s, 2H), 6.32 (dd, J = 7.9, 2.3 Hz, 1H), 6.20 (s, 1H), 5.04 (s, 2H), 4.83 (s, 2H).

[0474] Intermediate 60 Isoindolin-2-yl(2-(m-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)methanone [Chemistry] Synthesized according to General Procedure A, Step 2. Yield: (0.107 g, 36%). ES-MS [M+H] + : 457.9, Rt = 3.20 min (Method - D1).

[0475] (Example 40) (6-Amino-2-(m-tolylamino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

Chemical Structure

[0476] Intermediate 61 (2-((3-Chlorophenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

Chemical Structure

[0477] (Example 41) (2-((3-Chlorophenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone [Chemical formula] Synthesized according to General Procedure A, Step 3. Yield: (0.020 g, 37%). ES-MS [M+H] + : 366.1, Rt = 19.152 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (s, 1H), 7.94 (t, J = 2.1 Hz, 1H), 7.69 (ddd, J = 8.3, 2.0, 0.9 Hz, 1H), 7.50 - 7.36 (m, 1H), 7.36 - 7.18 (m, 4H), 6.96 (s, 1H), 6.95 - 6.81 (m, 1H), 6.25 (d, J = 0.7 Hz, 1H), 5.04 (s, 2H), 4.83 (s, 2H).

[0478] General Procedure D-1 [Chemical formula] Step 1

[0479] To a stirred solution of the appropriate aryl chloride derivative (e.g., 4,6-dichloro-2-(methylsulfonyl)pyrimidine) (1.0 eq) in dioxane (2 mL / mmol), the appropriate amine (e.g., 2-methoxyaniline) (1.0 eq) and DIPEA (3.71 mL, 21.3 mmol, 1.2 eq) were added. The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford the desired amine compound (e.g., 6-chloro-N-(2-methoxyphenyl)-2-(methylsulfonyl)pyrimidin-4-amine). Step 2

[0480] To a stirred solution of the appropriate sulfonyl derivative (e.g., 6-chloro-N-(2-methoxyphenyl)-2-(methylsulfonyl)pyrimidin-4-amine) (1.0 eq) in DMSO (4 mL / mmol), potassium cyanide (1.0 eq) was added. The resulting mixture was stirred at room temperature for 30 min. Then water was added and the solution was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (50% EtOAc / hexane) to afford the desired carbonitrile derivative (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carbonitrile). Step 3

[0481] To a stirred solution of the appropriate carbonitrile (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carbonitrile) (1.0 eq) in water (7 mL / mmol) and ethanol (7 mL / mmol), KOH (10.0 eq) at room temperature was added. The resulting mixture was stirred under reflux for 1 hour. The mixture was then cooled to room temperature and acidified to pH 3 - 4 by adding 3N HCl. Then, EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (30 to 100% EtOAc / hexane) to obtain the desired carboxylic acid compound (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxylic acid).

[0482] Intermediate 62 6-Chloro-N-(2-methoxyphenyl)-2-(methylsulfonyl)pyrimidin-4-amine [Chemical Structure] Synthesized according to General Procedure D-1, Step 1. Isolated as a white solid. Yield: (7.0 g, 95%). ES-MS [M + H] + : 314.0, Rt = 5.78 min (Method - A1).

[0483] Intermediate 63 4-Chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carbonitrile [Chemical Structure] Synthesized according to General Procedure D-1, Step 2. Isolated as a white solid. Yield: (1.69 g, 50%). ES-MS [M + H] + : 261.0, Rt = 2.77 min (Method - D1).

[0484] Intermediate 64 4-Chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxylic acid

Chem.

[0485] Intermediate 65 2-Chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylic acid

Chem.

[0486] THF:H 2 To a stirred mixture of methyl 2-chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylate (6.17 g, 21.00 mmol, 1.0 eq.) in THF:H₂O (1:1, 240 mL), lithium hydroxide (4.41 g, 105.03 mmol, 5.0 eq) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness, acidified by addition of concentrated HCl, extracted with EtOAc / MeOH (×3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 2-chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylic acid as a yellow solid, which was used without further purification. Yield: (5.97 g, quantitative yield). ES-MS [M+H] + : 280.0 Rt = 4.53 min (method-A1).

[0487] General procedure D-2

Chem.

[0488] Appropriate carboxylic acid compound (e.g., 4-chloro-6-((2-methoxyphenyl)-amino)pyrimidine-2-carboxylic acid) (1.0 eq) was placed in N 2 under an atmosphere of SOCl 2 (5 mL / mmol) and stirred at 90 °C for 3 h. The mixture was then cooled to room temperature and the excess SOCl 2 was removed under vacuum. The resulting crude residue was dissolved in THF (5 mL / mmol), then an appropriate amine (e.g., 1-phenylpiperazine) (1.0 eq) and Et 3 N (1 eq) were added. The mixture was stirred at room temperature for 16 h. The mixture was then diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The resulting crude product was purified by flash column chromatography (50 to 100% EtOAc / hexane) to give the desired amide (e.g., (4-chloro-6-((2-methoxyphenyl)amino)pyrimidin-2-yl)(4-phenylpiperazin-1-yl)methanone). Step 1 Alternative procedure (Step 1B)

[0489] T3P (50% solution in ethyl acetate, 2.0 eq) was added to a suspension of the appropriate carboxylic acid (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxylic acid) (1.0 eq), the corresponding amine (e.g., (2-methoxyphenyl)amino) (1.5 eq) and DIPEA (5.0 eq.) in DCM (5 mL / mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO 3 aqueous solution. The mixture was extracted with ethyl acetate (×3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (50 to 100% EtOAc / hexane) to give the desired product (e.g., 4-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxamide).

[0490] Intermediate 66 (4-chloro-6-((2-methoxyphenyl)amino)pyrimidin-2-yl)(4-phenylpiperazin-1-yl)methanone

Chemical formula

[0491] Intermediate 67 4-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxamide

Chemical formula

[0492] Intermediate 68 4-chloro-6-((2-methoxyphenyl)amino)-N-phenylpyrimidine-2-carboxamide

Chemical formula

[0493] Intermediate 69 2-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxamide [Chemistry] Synthesized according to Procedure D-2, Step 1B. Yield: (0.229 g, 27% yield). ES-MS [M+H] + : 395.1 Rt = 7.078 min (Method - A1).

[0494] Intermediate 70 2-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)-N-methylpyrimidine-4-carboxamide [Chemistry] Synthesized according to the general Procedure D-2, Step 1B. Yield: (0.693 g, 79% yield). ES-MS [M+H] + : 409.0 Rt = 6.801 min (Method - A1).

[0495] Intermediate 71 2-Chloro-6-((2-methoxyphenyl)amino)-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine-4-carboxamide [Chemistry] Synthesized according to Procedure D-2, Step 1B. Yield: (0.326 g, 47% yield). ES-MS [M+H] + : 423.0 Rt = 6.890 min (Method - A1).

[0496] Intermediate 72 2-Chloro-6-((2-methoxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine-4-carboxamide [Chemistry] Synthesized according to Procedure D-2, Step 1B. Yield: (0.479 g, 76% yield). ES-MS [M+H] + : 409.0 Rt = 7.212 min (Method - A1).

[0497] Intermediate 73 (2-Chloro-6-((2-methoxyphenyl)amino)pyrimidin-4-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone

Chemical Structure

[0498] Intermediate 74 (2-Chloro-6-((2-methoxyphenyl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

Chemical Structure

[0499] General Procedure D-3

Chemical Structure

[0500] Method 1: Oxalyl chloride (1.5 eq) was added to a stirred solution of 4,6-dichloropicolinic acid (1.0 eq) in DCM (3 mL / mmol) and DMF (10 drops) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated to dryness and dissolved in DCM (3 mL / mmol) and DIPEA (2.0 - 3.0 eq). Then an appropriate amine (e.g., N-methylaniline) (1.2 eq) was added and the resulting mixture was stirred at room temperature for 4 h. After completion, the mixture was concentrated to dryness and the crude product was subjected to silica gel column chromatography (hexane:EtOAc, 90:10 to 75:25) to obtain the desired amide product (e.g., 4,6-dichloro-N-methyl-N-phenylpicolinamide).

[0501] Method 2: T3P (2.0 eq of a 50% solution in EtOAc) was added to a suspension of 4,6-dichloropicolinic acid (1.0 eq), an appropriate amine (e.g., 1-phenylpiperazine) (1.1 eq.) and DIPEA (5.0 eq.) in DCM (4 mL / mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO 3 aqueous solution. The mixture was extracted with ethyl acetate (×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The resulting crude product was purified by flash column chromatography (EtOAc / heptane, 50 - 100) to obtain the desired product (e.g., (4,6-dichloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone). Step 2

[0502] Method 1: To a stirred solution of the appropriate amine (e.g., 2-methoxyaniline) (0.80 g, 6.5 mmol, 2.0 eq) in DMF (7 mL), NaH (60% suspension in mineral oil 0.785 g, 19.62 mmol, 6.0 eq) was added at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes. Then, the appropriate aryl dichloride (e.g., 4,6-dichloro-N-methyl-N-phenylpicolinamide) was added and the mixture was stirred at 100 °C for 30 minutes. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were washed with additional brine containing 10% HCl and dried over Na 2 SO 4 , filtered, and concentrated. The crude product was subjected to silica gel column chromatography (hexane:EtOAc, from 95:05 to 80:20) to obtain the desired product (e.g., 6-chloro-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide).

[0503] Method 2: Dppf (6 mol%) and Pd(OAc) 2 (3 mol%) were added to a degassed solution of the appropriate dichloride (e.g., 4,6-dichloro-N-(2,3-dihydro-1H-inden-2-yl)picolinamide) (1.0 eq), the appropriate arylamine (e.g., e.g., 2-methylaniline) (1.0 eq) and K 3 PO 4 (2.0 eq) in dioxane (5 mL / mmol). The resulting mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. Then, the mixture was diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over anhydrous MgSO 4 , filtered, and concentrated. The resulting crude product was purified by flash column chromatography (hexane:EtOAc, 60:40) to obtain the desired product (e.g., 4-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(o-tolylamino)picolinamide).

[0504] Intermediate 75 4,6-Dichloro-N-methyl-N-phenylpicolinamide

Chem.

[0505] Intermediate 76 (4,6-Dichloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

Chem.

[0506] Intermediate 77 (4,6-Dichloropyridin-2-yl)(isoindolin-2-yl)methanone

Chem.

[0507] Intermediate 78 (4,6-Dichloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

Chem.

[0508] Intermediate 79 4,6-Dichloro - N-(2,3 - dihydro - 1H - inden - 2 - yl) picolinamide

Chemical Structure

[0509] Intermediate 80 4,6-Dichloro - N-(2,3 - dihydro - 1H - inden - 2 - yl) picolinamide

Chemical Structure

[0510] Intermediate 81 (4,6 - Dichloropyridin - 2 - yl)(4 - phenylpiperazin - 1 - yl) methanone

Chemical Structure

[0511] Intermediate 82 4,6 - Dichloro - N - phenylpicolinamide [Chem.] Synthesized according to the general procedure D-3, step 1, method 2. Yield: (3.64 g, 87%). ES-MS [M+H] + : 267.0, Rt = 6.93 min (method - A1).

[0512] Intermediate 83 (4,6-Dichloropyridin-2-yl)(isoindolin-2-yl)methanone [Chem.] Synthesized according to the general procedure D-3, step 1, method 2. Yield: (1.271 g, 84%). ES-MS [M+H] + : 294.1, Rt = 6.943 min (method - A1).

[0513] Intermediate 84 (4,6-Dichloropyridin-2-yl)(indolin-1-yl)methanone [Chem.] Synthesized according to the general procedure D-3, step 1, method 2. The compound was used without further purification. Yield: (1.5 g, 98%). ES-MS [M+H] + : 294.1, Rt = 3.09 min (method - D1).

[0514] Intermediate 85 4,6-Dichloro-N-phenylpicolinamide [Chem.] Synthesized according to the general procedure D-3, step 1, method 1. Yield: (0.122 g, 83%). ES-MS [M+H] +: 267.0, Rt = 6.82 min (Method - A1).

[0515] Intermediate 86 4,6 - Dichloro - N - (1,2,3,4 - tetrahydronaphthalen - 2 - yl) picolinamide [Chem.] Synthesized according to general procedure D - 3, step 1, method 1. Yield: (0.720 g, 67%). ES - MS [M + H] + : 322.1, Rt = 6.443 min (Method - A1).

[0516] Intermediate 87 4,6 - Dichloro - N - phenylpicolinamide [Chem.] Synthesized according to general procedure D - 3, step 1, method 2. The crude product was used without further purification. Yield: (1.25 g, 89%). ES - MS [M + H] + : 267.0, Rt = 6.82 min (Method - A1).

[0517] Intermediate 88 4,6 - Dichloro - N - (2,3 - dihydro - 1H - inden - 2 - yl) picolinamide [Chem.] Synthesized according to general procedure D - 3, step 1, method 2. Yield: (1.08 g, 68%). ES - MS [M + H] + : 308.0, Rt = 7.04 min (Method - A1).

[0518] Intermediate 89 4,6 - Dichloro - N - (2,3 - dihydro - 1H - inden - 2 - yl) - N - methylpicolinamide [Chemical] Synthesized according to the general procedure D-3, step 1, method 2. Yield: (0.624 g, 25%). ES-MS [M+H] + : 321.1, Rt = 6.842 min (method - A1).

[0519] Intermediate 90 4,6-Dichloro-N-methyl-N-phenylpicolinamide [Chemical] Synthesized according to the general procedure D-3, step 1, method 2. Yield: (2.22 g, 76%). ES-MS [M+H] + : 281.0, Rt = 6.327 min (method - A1).

[0520] Intermediate 91 4,6-Dichloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)picolinamide [Chemical] Synthesized according to the general procedure D-3, step 1, method 2. Yield: (3.18 g, 94%). ES-MS [M+H] + : 325.0, Rt = 6.800 min (method - A1).

[0521] Intermediate 92 4,6-Dichloro-N-(m-tolyl)picolinamide [Chemical] Synthesized according to the general procedure D-3, step 1, method 2. Yield: (0.639 g, 87%). ES-MS [M-H] - : 279.2, Rt = 7.133 min (method - A1).

[0522] Intermediate 93 4,6-Dichloro-N-(3,4-dimethylphenyl)picolinamide [Chemical formula] Synthesized according to general procedure D-3, step 1, method 2. Yield: (0.470 g, 61%). ES-MS [M-H] - : 279.2, Rt = 7.133 min (method-A1).

[0523] Intermediate 94 (4,6-Dichloropyridin-2-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone [Chemical formula] Synthesized according to general procedure D-3, step 1, method 2. Yield: (0.50 g, quantitative). ES-MS [M+H] + : 307.0, Rt = 6.76 min (method-A1).

[0524] Intermediate 95 6-Chloro-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide [Chemical formula] Synthesized according to general procedure D-3, step 2, method 1. The product was isolated as a beige solid. Yield: (0.140 g, 7%). ES-MS [M+H] + : 368.2, Rt = 6.98 min (method-A1).

[0525] Intermediate 96 (6-Chloro-4-((2-methoxyphenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone [Chemical formula] Synthesized according to the general procedure D-3, step 2, method 1. Yield: (0.548 g, 20%). ES-MS [M+H] + : 423.1, Rt = 6.742 min (method - A1).

[0526] Intermediate 97 (6-chloro-4-((2-fluorophenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone [Chemical formula] Synthesized according to the general procedure D-3, step 2, method 1. Yield: (0.180 g, 34%). ES-MS [M+H] + : 411.1, Rt = 6.737 min (method - A1).

[0527] Intermediate 98 (6-chloro-4-((2-chlorophenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone [Chemical formula] Synthesized according to the general procedure D-3, step 2, method 1. Yield: (0.415 g, using crude product). ES-MS [M+H] + : 427.0, Rt = 6.956 min (method - A1).

[0528] Intermediate 99 (6-chloro-4-((2-methoxyphenyl)amino)pyridin-2-yl)(isoindolin-2-yl)methanone [Chemical formula] Synthesized according to the general procedure D-3, step 2, method 1. The product was isolated as a green solid. Yield: (0.228 g, 14%). ES-MS [M+H] + : 380.1, Rt = 6.998 min (Method - A1).

[0529] Intermediate 100 (6-Chloro-4-((2-methoxyphenyl)amino)pyridin-2-yl)(indolin-1-yl)methanone

Chemical Structure

[0530] Intermediate 101 6-Chloro-4-((2-methoxyphenyl)amino)-N-phenylpicolinamide

Chemical Structure

[0531] Intermediate 102 6-Chloro-4-((2-methoxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide

Chemical Structure

[0532] Intermediate 103 6-Chloro-4-((2-methoxyphenyl)amino)-N-phenylpicolinamide and 4-chloro-6-((2-methoxyphenyl)amino)-N-phenylpicolinamide

Chemical Structure

[0533] Intermediate 104 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((2-methoxyphenyl)amino)picolinamide

Chemical Structure

[0534] Intermediate 105 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((2-methoxyphenyl)(methyl)amino)-picolinamide

Chemical Structure

[0535] Intermediate 106 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((2-fluorophenyl)amino)picolylamide and 4-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-fluorophenyl)amino)picolylamide

Chem.

[0536] Intermediate 107 6-Chloro-4-((2-chlorophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolylamide

Chem.

[0537] Intermediate 108 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((2-methoxy-4-methylphenyl)amino)-picolylamide

Chem.

[0538] Intermediate 109 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((4-fluoro-2-methoxyphenyl)amino)picolylamide

Chemical formula

[0539] Intermediate 110 4-(Benzo[d][1,3]dioxol-4-ylamino)-6-chloro-N-phenylpicolylamide

Chemical formula

[0540] Intermediate 111 6-Chloro-4-((2-fluorophenyl)amino)-N-phenylpicolylamide

Chemical formula

[0541] Intermediate 112 4-Chloro-6-((2-fluorophenyl)amino)-N-phenylpicolylamide

Chemical formula

[0542] Intermediate 113 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(o-tolylamino)picolinamide

Chemical Structure

[0543] Intermediate 114 (4-Chloro-6-((2-hydroxyphenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

Chemical Structure

[0544] Intermediate 115 6-(Benzo[d][1,3]dioxol-4-ylamino)-4-chloro-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

Chemical Structure

[0545] Intermediate 116 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-fluoro-3-methylphenyl)amino)picolylamide

Chemical Structure

[0546] Intermediate 117 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-hydroxy-3-methylphenyl)amino)picolylamide

Chemical Structure

[0547] Intermediate 118 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-fluorophenyl)amino)picolylamide

Chemical Structure

[0548] Intermediate 119 4-Chloro-6-((2-methoxyphenyl)amino)-N-phenylpicolinamide

Chemical Structure

[0549] Intermediate 120 6-(Benzo[d][1,3]dioxol-4-ylamino)-4-chloro-N-phenylpicolinamide

Chemical Structure

[0550] Intermediate 121 (6-(Benzo[d][1,3]dioxol-4-ylamino)-4-chloropyridin-2-yl)(isoindolin-2-yl)methanone

Chemical Structure

[0551] Intermediate 122 (4-Chloro-6-((2-methoxyphenyl)amino)pyridin-2-yl)(isoindolin-2-yl)methanone

Chemical formula

[0552] Intermediate 123 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(m-tolylamino)picolylamide

Chemical formula

[0553] Intermediate 124 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((4-fluorophenyl)amino)picolylamide

Chemical formula

[0554] Intermediate 125 4-Chloro-6-((2-cyanophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolylamide [Chemical formula] Synthesized according to the general procedure D-3, step 2, method 2. Yield: (0.405 g, using the crude product). ES-MS [M+H] + : 389.1, Rt = 6.895 min (method - A1).

[0555] Intermediate 126 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-methoxyphenyl)amino)picolylamide [Chemical formula] Synthesized according to the general procedure D-3, step 2, method 2. Yield: (0.274 g, using the crude product). ES-MS [M+H] + : 394.0, Rt = 7.222 min (method - A1).

[0556] Intermediate 127 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)picolylamide [Chemical formula] Synthesized according to the general procedure D-3, step 2, method 1. Isolated as a beige solid. Yield: (0.285 g, 74%). ES-MS [M+H] + : 395.0, Rt = 7.538 min (method - A1).

[0557] Intermediate 128 (4-Chloro-6-((2-methoxyphenyl)amino)pyridin-2-yl)(isoindolin-2-yl)methanone [Chemical formula] Synthesized according to the general procedure D-3, step 1, method 2. Yield: (0.240 g, using the crude product). ES-MS [M+H] + : 380.1, Rt = 7.149 min (method - A1).

[0558] Intermediate 129 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(m-tolylamino)picolinamide

Chemical formula

[0559] Intermediate 130 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((4-fluorophenyl)amino)picolinamide

Chemical formula

[0560] Intermediate 131 4-Chloro-6-((2-cyanophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

Chemical formula

[0561] Intermediate 132 4 - Chloro - N - (2,3 - dihydro - 1H - inden - 2 - yl) - 6 - ((3 - methoxyphenyl)amino)picolinamide

Chemical formula

[0562] Intermediate 133 (4 - Chloro - 6 - ((3 - fluorophenyl)amino)pyridin - 2 - yl)(4 - phenylpiperazin - 1 - yl)methanone

Chemical formula

[0563] Intermediate 134 4 - Chloro - N - (2,3 - dihydro - 1H - inden - 2 - yl) - 6 - ((2 - methoxyphenyl)amino) - N - methyl - picolinamide

Chemical formula

[0564] Intermediate 135 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-fluorophenyl)amino)-N-methylpicolinamide

Chemical formula

[0565] Intermediate 136 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-fluoro-2-methylphenyl)amino)picolinamide

Chemical formula

[0566] Intermediate 137 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-methoxyphenyl)amino)picolinamide

Chemical formula

[0567] Intermediate 138 4-Chloro-6-((2-cyanophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

Chem.

[0568] Intermediate 139 4-Chloro-6-((3,5-difluorophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

Chem.

[0569] Intermediate 140 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((4-fluorophenyl)amino)picolinamide

Chem.

[0570] Intermediate 141 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(m-tolylamino)picolinamide

Chem.

[0571] Intermediate 142 4-Chloro-6-((2-hydroxyphenyl)amino)-N-methyl-N-phenylpicolinamide

Chemical Structure

[0572] Intermediate 143 4-Chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((2-fluorophenyl)amino)picolinamide

Chemical Structure

[0573] Intermediate 144 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-hydroxyphenyl)amino)picolinamide

Chemical Structure

[0574] Intermediate 145 4-Chloro-6-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide

Chemical Structure

[0575] Intermediate 146 4-Chloro-6-((2-fluorophenyl)amino)-N-methyl-N-phenylpicolinamide

Chemical Structure

[0576] Intermediate 147 4-Chloro-6-((3-fluorophenyl)amino)-N-methyl-N-phenylpicolinamide

Chemical Structure

[0577] Intermediate 148 (4-chloro-6-((3-fluorophenyl)amino)pyridin-2-yl)(isoindolin-2-yl)methanone

Chem.

[0578] Intermediate 149 4-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-hydroxyphenyl)amino)-N-methyl-picolinamide

Chem.

[0579] Intermediate 150 4-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-fluorophenyl)amino)-N-methylpicolinamide

Chem.

[0580] Intermediate 151 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)picolylamide

Chemical formula

[0581] Intermediate 152 4-Chloro-6-((3-fluorophenyl)amino)-N-phenylpicolylamide

Chemical formula

[0582] Intermediate 153 4-Chloro-6-((3-methoxyphenyl)amino)-N-phenylpicolylamide

Chemical formula

[0583] Intermediate 154 4-Chloro-6-((3-fluorophenyl)amino)-N-(m-tolyl)picolylamide

Chemical formula

[0584] Intermediate 155 4-Chloro-N-(3,4-dimethylphenyl)-6-((3-fluorophenyl)amino)picolylamide

Chemical formula

[0585] Intermediate 156 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-fluorophenyl)amino)picolylamide

Chemical formula

[0586] General procedure E

Chemical formula

[0587] XPhos (5 - 10 mol%) and Pd 2 (dba) 3(3 - 6 mol%) was added to a degassed solution of the appropriate carboxamide (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxamide) (1.0 eq), tert-butyl carbamate (3.0 eq) and Cs 2 CO 3 (3.0 eq) in dioxane (4.0 mL / mmol). The resulting mixture was stirred at 100 °C for 18 h under a nitrogen atmosphere. The mixture was then diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over MgSO 4 4, filtered and concentrated. The resulting crude product was purified by flash column chromatography (50 to 100% EtOAc / hexane) to afford the desired product (e.g., tert-butyl (6-((2-methoxyphenyl)amino)-2-(4-phenylpiperazine-1-carbonyl)pyrimidin-4-yl)carbamate).

[0588] Intermediate 157 Tert-butyl (6-((2-methoxyphenyl)amino)-2-(4-phenylpiperazine-1-carbonyl)pyrimidin-4-yl)carbamate

Chemical Structure

[0589] Intermediate 158 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-methoxyphenyl)amino)-pyrimidin-4-yl)carbamate

Chemical Structure

[0590] Intermediate 159 Tert-butyl (6-((2-methoxyphenyl)amino)-2-(phenylcarbamoyl)pyrimidin-4-yl)carbamate

Chemical Structure

[0591] Intermediate 160 Tert-butyl (4-((2-methoxyphenyl)amino)-6-(4-phenylpiperazine-1-carbonyl)pyridin-2-yl)carbamate

Chemical Structure

[0592] Intermediate 161 Tert-butyl (4-((2-fluorophenyl)amino)-6-(4-phenylpiperazine-1-carbonyl)pyridin-2-yl)carbamate

Chemical Structure

[0593] Intermediate 162 tert-Butyl (6-(isoindoline-2-carbonyl)-4-((2-methoxyphenyl)amino)pyridin-2-yl)carbamate

Chem.

[0594] Intermediate 163 tert-Butyl (6-(indoline-1-carbonyl)-4-((2-methoxyphenyl)amino)pyridin-2-yl)carbamate

Chem.

[0595] Intermediate 164 tert-Butyl (4-((2-methoxyphenyl)amino)-6-(phenylcarbamoyl)pyridin-2-yl)carbamate and tert-butyl (2-((2-methoxyphenyl)amino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

Chem.

[0596] Intermediate 165 Tert-butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((2-methoxyphenyl)amino)pyridin-2-yl)carbamate

Chem.

[0597] Intermediate 166 Tert-butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((2-fluorophenyl)amino)pyridin-2-yl)carbamate and tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-fluorophenyl)amino)pyridin-4-yl)carbamate

Chem.

[0598] Intermediate 167 Tert-butyl (4-((2-chlorophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-2-yl)carbamate

Chem.

[0599] Intermediate 168 Tert-butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((2-methoxy-4-methylphenyl)-amino)pyridin-2-yl)carbamate

Chemical formula

[0600] Intermediate 169 Tert-butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((4-fluoro-2-methoxyphenyl)-amino)pyridin-2-yl)carbamate

Chemical formula

[0601] Intermediate 170 Tert-butyl (4-(benzo[d][1,3]dioxol-4-ylamino)-6-(phenylcarbamoyl)pyridin-2-yl)carbamate

Chemical formula

[0602] Intermediate 171 Tert-butyl (4-((2-fluorophenyl)amino)-6-(phenylcarbamoyl)pyridin-2-yl)carbamate

Chem.

[0603] Intermediate 172 Tert-butyl (2-((2-fluorophenyl)amino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

Chem.

[0604] Intermediate 173 Tert-butyl (4-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-methoxyphenyl)amino)-pyrimidin-2-yl)carbamate

Chem.

[0605] Intermediate 174 Tert-butyl (4-((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((2-methoxyphenyl)-amino)pyrimidin-2-yl)carbamate [Chemical formula] It was synthesized according to the general procedure E. Yield: (0.330 g, 40% yield). ES-MS [M+H] + : 490.1 Rt = 6.267 minutes (Method - A1).

[0606] Intermediate 175 Tert-butyl (4-((2-methoxyphenyl)amino)-6-(methyl(1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)pyrimidin-2-yl)carbamate [Chemical formula] It was synthesized according to the general procedure E. Yield: (0.062 g, 20% yield). ES-MS [M+H] + : 504.1 Rt = 6.377 minutes (Method - A1).

[0607] Intermediate 176 Tert-butyl (4-((2-methoxyphenyl)amino)-6-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)-pyrimidin-2-yl)carbamate [Chemical formula] It was synthesized according to the general procedure E. Yield: (0.301 g, 53% yield). ES-MS [M+H] + : 490.2 Rt = 7.289 minutes (Method - A1).

[0608] Intermediate 177 Tert-butyl (4-((2-methoxyphenyl)amino)-6-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-pyrimidin-2-yl)carbamate [Chemical formula] Synthesized according to the general procedure E. Yield: (0.343 g, 45% yield). ES-MS [M+H] + : 476.2 Rt = 6.987 minutes (Method - A1).

[0609] Intermediate 178 Tert-butyl (4-(isoindoline-2-carbonyl)-6-((2-methoxyphenyl)amino)pyrimidin-2-yl)carbamate

Chemical formula

[0610] Intermediate 179 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-(o-tolylamino)pyridin-4-yl)carbamate

Chemical formula

[0611] Intermediate 180 Tert-butyl (2-((2-hydroxyphenyl)amino)-6-(4-phenylpiperazine-1-carbonyl)pyridin-4-yl)carbamate

Chemical formula

[0612] Intermediate 181 Tert - butyl (2 - (benzo[d][1,3]dioxol - 4 - ylamino) - 6 - ((2,3 - dihydro - 1H - inden - 2 - yl)carbamoyl) - pyridin - 4 - yl)carbamate

Chem.

[0613] Intermediate 182 Tert - butyl (2 - ((2,3 - dihydro - 1H - inden - 2 - yl)carbamoyl) - 6 - ((2 - fluoro - 3 - methylphenyl) - amino)pyridin - 4 - yl)carbamate

Chem.

[0614] Intermediate 183 Tert - butyl (2 - ((2,3 - dihydro - 1H - inden - 2 - yl)carbamoyl) - 6 - ((2 - hydroxy - 3 - methylphenyl) - amino)pyridin - 4 - yl)carbamate

Chem.

[0615] Intermediate 184 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-fluorophenyl)amino)pyridin-4-yl)carbamate

Chem.

[0616] Intermediate 185 Tert-butyl (2-((2-methoxyphenyl)amino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

Chem.

[0617] Intermediate 186 Tert-butyl (2-(benzo[d][1,3]dioxol-4-ylamino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

Chem.

[0618] Intermediate 187 Tert-butyl (2-(benzo[d][1,3]dioxol-4-ylamino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate

Chem.

[0619] Intermediate 188 Tert-butyl (2-(isoindoline-2-carbonyl)-6-((2-methoxyphenyl)amino)pyridin-4-yl)carbamate

Chem.

[0620] Intermediate 189 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-(m-tolylamino)pyridin-4-yl)carbamate

Chem.

[0621] Intermediate 190 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((4-fluorophenyl)amino)pyridin-4-yl)carbamate [Chemistry] It was synthesized according to the general procedure E. Yield: (0.314 g, 97%, over 2 steps). ES-MS [M+H] + : 463.2, Rt = 7.360 min (Method - A1).

[0622] Intermediate 191 Tert-butyl (2-((2-cyanophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate [Chemistry] It was synthesized according to the general procedure E. Yield: (0.059 g, 12%, over 2 steps). ES-MS [M+H] + : 470.2, Rt = 7.103 min (Method - A1).

[0623] Intermediate 192 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-methoxyphenyl)amino)pyridin-4-yl)carbamate [Chemistry] It was synthesized according to the general procedure E. Yield: (0.183 g, 55%, over 2 steps). ES-MS [M+H] + : 475.3, Rt = 7.333 min (Method - A1).

[0624] General procedure F [Chemistry]

[0625] Dppf (6 mol%) and Pd(OAc) 2(3 mol%) was added to a degassed solution of the appropriate aryl dichloride compound (e.g., 4,6-dichloropicolinamide) (1.0 eq), the appropriate arylamine (e.g., 2-chloroaniline) (1.0 eq) and K 3 PO 4 (2.0 eq) in dioxane (5 mL / mmol). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. Subsequently, tert-butyl carbamate (3 eq) was added together with an additional amount of dppf (6 mol%) and Pd(OAc) 2 (2 mol%). The mixture was stirred at 90 °C for 18 h. The mixture was then diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over MgSO 4 , filtered and concentrated. The resulting crude product was purified by flash column chromatography (hexane:EtOAc, 60:40) to give the desired product (e.g., tert-butyl (2-((2-chlorophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate).

[0626] Intermediate 193 Tert-butyl (2-((2-chlorophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate

Chemical Structure

[0627] Intermediate 194 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-(pyridin-3-ylamino)pyridin-4-yl)carbamate

Chemical Structure

[0628] Intermediate 195 Tert-butyl (4-((2-hydroxy-4-methylphenyl)amino)-6-(phenylcarbamoyl)pyridin-2-yl)carbamate

Chemical Structure

[0629] Intermediate 196 Tert-butyl (4-((4-fluoro-2-hydroxyphenyl)amino)-6-(phenylcarbamoyl)pyridin-2-yl)carbamate

Chemical Structure

[0630] Intermediate 197 Tert-butyl (6-(phenylcarbamoyl)-4-(pyridin-2-ylamino)pyridin-2-yl)carbamate

Chemical Structure

[0631] Intermediate 198 Tert - butyl (6 - (phenylcarbamoyl) - 4 - (pyridin - 3 - ylamino)pyridin - 2 - yl)carbamate

Chemical formula

[0632] Intermediate 199 Tert - butyl (2 - ((2,3 - dihydro - 1H - inden - 2 - yl)carbamoyl) - 6 - (m - tolylamino)pyridin - 4 - yl)carbamate

Chemical formula

[0633] Intermediate 200 Tert - butyl (2 - ((2,3 - dihydro - 1H - inden - 2 - yl)carbamoyl) - 6 - ((4 - fluorophenyl)amino)pyridin - 4 - yl)carbamate

Chemical formula

[0634] Intermediate 201 Tert-butyl (2-((2-cyanophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate [Chemical formula] Synthesized according to general procedure F. Yield: (0.059 g, 12%, over 2 steps). ES-MS [M+H] + : 470.2, Rt = 7.103 min (method - A1).

[0635] Intermediate 202 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-methoxyphenyl)amino)pyridin-4-yl)carbamate [Chemical formula] Synthesized according to general procedure F. Yield: (0.183 g, 55%, over 2 steps). ES-MS [M+H] + : 475.3, Rt = 7.333 min (method - A1).

[0636] Intermediate 203 Tert-butyl (2-(isoindoline-2-carbonyl)-6-((2-methoxyphenyl)amino)pyridin-4-yl)carbamate [Chemical formula] Synthesized according to general procedure F. Yield: (0.239 g, 82%, over 2 steps). ES-MS [M+H] + : 461.2, Rt = 7.309 min (method - A1).

[0637] Intermediate 204 Tert-butyl (2-((3-fluorophenyl)amino)-6-(4-phenylpiperazine-1-carbonyl)pyridin-4-yl)carbamate

Chem.

[0638] Intermediate 205 Tert-butyl (2-(((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((2-methoxyphenyl)amino)pyridin-4-yl)carbamate

Chem.

[0639] Intermediate 206 Tert-butyl (2-(((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((3-fluorophenyl)amino)pyridin-4-yl)carbamate

Chem.

[0640] Intermediate 207 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-fluoro-2-methylphenyl)amino)pyridin-4-yl)carbamate

Chem.

[0641] Intermediate 208 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-methoxyphenyl)amino)pyridin-4-yl)carbamate

Chem.

[0642] Intermediate 209 Tert-butyl (2-((2-cyanophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate

Chem.

[0643] Intermediate 210 Tert-butyl (2-((3,5-difluorophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate

Chem.

[0644] Intermediate 211 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((4-fluorophenyl)amino)pyridin-4-yl)carbamate

Chem.

[0645] Intermediate 212 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-(m-tolylamino)pyridin-4-yl)carbamate

Chem.

[0646] Intermediate 213 Tert-butyl (2-((2-hydroxyphenyl)amino)-6-(methyl(phenyl)carbamoyl)pyridin-4-yl)carbamate

Chem.

[0647] Intermediate 214 Tert-butyl (2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamoyl)-6-((2-fluorophenyl)amino)-pyridin-4-yl)carbamate

Chem.

[0648] Intermediate 215 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-hydroxyphenyl)amino)pyridin-4-yl)carbamate

Chem.

[0649] Intermediate 216 Tert-butyl (2-((2-methoxyphenyl)amino)-6-(methyl(phenyl)carbamoyl)pyridin-4-yl)carbamate [Chemical formula] Synthesized according to general procedure F. Yield: (0.310 g, 97%, over 2 steps). ES-MS [M-H]-: 447.5, Rt = 6.931 min (Method-A1).

[0650] Intermediate 217 Tert-butyl (2-((2-fluorophenyl)amino)-6-(methyl(phenyl)carbamoyl)pyridin-4-yl)carbamate [Chemical formula] Synthesized according to general procedure F. Yield: (0.240 g, 77%, over 2 steps). ES-MS [M-H]-: 435.4, Rt = 6.863 min (Method-A1).

[0651] Intermediate 218 Tert-butyl (2-((3-fluorophenyl)amino)-6-(methyl(phenyl)carbamoyl)pyridin-4-yl)carbamate [Chemical formula] Synthesized according to general procedure F. Yield: (0.304 g, 98%, over 2 steps). ES-MS [M+H]+-: 437.2, Rt = 6.917 min (Method-A1).

[0652] Intermediate 219 Tert-butyl (2-((3-fluorophenyl)amino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate [Chemical formula] Synthesized according to the general procedure F. Yield: (0.132 g, 22%, over 2 steps). ES-MS [M+H]+-: 449.2, Rt = 7.249 min (Method - A1).

[0653] Intermediate 220 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((2-hydroxyphenyl)amino)-pyridin-4-yl)carbamate

Chemical formula

[0654] Intermediate 221 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((2-fluorophenyl)amino)-pyridin-4-yl)carbamate

Chemical formula

[0655] Intermediate 222 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-methoxyphenyl)amino)pyridin-4-yl)carbamate

Chemical formula

[0656] Intermediate 223 Tert-butyl (2-((3-fluorophenyl)amino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

Chemical Structure

[0657] Intermediate 224 Tert-butyl (2-((3-methoxyphenyl)amino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

Chemical Structure

[0658] Intermediate 225 Tert-butyl (2-((3-fluorophenyl)amino)-6-(m-tolylcarbamoyl)pyridin-4-yl)carbamate

Chemical Structure

[0659] Intermediate 226 Tert-butyl (2-((3,4-dimethylphenyl)carbamoyl)-6-((3-fluorophenyl)amino)pyridin-4-yl)carbamate

Chem.

[0660] Intermediate 227 Tert-butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-fluorophenyl)amino)pyridin-4-yl)carbamate

Chem.

[0661] General Procedure G

Chem.

[0662] To a stirred solution of 2-amino-6-chloroisonicotinic acid (1.0 eq), appropriate amine (e.g., phenylaniline) (1.0 eq) and HATU (0.7 eq) in DMF (8 mL / mmol), DIPEA (1.3 eq) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The obtained crude product was purified by flash column chromatography (EtOAc / heptane, 50~100) to give the desired product (e.g., 2-amino-6-chloro-N-phenylisonicotinamide).

[0663] Intermediate 228 2-Amino-6-chloro-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)isonicotinamide

Chemical Structure

[0664] Intermediate 229 2-Amino-6-chloro-N-methyl-N-phenylisonicotinamide

Chemical Structure

[0665] Intermediate 230 2-Amino-6-chloro-N-(2,3-dihydro-1H-inden-2-yl)-N-methylisonicotinamide

Chemical Structure

[0666] Intermediate 231 2-Amino-6-chloro-N-(1,2,3,4-tetrahydronaphthalen-2-yl)isonicotinamide

Chemical Structure

[0667] Intermediate 232 2-Amino-6-chloro-N-phenylisonicotinamide

Chemical Structure

[0668] Intermediate 233 2-Amino-6-chloro-N-(2,3-dihydro-1H-inden-2-yl)isonicotinamide

Chemical Structure

[0669] General procedure H

Chemical Structure

[0670] To a stirred solution of the appropriate 4,6-dichloropicolinamide (e.g., (4,6-dichloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone) (1.0 eq) in dry DMF (5 mL / mmol) at 0 °C, NaN 3 (3.0 eq) was added. The mixture was stirred at 90 °C for 16 h. Then, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with brine and MgSO 4It was dried, filtered, and concentrated. The crude residue was dissolved in MeOH (25 mL), and then NaBH 4 (2 eq) was added at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. Then the solvent was evaporated, the residue was diluted with water, and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO 4 , filtered, and concentrated. The obtained crude product was purified by flash column chromatography (hexane:EtOAc, 80:20 to 0:100) to give the desired product (e.g., (4-amino-6-chloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone).

[0671] Intermediate 234 (4-amino-6-chloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

Chemical formula

[0672] Intermediate 235 (4-amino-6-chloropyridin-2-yl)(isoindolin-2-yl)methanone

Chemical formula

[0673] General Procedure I

Chemical formula

[0674] BINAP (10 mol%) and Pd 2 (dba) 3 (6 mol%) were added to a degassed solution of the appropriate 2 - amino - 6 - chloroisonicotinamide (e.g., 2 - amino - 6 - chloro - N - methyl - N-(1,2,3,4 - tetrahydronaphthalen - 2 - yl)isonicotinamide) (1.0 eq), the appropriate aniline (e.g., 2 - aminophenol) (1.1 eq), and Cs 2 CO 3 (2.8 eq) in dioxane (6 mL / mmol). The resulting mixture was stirred at 100 °C for 20 h. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude product was purified by flash column chromatography (10 - 20% EtOAc / hexane) to give the desired product (e.g., 2 - amino - 6 - ((2 - hydroxyphenyl)amino)-N - methyl - N-(1,2,3,4 - tetrahydronaphthalen - 2 - yl)isonicotinamide). Method 2

[0675] XantPhos (10 mol%) and Pd(OAc) 2 (5 mol%) were added to a degassed solution of the corresponding 4 - amino - 6 - chloropicolinamide (e.g., (4 - amino - 6 - chloropyridin - 2 - yl)(4 - phenylpiperazin - 1 - yl)methanone) (1.0 eq), the corresponding amine (e.g., 2 - fluoroaniline) (1.1 eq), and Cs 2 CO 3 (2.5 eq) in dioxane (5 mL / mmol). The mixture was stirred at 100 °C for 18 h. Then the solvent was evaporated under vacuum and the resulting crude residue was purified by silica gel column chromatography (eluent DCM:MeOH, 100:0 to 0:100) to give the desired product (e.g., (4 - amino - 6 - ((2 - fluorophenyl)amino)pyridin - 2 - yl)(4 - phenylpiperazin - 1 - yl)methanone).

[0676] (Example 42) 2-Amino-6-((2-hydroxyphenyl)amino)-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)isonicotinamide

Chemical Structure

[0677] (Example 43) 2-Amino-6-((2-hydroxyphenyl)amino)-N-methyl-N-phenylisonicotinamide

Chemical Structure

[0678] (Example 44) 2-Amino-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-hydroxyphenyl)amino)-N-methyl-isonicotinamide [Chemical formula] Synthesized according to General Procedure I, Method 1. This compound was purified by semi-preparative HPLC (Method - E1). Yield: (0.101 g, 28%). ES-MS [M+H]+: 375.1, Rt = 17.825 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 8.06 (s, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.41 - 7.07 (m, 9H), 6.89 - 6.79 (m, 4H), 6.74 (ddd, J = 8.5, 5.6, 3.2 Hz, 2H), 6.13 - 5.88 (m, 7H), 5.75 (d, J = 2.5 Hz, 2H), 5.34 (s, 1H), 4.65 (d, J = 8.9 Hz, 2H), 3.04 (d, J = 7.8 Hz, 7H), 2.78 (s, 4H), 2.72 (d, J = 5.6 Hz, 2H).

[0679] (Example 45) 2-Amino-6-((2-hydroxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)isonicotinamide

Chem.

[0680] (Example 46) 2-Amino-6-((2-hydroxyphenyl)amino)-N-phenylisonicotinamide

Chem.

[0681] (Example 47) 2 - Amino - N - (2,3 - dihydro - 1H - inden - 2 - yl) - 6 - ((2 - hydroxyphenyl)amino)isonicotinamide

Chemical formula

[0682] (Example 48) (4-Amino-6-((2-fluorophenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone [Chemical Structure] Synthesized according to General Procedure I, Method 2. Yield: (0.008 g, 2%). ES-MS [M-H]⁻: 390.3, Rt = 19.100 min (Method - B1). 1 ¹H NMR (400 MHz, DMSO-d 6 ) δ 8.28 (d, J = 1.6 Hz, 1H), 7.91 (td, J = 8.3, 1.7 Hz, 1H), 7.36 - 7.11 (m, 3H), 7.07 (td, J = 7.7, 1.5 Hz, 1H), 7.02 - 6.87 (m, 3H), 6.81 (t, J = 7.3 Hz, 1H), 6.24 (d, J = 1.8 Hz, 1H), 6.05 (d, J = 1.8 Hz, 1H), 6.00 (s, 2H), 3.67 (dt, J = 24.1, 5.1 Hz, 4H), 3.11 (dt, J = 40.0, 5.2 Hz, 4H).

[0683] General procedure J-1

Chem.

[0684] To a stirred solution of (4-amino-6-chloropyridin-2-yl)(isoindolin-2-yl)methanone (0.925 g, 3.4 mmol, 1.0 eq) in dioxane (26 mL) were added di-tert-butyl dicarbonate (2.21 g, 10.1 mmol, 3.0 eq), DMAP (0.40 g, 3.3 mmol, 1.0 eq) and triethylamine (1.50 mL, 10.8 mmol, 3.2 eq). The resulting mixture was stirred at 100 °C for 16 h. The mixture was then cooled to room temperature and diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over MgSO 4 and filtered, and concentrated. The resulting crude product was purified by flash column chromatography (hexane:EtOAc 60:40) to give the desired product tert-butyl (2-chloro-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate. Method 2

[0685] Dppf (6 mol%) and Pd(OAc) 2 (2 mol%) were added to the corresponding 4,6-dichloropicolinamide (e.g., (4,6-dichloropyridin-2-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone) (1.0 eq), tert-butyl carbamate (3.0 eq) and K 2 CO 3It was added to the degassed solution of (2.0 eq). The resulting mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere. Subsequently, the mixture was diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The obtained crude product was purified by flash column chromatography (hexane:EtOAc 60:40) to give the desired product (e.g., tert-butyl (4-chloro-6-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyridin-2-yl)carbamate).

[0686] Intermediate 236 Tert-butyl (2-chloro-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate [Chemical formula] It was synthesized according to General Procedure J-1, Method 1. Yield: (0.900 g, 71%). ES-MS [M+H] + : 374.9, Rt = 3.17 min (Method-D1).

[0687] Intermediate 237 Tert-butyl (4-chloro-6-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyridin-2-yl)carbamate [Chemical formula] It was synthesized according to General Procedure J-1, Method 2. Yield: (0.50 g, 75%). ES-MS [M+H] + : 388.1, Rt = 7.21 min (Method-A1).

[0688] Intermediate 238 Tert-butyl (4-chloro-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-2-yl)carbamate [Chemical] It was synthesized according to the general procedure J-1, Method 2. Yield: (0.370 g, 97%). ES-MS [M+H] + : 388.1, Rt = 7.41 min (Method - A1).

[0689] General procedure J-2 [Chemical] Method 1

[0690] Dppf (6 mol%) and Pd(OAc) 2 (2 mol%) were added to a degassed solution of the appropriate aryl chloride (e.g., tert-butyl (2-chloro-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate) (1.0 eq), the appropriate aniline (e.g., 2-aminophenol) (3.0 eq), and K 3 PO 4 (2.0 eq) in dioxane (6.4 mL / mmol). The resulting mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere. The mixture was then diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over MgSO 4 and filtered, and concentrated. The resulting crude product was purified by flash column chromatography (hexane:EtOAc 60:40) to give the desired product (e.g., tert-butyl (2-((2-hydroxyphenyl)amino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate). Method 2

[0691] XPhos (5 mol%) and Pd 2 (dba) 3(3 mol%) was added to a degassed solution of the corresponding (e.g., tert-butyl (4-chloro-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-2-yl)carbamate) (1.0 eq), the appropriate aniline (e.g., 3-methoxyaniline) (3.0 eq), and Cs 2 CO 3 (3.0 eq) in dioxane (3 mL / mmol). The resulting mixture was stirred at 100 °C for 18 h under a nitrogen atmosphere. The mixture was then diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over MgSO 4 , filtered, and concentrated. The resulting crude product was purified by flash column chromatography (hexane:EtOAc 60:40) to afford the desired product (e.g., tert-butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((3-methoxyphenyl)amino)pyridin-2-yl)carbamate).

[0692] Intermediate 239 Tert-butyl (2-((2-fluorophenyl)amino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate [Chemical Structure] Synthesized according to General Procedure J-2, Method 1. Yield: (0.110 g, 20%). ES-MS [M+H] + : 449.9, Rt = 7.214 min (Method-A1).

[0693] Intermediate 240 Tert-butyl (2-((2-hydroxyphenyl)amino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate [Chemical Structure] Synthesized according to General Procedure J-2, Method 1. Yield: (0.250 g, 47%). ES-MS [M+H] + : 447.2, Rt = 6.951 min (Method - A1).

[0694] (Example 49) (6-Amino-4-((2-hydroxyphenyl)amino)pyridin-2-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone [Chemical Structure] Synthesized according to the general procedure J-2, Method 2. This compound was isolated directly after Step 3 and purified by semi-preparative HPLC (Method - E1). Yield: (0.130 g, 71%). ES-MS [M - H]-: 361.2, Rt = 16.433 min (Method - B1). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.49 (d, J = 4.8 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.37 - 7.10 (m, 4H), 7.05 (d, J = 6.9 Hz, 1H), 7.02 - 6.85 (m, 2H), 6.79 (ddt, J = 11.4, 5.9, 2.9 Hz, 1H), 6.19 (dd, J = 12.4, 1.9 Hz, 1H), 5.86 (dd, J = 5.9, 1.9 Hz, 1H), 5.65 (d, J = 4.8 Hz, 2H), 4.67 (d, J = 18.8 Hz, 2H), 3.77 (t, J = 5.9 Hz, 1H), 3.65 (t, J = 5.8 Hz, 1H), 2.84 (q, J = 6.6, 6.2 Hz, 2H).

[0695] Intermediate 241 Tert-butyl (4-(benzo[d][1,3]dioxol-4-ylamino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-pyridin-2-yl)carbamate [Chemical formula] Synthesized according to the general procedure J-2, method 2. Yield: (0.240 g, 50%). ES-MS [M+H] + : 489.1, Rt = 7.24 min (method - A1).

[0696] Intermediate 242 Tert-butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((3-methoxyphenyl)amino)pyridin-2-yl)carbamate [Chemical formula] Synthesized according to the general procedure J-2, method 2. Yield: (0.130 g, 42%). ES-MS [M+H] + : 475.3, Rt = 7.259 min (method - A1).

[0697] General procedure K [Chemical formula] Step 1

[0698] BINAP (10 mol%) and Pd 2 (dba) 2 (5 mol%) were added to a degassed solution of the appropriate aryl chloride (e.g., 6-chloro-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide) (1.0 eq), diphenylmethanimine (1.2 eq) and NaOtBu (1.4 eq) in toluene (29 mL / mmol). The resulting mixture was stirred under reflux for 18 h. The mixture was then diluted with EtOAc and filtered through a Celite / SiO 2 pad...

Claims

1. A compound of formula (IA): 【Chemical 451】 or a pharmaceutically acceptable salt or solvate thereof (wherein, A １ , A ２ and A ３ are each independently selected from the group consisting of N and CH, provided that A １ , A ２ or A ３ at least one of is N, and A １ , A ２ or A ３ are conditioned that no more than two of them are N R １ａ is selected from the group consisting of -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 optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, hydroxy, -CN, -ORb 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 groups are optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, hydroxy, -CN, -ORb ａ , -SRb ａ , -N(Rb ａ ) ２ , -C １～４ alkyl (optionally substituted with one, two or three halogen atoms), 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 optionally substituted -O-(C ６～１０ aryl); and said -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 The heterocyclyl is optionally fused to a further (second) ring as required, R ２ａ is selected from the group consisting of hydrogen and -C １～４ alkyl, wherein said -C １～４ alkyl is optionally substituted; or R １ａ and R ２ａ together with the nitrogen atom to which they are attached form an optionally substituted 5- to 10-membered heterocyclic ring, said 5- to 10-membered heterocyclic ring optionally containing one, two or three additional heteroatoms selected from the group consisting of N, S or O, and said 5- to 10-membered heterocyclic ring being optionally fused to a phenyl ring, Rb ａ is each, independently, hydrogen, -C １～４ alkyl, -C ３～１０ cycloalkyl or -(5- to 10-membered)-C ２～９ heterocyclyl, and the -C １～４ alkyl, -C ３～１０ cycloalkyl or -(5- to 10-membered)-C ２～９ heterocyclyl group is optionally substituted by one, two or three fluorine atoms, R ３ａ is selected from the group consisting of -C ６～１０ aryl, -(5- to 10-membered)-C １～９ heteroaryl, -C ３～１０ cycloalkyl and -(5- to 10-membered)-C ２～９ heterocyclyl, and said -C ６～１０ aryl, -(5- to 10-membered)-C １～９ heteroaryl, -C ３～１０ cycloalkyl and -(5- to 10-membered)-C ２～９ heterocyclyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, -CN, -ORb ａ , -SRb ａ , -N(Rb ａ ) ２ , -C １～４ alkyl (optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, -CN, -ORb ａ and -N(Rb ａ ) ２ ), 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 are each optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, hydroxy, -CN, -ORb ６～１０ , -SRb, -N(Rb), -Calkyl (optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, -CN, -ORb and -N(Rb)), optionally substituted -Caryl, optionally substituted -(5- to 10-membered)-Cheteroaryl and -(5- to 10-membered)-Cheterocyclyl, and said -Caryl is optionally fused to a 5- or 6-membered heterocyclic ring).

2. A １ is N, and A ２ and A ３ are each CH, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. (i) A ２ is N, and A １ and A ３ are each CH, or (ii) A ３ is N, and A １ and A ２ are each CH, or (iii) A １ and A ２ are both N, and A ３ is CH, or (iv) A １ and A ３ are both N, and A ２ is CH, or (v) A ２ and A ３ are both N, and A １ is CH, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

4. R ３ａ is unsubstituted -C ６～１０ aryl, or substituted by one, two or three substituents independently selected from the group consisting of halogen, hydroxy, -CN, -O(C １～４ alkyl), -S(C １～４ alkyl), -N(C １～４ alkyl) ２ , -NH(C １～４ alkyl) and -C １～４ alkyl (substituted by one, two or three substituents independently selected from the group consisting of halogen, -CN, -O(C １～４ alkyl), -N(C １～４ alkyl) ２ and -NH(C １～４ alkyl) as required), and is substituted by one or two substituents independently selected from the group consisting of -C ６～１０ aryl, or R ３ａ is phenyl substituted by one or two substituents independently selected from the group consisting of F, Cl, Br, I, hydroxy, methyl, methoxy and -CN, or R ３ａ is phenyl substituted by F or hydroxy at the ortho or meta position of the phenyl ring, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.

5. R ３ａ is unsubstituted -C fused to a 5- or 6-membered heterocyclic ring ６～１０ aryl, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.

6. R ３ａ is a non-substituted -(5- to 10-membered)-C ６～９ heteroaryl, or is substituted, optionally, by one, two or three substituents independently selected from the group consisting of halogen, hydroxy, -CN, -O(C １～４ )alkyl, -S(C １～４ )alkyl, -N(C １～４ alkyl), ２ -NH(C １～４ alkyl) and -C １～４ alkyl (substituted by one, two or three substituents independently selected from the group consisting of halogen, -CN, -O(C １～４ )alkyl, -N(C １～４ alkyl) ２ and -NH(C １～４ alkyl)), and is a -(5- to 10-membered)-C ６～９ heteroaryl substituted by one or two substituents independently selected from the group consisting of those described above, a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.

7. R ３ａ is unsubstituted -C ３～１０ cycloalkyl, or is substituted by one, two or three substituents independently selected from the group consisting of halogen, hydroxy, -CN, -O(C １～４ alkyl, -S(C １～４ alkyl, -N(C １～４ alkyl) ２ , -NH(C １～４ alkyl) and -C １～４ alkyl (substituted by one, two or three substituents independently selected from the group consisting of halogen, -CN, -O(C １～４ alkyl, -N(C １～４ alkyl) ２ and -NH(C １～４ alkyl)) and is substituted by one or two substituents independently selected from the group consisting of -C ３～１０ cycloalkyl, the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.

8. R ３ａ is independently selected from the group consisting of halogen, hydroxy, -CN, -ORb ａ , -SRb ａ , -N(Rb ａ ), ２ , -C １～４ alkyl (optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, -CN, -ORb ａ and -N(Rb ａ ), ２ 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 with one, two or three substituents independently selected from the group consisting of -(5- to 10-membered)-C ２～９ heterocyclyl, a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof.

9. R ２ａ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R is H.

10. R ２ａ is -C １～４ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein is alkyl.

11. R １ａ But, -C ６～１０ Aryl or -C １～４ Alkyl-C ６～１０ aryl, ６～１０ Aryl or -C １～４ Alkyl-C ６～１０ Aryl is halogen, hydroxy, -CN, -ORb ａ , -SRb ａ , -N(Rb ａ ) ２ , -C １～４ alkyl (optionally substituted with 1, 2 or 3 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; Rb ａ is as defined in claim 1, and said -C ６～１０ 11. The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt or solvate thereof, wherein the aryl is optionally fused to a further (second) ring.

12. R １ａ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R is unsubstituted phenyl or unsubstituted benzyl.

13. R １ａ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R is phenyl fused to a 5- or 6-membered heterocyclic ring.

14. R １ａ is -C ３～１０ cycloalkyl or -C １～４ alkyl-C ３～１０ cycloalkyl, wherein said -C ３～１０ cycloalkyl or -C １～４ alkyl-C ３～１０ cycloalkyl is optionally substituted by one, two or three substituents independently selected from the group consisting of halogen, hydroxy, -CN, -ORb ａ , -SRb ａ , -N(Rb ａ ) ２ , -C １～４ alkyl (optionally substituted 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 Rb ａ is as defined in claim 1, and wherein said -C ３～１０ cycloalkyl is optionally fused to a further (second) ring, a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof.

15. R １ａ is unsubstituted -C fused to a phenyl ring ３～１０ cycloalkyl, or R １ａ is -C fused to a phenyl ring ４～７ cycloalkyl, the compound according to any one of claims 1 to 10 or 14, or a pharmaceutically acceptable salt or solvate thereof.

16. Rb ａ is hydrogen or -C １～４ alkyl, a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt or solvate thereof.

17. R １ａ and R ２ａ together with the nitrogen atom to which they are attached form a 5- to 10-membered heterocyclic ring which is optionally substituted, said 5- to 10-membered heterocyclic ring optionally containing one, two or three additional heteroatoms selected from the group consisting of N, S or O, said 5- to 10-membered heterocyclic ring optionally being fused to a phenyl ring, or R １ａ and R ２ａ together with the nitrogen atom to which they are attached form a 5- or 6-membered ring which is optionally fused to a phenyl ring, a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof.

18. as follows: 【Chemical 452】 【Chemical 453】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of:

19. as follows: 【Chemical 454】 【Chemical 455】 【Chemical 456】 【Chemical 457】 【Chemical 458】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of:

20. as follows 【Chemical 459】 【Chemical 460】 The compound according to claim 1, selected from the group consisting of:

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

22. A composition for treating or preventing 1) a condition associated with altered activity of β-glucosylceramidase, 2) a lysosomal storage disorder, or 3) an α-synucleinopathy in a patient in need thereof, The composition comprising the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof.

23. A composition for treating or preventing a disease or disorder, The composition comprising the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof.

24. The composition according to claim 22 or 23, wherein the composition is administered in combination with at least one other therapeutic agent.

25. The composition according to claim 24, wherein the therapeutic agent is an enzyme for enzyme replacement therapy.

26. The composition according to claim 25, wherein the enzyme is β-glucosylceramidase or an analog thereof, preferably, the enzyme is imiglucerase.

27. The composition according to claim 25, wherein the therapeutic agent is a small molecule chaperone.

28. The composition according to claim 27, wherein the small molecule chaperone competitively binds to the enzyme, and preferably, the small molecule chaperone is selected from the group consisting of iminoalditol, imino sugar, amino sugar, thiophenyl glycoside, glycosidase, sulfatase, glycosyltransferase, phosphatase and peptidase inhibitor, and more preferably, the small molecule chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol and miglustat.

29. A composition for use as a medicament, comprising the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof.

30. Use of the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating or preventing a disease or disorder selected from the group consisting of Gaucher's disease, Parkinson's disease, Lewy body dementia, diffuse Lewy body disease, multiple system atrophy (MSA), epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis (MS), multiple myeloma, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), corticobasal degeneration, frontotemporal dementia, GBA1 Parkinson's, neurological Gaucher's disease, neuroaxonal dystrophy, neurodegenerative diseases associated with Parkinson's syndrome, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease and normal aging without impairment.

31. The pharmaceutical composition according to claim 21, for use in treating or preventing in a patient 1) a condition associated with an alteration in the activity of β-glucosylceramidase, 2) a lysosomal storage disorder, or 3) an α-synucleinopathy.

32. The pharmaceutical composition according to claim 21 for use in treating or preventing a disease or disorder, wherein the disease or disorder is selected from the group consisting of Gaucher's disease, Parkinson's disease, Lewy body dementia, diffuse Lewy body disease, multiple system atrophy (MSA), epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis (MS), multiple myeloma, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), corticobasal degeneration, frontotemporal dementia, GBA1 Parkinson's, neurological Gaucher's disease, axonal dystrophy, neurodegenerative diseases with Parkinson's syndrome, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and normal aging, preferably, the disease or disorder is Gaucher's disease or Parkinson's disease.

33. The pharmaceutical composition according to claim 31 or 32, characterized in that the pharmaceutical composition is administered in combination with at least one other therapeutic agent.

34. The pharmaceutical composition according to claim 33, wherein the therapeutic agent is an enzyme for enzyme replacement therapy, preferably, the enzyme is β-glucocerebrosidase or an analog thereof, more preferably, the enzyme is imiglucerase.

35. The pharmaceutical composition according to claim 33, wherein the therapeutic agent is a small molecule chaperone, preferably, the small molecule chaperone binds competitively to the enzyme, more preferably, the small molecule chaperone is selected from the group consisting of iminoalditol, iminosugar, amino sugar, thiophenylglycoside, glycosidase, sulfatase, glycosyltransferase, phosphatase, and peptidase inhibitors, more preferably, the small molecule chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin (NN-DNJ), ambroxol, and miglustat.

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