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

Abstract

The present application relates to compounds of formula (IA) and (IB): and their salts and solvates, 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 in the specification, as well as methods for their preparation, pharmaceutical compositions comprising them, and their use for the treatment and / or prevention of, for example, lysosomal storage diseases such as Gaucher's disease and α-synuclein diseases such as Parkinson's disease.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority from European patent application No. EP19383037.9 filed on November 25, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to heteroaryl compounds, particularly pyridyl, pyrimidinyl and triazinyl compounds, novel methods for their preparation, and the use of heteroaryl compounds in treating and / or preventing disorders associated with altered β-glucocerebrosidase activity, such as lysosomal storage diseases and α-synucleinopathies, in patients. The present disclosure also relates to the use of the Heteroaryl Compounds described herein in treating and / or preventing a medical disorder in a patient, such as Gaucher's disease, Parkinson's disease, dementia with Lewy bodies, 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 disease, neurological Gaucher disease, neuroaxonal dystrophy, neurodegenerative diseases associated with Parkinson's disease, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, or intact aging. Background Art

[0004] Gaucher disease is a very rare lysosomal storage disorder thought to be caused by a deficiency of β-glucocerebrosidase. Known β-glucocerebrosidase-related conditions are caused by a gene mutation that results in a deficiency of the enzyme β-glucocerebrosidase.

[0005] β-Glucocerebrosidase cleaves β-glucocerebroside from various substrates, and insufficient activity of the enzyme results in accumulation of substrates (i.e., gangliosides and oligosaccharides with terminal β-linked glucocerebrosides) in patients with diseases associated with β-glucocerebrosidase activity, such as Gaucher's disease. Beutler et al. (Mol Med. 1(1):82-92 (1994)) reported that glucocerebrosidase deficiency results in the accumulation of insoluble glucocerebroside in tissues, leading to the clinical manifestations of Gaucher's disease.

[0006] In many lysosomal diseases, such as Gaucher's disease, mutant enzymes often retain catalytic activity but fold improperly in the endoplasmic reticulum ("ER"). This triggers ER accumulation of the mutant protein, which ultimately tags it for proteasomal degradation via ubiquitination, thereby preventing the enzyme from being transported to the lysosome. See, e.g., Patniak et al., Journal of Medicinal Chemistry 55(12):5734-5748 (2012).

[0007] Gaucher's disease (or Gaucher's) is a heterogeneous disease with three subtypes. Most patients, i.e., those without neurological manifestations of the disease, are classified as type I. In type I, clinical manifestations include enlarged spleen and liver, thrombocytopenia, anemia, and bone disease. Types II and III are neurological forms and are classified based on the severity and onset of neurological disease. Type II is the most severe, with symptoms appearing at or near birth. The median life expectancy of patients with type II is 9 months. Type III develops later. See, e.g., Patniak et al., Journal of Medicinal Chemistry 55(12):5734-5748 (2012). Patients with Gaucher's disease exhibit hematological manifestations such as anemia and thrombocytopenia, as well as hepatosplenomegaly, skeletal deformities, and in some cases, neurological impairment. See, e.g., Boyd et al., Journal of Medicinal Chemistry 56(7):2705–2725 (2013).

[0008] Enzyme replacement therapy ("ERT") and substrate inhibition therapy ("SRT") are two treatments currently used for type I Gaucher disease. ERT involves long-term treatment by injecting a recombinant enzyme (imiglucerase) into the patient. While ERT may be effective in reducing and reversing the clinical symptoms of the disease, it is very costly. SRT is generally indicated for treating adult patients with mild to moderate type I Gaucher disease who are not suitable for ERT. The prescription drug iminoglycoside inhibits glucosylceramide synthase, thereby reducing the production of glucocerebroside in lysosomes. While SRT may be effective for some patients, it has side effects, including weight loss, diarrhea, tremors, and peripheral nerve damage. Both ERT and SRT are ineffective for neurological types II and III of Gaucher disease. See, for example, Patniak et al., Journal of Medicinal Chemistry 55(12):5734-5748 (2012).

[0009] Mutations in the gene encoding glucocerebrosidase are also a risk factor for alpha-synucleinopathies, such as Parkinson's disease and diffuse Lewy body disease. Parkinson's disease is a degenerative disease of the central nervous system associated with the death of dopamine-containing cells in the midbrain. Diffuse Lewy body disease is a form of dementia that is sometimes confused with Alzheimer's disease.

[0010] Small molecules can allosterically or competitively bind to mutant β-glucocerebrosidase, thereby stabilizing the enzyme to prevent degradation (chaperone), constituting an important therapeutic target in diseases associated with altered β-glucocerebrosidase activity. By binding and stabilizing mutant proteins, these chemical chaperones promote protein folding and ultimately increase their transport to lysosomes. The improved transport of mutant proteins from the ER to lysosomes leads to a reduction in lysosomal size and correction of storage. These chaperones can also increase the stability of mutant enzymes to degradation in lysosomes. See, for example, Patniak et al., Journal of Medicinal Chemistry 55(12):5734-5748(2012).

[0011] It has surprisingly been found that compounds of formula (IA) and (IB) are able to bind to β-glucocerebrosidase, thereby stabilizing the enzyme against denaturation. Summary of the Invention

[0012] The present disclosure relates to the discovery that Heteroaryl Compounds represented by Formula (IA) and (IB) are capable of binding to β-glucocerebrosidase (mutated or unmutated) and are therefore useful for treating or preventing, for example, lysosomal storage diseases (such as Gaucher's disease) or α-synucleinopathies (such as Parkinson's disease), or other conditions associated with altered β-glucocerebrosidase activity.

[0013] In one aspect, the present disclosure provides compounds represented by the following formulae (IA) and (IB), and pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as "compounds of the disclosure" (each individually referred to hereinafter as a "compound of the disclosure").

[0014] In another aspect, the present disclosure provides a method for treating or preventing a condition associated with altered β-glucocerebrosidase activity in a patient in need thereof. The method comprises administering to a patient in need thereof an effective amount of a compound of the present disclosure.

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

[0016] In another aspect, the present disclosure provides a method of treating or preventing an α-synucleinopathy, such as Parkinson's disease, in a patient in need thereof by administering an effective amount of a compound of the present disclosure.

[0017] In another aspect, the present disclosure relates to a method of treating or preventing a disease or disorder selected from the group consisting of: Gaucher's disease, Parkinson's disease, dementia with Lewy bodies, 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 disease, neurological Gaucher disease, neuroaxial dystrophy, neurodegenerative diseases with Parkinson's disease, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and intact aging.

[0018] In another aspect, the methods described herein further comprise 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 competitively binds to the enzyme. In another aspect, the small molecule chaperone is selected from the group consisting of iminoalditols, iminosugars, aminosugars, thiophenylglycosides, 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.

[0019] 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.

[0020] In another aspect, the present disclosure provides a compound of the present disclosure as described herein for use in preventing or treating a disorder associated with altered β-glucocerebrosidase activity in a patient in need thereof.

[0021] In another aspect, the present disclosure provides a compound of the present disclosure as described herein for use in preventing or treating a lysosomal storage disease such as Gaucher's disease.

[0022] In another aspect, the present disclosure provides a compound of the present disclosure as described herein for use in preventing or treating an α-synucleinopathy such as Parkinson's disease.

[0023] In another aspect, the present disclosure provides a compound of the present disclosure as described herein for use in preventing or treating a disease or disorder selected from the group consisting of Gaucher's disease, Parkinson's disease, dementia with Lewy bodies, 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 disease, neurological Gaucher's disease, neuroaxonal dystrophy, neurodegenerative diseases associated with Parkinson's disease, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and intact aging.

[0024] In another aspect, the present disclosure also relates to the use of the compounds of the present disclosure as described herein for treating or preventing disorders associated with altered β-glucocerebrosidase activity, such as the lysosomal storage diseases and α-synucleinopathies described herein, in a patient in need thereof.

[0025] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as described herein and at least one pharmaceutically acceptable excipient.

[0026] In another aspect, the present disclosure provides a compound of the present disclosure as described herein for use as a medicament.

[0027] In another aspect, the present disclosure provides the use of a compound of the present disclosure as described herein in the preparation of a medicament for preventing or treating a disorder associated with altered β-glucocerebrosidase activity, such as the lysosomal storage diseases and α-synucleinopathies described herein, in a patient in need thereof.

[0028] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as described herein and at least one pharmaceutically acceptable excipient for use in treating or preventing a condition associated with altered β-glucocerebrosidase activity, such as the lysosomal storage diseases and α-synucleinopathies described herein, in a patient in need thereof.

[0029] Other aspects and advantages of the present disclosure will become apparent from the following detailed description of the present disclosure.The embodiments and advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0030] It should be understood that the foregoing summary of the invention and the following detailed description are exemplary and explanatory only and are not restrictive of the present disclosure, as claimed. DETAILED DESCRIPTION

[0031] One aspect of the present disclosure is based on the use of compounds of the present disclosure for binding to β-glucocerebrosidase. In view of this property, it is expected that the compounds of the present disclosure can be used to treat or prevent, for example, Gaucher's disease and other diseases or conditions described herein.

[0032] Compounds of the present disclosure that can be used in this aspect of the disclosure are compounds of formula (IA) and formula (IB):

[0033]

[0034] and pharmaceutically acceptable salts and solvates thereof, wherein A 1 、A 2 、A 3 、R 1a 、R 2a 、R 3a 、B 1 、B 2 、R 1b 、R 2b and R 3b As defined below.

[0035] In another aspect, the compound of the present disclosure is a compound of formula (IA):

[0036]

[0037] and pharmaceutically acceptable salts and solvates thereof, wherein

[0038] A 1 、A 2 and A 3 Each independently selected from N, CH and C(R 4a ), the prerequisite is that A 1 、A 2 or A 3 At least one of them is N;

[0039] Each R 4a are independently selected from halogen, -C 1-4 Alkyl, -C 1-4 a group consisting of an alkoxy group and -CN;

[0040] R 1a Choose Free-C 1-4 Alkyl, -C 3-10 Cycloalkyl, -C 1-4 Alkyl-C 3-10 Cycloalkyl, -C6-10 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 Heterocyclic group, -C 1-4 Alkyl-(5- to 10-membered)-C 2-9 Heterocyclyl and -C(=O)Ra a The group consisting of, wherein the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a )2, optionally substituted by 1, 2 or 3 halogen atoms -C 1-4 Alkyl, 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 and wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to another (second) ring; and

[0041] R 2a Selected from hydrogen, -C 1-4 Alkyl and C 3-6 The group consisting of cycloalkyl groups, wherein the -C 1-4 The alkyl group is optionally substituted; or

[0042] 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, wherein said heterocyclic ring optionally contains 1, 2 or 3 additional heteroatoms selected from the group consisting of N, S, O, and wherein said heterocyclic ring is optionally fused to a benzene ring;

[0043] Ra a Choose Free-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)-C1-9 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 group consisting of heterocyclyl, wherein the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a )2, optionally substituted by 1, 2 or 3 halogen atoms -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 and wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to another (second) ring;

[0044] Each Rb a are independently hydrogen, -C 1-4 Alkyl, -C 3-10 Cycloalkyl or -(5- to 10-membered)-C 2-9 heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl group is optionally substituted with 1, 2 or 3 fluorine atoms; and

[0045] R 3a Choose Free-C 6-10 Aryl, -(5- to 10-membered)-C 1-9 Heteroaryl, -C 3-10 Cycloalkyl and -(5- to 10-membered)-C 2-9 The group consisting of heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb a and -N(Rb a )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C2-9 and wherein the -C 6-10 The aryl group is optionally fused to a 5- or 6-membered heterocyclic ring.

[0046] In some aspects, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts and solvates thereof, wherein

[0047] A 1 、A 2 and A 3 Each independently selected from N, CH and C(R 4a ), the prerequisite is that A 1 、A 2 or A 3 At least one of them is N;

[0048] Each R 4a are independently selected from halogen, -C 1-4 Alkyl, -C 1-4 a group consisting of an alkoxy group and -CN;

[0049] R 1a Choose Free-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 Heterocyclic group, -C 1-4 Alkyl-(5- to 10-membered)-C 2-9 Heterocyclyl and -C(=O)Ra a The group consisting of, wherein the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a )2, optionally substituted by 1, 2 or 3 halogen atoms -C 1-4 Alkyl, 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 6-10and wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to another (second) ring; and

[0050] R 2a Selected from hydrogen, -C 1-4 Alkyl and C 3-6 The group consisting of cycloalkyl groups, wherein the -C 1-4 The alkyl group is optionally substituted; or

[0051] 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, wherein said heterocyclic ring optionally contains 1, 2 or 3 additional heteroatoms selected from the group consisting of N, S, O, and wherein said heterocyclic ring is optionally fused to a benzene ring;

[0052] Ra a Choose Free-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 The group consisting of heterocyclyl, wherein the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a )2, optionally substituted by 1, 2 or 3 halogen atoms -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 and wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to another (second) ring;

[0053] Each Rb aare independently hydrogen, -C 1-4 Alkyl, -C 3-10 Cycloalkyl or -(5- to 10-membered)-C 2-9 heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl group is optionally substituted with 1, 2 or 3 fluorine atoms; and

[0054] R 3a Choose Free-C 6-10 Aryl, -(5- to 10-membered)-C 1-9 Heteroaryl, -C 3-10 Cycloalkyl and -(5- to 10-membered)-C 2-9 The group consisting of heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb a and -N(Rb a )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the group consisting of heterocyclic groups are substituted.

[0055] In another aspect, 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 One of them is N.

[0056] In another aspect, 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 Two of them are N.

[0057] In another aspect, 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 is N. In some embodiments of this aspect, the compound of formula (IA) is not

[0058] or a pharmaceutically acceptable salt thereof.

[0059] In some aspects, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein A 1 、A 2 and A 3 No more than two of them are N.

[0060] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein A 1 N and A 2 and A 3 Each independently selected from CH and C(R 4a In another embodiment, A 2 and A 3 All are CH.

[0061] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein A 2 N and A 1 and A 3 Each independently selected from CH and C(R 4a In another embodiment, A 1 and A 3 All are CH.

[0062] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein A 3 N and A 1 and A 2 Each independently selected from CH and C(R 4a In another embodiment, A 1 and A 2 All are CH.

[0063] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein A 1 and A 2 Both N and A 3 is CH or C(R 4a In another embodiment, A 3 For CH.

[0064] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein A 1 and A 3 Both N and A 2 is CH or C(R 4a In another embodiment, A 2 For CH.

[0065] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein A 2 and A 3 Both N and A 1 is CH or C(R 4a In another embodiment, A 1 In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 3a is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb a and -N(Rb a )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the heterocyclic group are substituted -C 6-10 In another embodiment, R 3a For unsubstituted -C 6-10 Aryl or 1 or 2 each independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 6-10 On the other hand, R 3a For unsubstituted -C 6-10 In another aspect, R 3a is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4)alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 6-10 On the other hand, R 3a -C 6-10 aryl, and preferably phenyl substituted by 1 or 2 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. On the other hand, R 3a In another aspect, the substituent is connected to the meta position of the phenyl group. In another aspect, the substituent is connected to the ortho position of the phenyl group. In another aspect, the substituent is connected to the para position of the phenyl group.

[0066] In some aspects, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 3a is phenyl substituted by 1 or 2 substituents each independently selected from the group consisting of F, Cl, Br, I, hydroxy, methyl, methoxy and -CN. 3a is a phenyl group substituted with F or hydroxyl at the ortho or meta position of the phenyl group. 3a is a phenyl group substituted with F or hydroxyl at the ortho position of the phenyl group. 3a is a phenyl group substituted by F or hydroxy at the meta position of the phenyl group.

[0067] In some aspects, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 3a is an unsubstituted -C fused to a 5- or 6-membered heterocyclic ring 6-10 In some aspects, R 3a is an unsubstituted phenyl fused to a 5- or 6-membered heterocyclic ring. In some aspects, the 5- or 6-membered heterocyclic ring contains 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O, and the remaining atoms are carbon atoms. In some aspects, the fused heterocyclic ring is a 5-membered ring with 1 or 2 oxygen atoms. In some aspects, the fused heterocyclic ring is a 6-membered ring with 1 or 2 oxygen atoms. In some aspects, R 3a for

[0068]

[0069] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 3a is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb a and -N(Rb a )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 -(5 or 10 membered)-C 1-9 In another aspect, R 3a is unsubstituted -(5 to 10 members)-C 1-9 Heteroaryl or 1 or 2 independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 -(5 to 10 membered)-C 1-9 In another aspect, R 3a is unsubstituted -(5 to 10 members)-C 1-9 In another aspect, R 3a is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 -(5 to 10 membered)-C 1-9In some aspects, -(5- to 10-membered)-C 1-9 Heteroaryl is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

[0070] On the other hand, R 3a is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb a and -N(Rb a )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the heterocyclic group are substituted -C 3-10 On the other hand, R 3a For unsubstituted -C 3-10 Cycloalkyl or 1 or 2 independently selected from 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 optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 3-10 On the other hand, R 3a is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 The substituents of the group consisting of alkyl groups substituted with C 4-6 Cyclohexyl. On the other hand, R 3ais substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 The cyclohexyl group is substituted with the alkyl group as a substituent.

[0071] On the other hand, R 3a is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb a and -N(Rb a )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 -(5- to 10-membered)-C 2-9 Heterocyclic group.

[0072] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 2a H and R 1a As defined above.

[0073] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 2a -C 1-4 Alkyl and R 1a As defined above. In another aspect, R 2a On the other hand, R 2a It is a methyl group.

[0074] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 1a -C 6-10 Aryl or -C 1-4 Alkyl-C 6-10Aryl, wherein the aryl or alkylaryl is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a )2, optionally substituted by 1, 2 or 3 halogen atoms -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the group consisting of heterocyclic groups are substituted, wherein Rb a As defined above, and wherein the aryl group is optionally fused to another (second) ring.

[0075] On the other hand, R 1a For unsubstituted C 6-10 Aryl or 1, 2 or 3 each independently selected from halogen, hydroxyl, -CN, -ORb a 、-SRb a 、-N(Rb a ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb a and -N(Rb a )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the heterocyclic group substituted C 6-10 Aryl, where Rb a As defined above; and wherein the aryl group is optionally fused to another (second) ring. In another aspect, R 1a For unsubstituted -C 6-10 Aryl or 1 or 2 each independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 6-10 On the other hand, R 1a For unsubstituted -C6-10 On the other hand, R 1a is unsubstituted phenyl. On the other hand, R 1a is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 6-10 In some aspects, R 1a is an unsubstituted C fused to a 5- or 6-membered heterocyclic ring 6-10 In some aspects, the 5- or 6-membered heterocyclic ring contains 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O, and the remaining atoms are carbon atoms. In some aspects, the fused heterocyclic ring is a 5-membered ring with 1 or 2 oxygen atoms. In some aspects, the fused heterocyclic ring is a 6-membered ring with 1 or 2 oxygen atoms. In some aspects, R 1a for

[0076]

[0077] On the other hand, R 1a For unsubstituted -C 1-4 Alkyl-C 6-10 Aryl or optionally substituted by 1, 2 or 3 each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb a and -N(Rb a )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the heterocyclic group are substituted -C 1-4 Alkyl-C 6-10 Aryl, where Rb a As defined above; and wherein the aryl group is optionally fused to another (second) ring. In another aspect, R 1a For unsubstituted -C1-4 Alkyl-C 6-10 Aryl or 1 or 2 each independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 1-4 Alkyl-C 6-10 On the other hand, R 1a For unsubstituted -C 1-4 Alkyl-C 6-10 On the other hand, R 1a is unsubstituted benzyl or phenethyl. On the other hand, R 1a is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 1-4 Alkyl-C 6-10 Aryl.

[0078] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 1a -C 3-10 Cycloalkyl or -C 1-4 Alkyl-C 3-10 Cycloalkyl, wherein the cycloalkyl or alkylcycloalkyl is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a )2, optionally substituted by 1, 2 or 3 halogen atoms -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the group consisting of heterocyclic groups are substituted, wherein Rb a As defined above; and wherein the cycloalkyl group is optionally fused to another (second) ring. In another aspect, R 1a is an unsubstituted -C fused to a benzene ring 3-10 On the other hand, R 1a -C fused to a benzene ring 4-7 Cycloalkyl.

[0079] On the other hand, R 1a is an unsubstituted pentyl or hexyl ring fused to a benzene ring.

[0080] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein Rb a is hydrogen or -C 1-4 alkyl.

[0081] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 1a and R 2a Together with the nitrogen atom to which they are attached, they form an optionally substituted 5- to 10-membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1, 2 or 3 additional heteroatoms selected from the group consisting of N, S, O, and wherein said heterocyclic ring is optionally fused to a benzene ring. 1a and R 2a Together with the nitrogen atom, it forms a -C 1-4 Alkyl (such as methyl or ethyl), optionally C 1-4 Alkyl or -O(C 1-4 Alkyl) substituted-C 6-10 Aryl (such as phenyl) or -C(=O)O(C 1-4 alkyl)-substituted piperazinyl ring.

[0082] In another aspect, the compounds of the present disclosure are compounds of formula (IA) and pharmaceutically acceptable salts thereof, wherein R 1a and R 2a Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered ring optionally fused to a benzene ring. 1a and R 2a Together with the nitrogen atom to which they are attached, they form a 5- or 6-membered ring fused to the benzene ring. 1a and R 2a Together with the nitrogen atoms to which they are attached, they form

[0083]

[0084] In another aspect, the present disclosure provides a compound of formula (IA) of the present disclosure selected from the group consisting of

[0085] and pharmaceutically acceptable salts and solvates thereof.

[0086] In another aspect, the present disclosure provides a compound of formula (IA) of the present disclosure selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0087] In another aspect, the present disclosure provides a compound of formula (IA) of the present disclosure selected from the group consisting of

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] and pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt (HCl salt).

[0094] In another aspect, the present disclosure provides a compound of formula (IA) of the present disclosure selected from the group consisting of

[0095]

[0096] In another aspect, the compound of the present disclosure is a compound of formula (IB):

[0097]

[0098] and pharmaceutically acceptable salts and solvates thereof, wherein

[0099] B 1 and B 2 Each independently selected from N, CH and C(R 4b ), the prerequisite is that B 1 or B 2 At least one of them is N;

[0100] Each R4b are independently selected from halogen, -C 1-4 Alkyl, -C 1-4 a group consisting of an alkoxy group and -CN;

[0101] X and Y are independently selected from a free bond (ie, absent), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 a group consisting of alkylene-C(=O);

[0102] R 1b Choose Free-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 Heterocyclic group, -C 1-4 Alkyl-(5- to 10-membered)-C 2-9 Heterocyclyl and -C(=O)Ra b The group consisting of, wherein the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b )2, optionally substituted by 1, 2 or 3 halogen atoms -C 1-4 Alkyl, 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 and wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to another (second) ring; and

[0103] Ra b Choose Free-C 1-4 Alkyl, -C 3-10 Cycloalkyl, -C 1-4 Alkyl-C 3-10 Cycloalkyl, -C 6-10 Aryl, -C 1-4 Alkyl-C6-10 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 group consisting of heterocyclyl, wherein the alkyl, cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b )2, optionally substituted by 1, 2 or 3 halogen atoms -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 and wherein the cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl are optionally fused to another (second) ring;

[0104] Each Rb b are independently hydrogen, -C 1-4 Alkyl, -C 3-10 Cycloalkyl or -(5- to 10-membered)-C 2-9 heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl group is optionally substituted with 1, 2 or 3 fluorine atoms; and

[0105] R 2b and R 3b Each independently selected from 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 The group consisting of heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b ) 2, optionally 1 or 2 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C 1-4Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the group consisting of heterocyclic groups are substituted.

[0106] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein B 1 and B 2 is N.

[0107] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein B 1 N and B 2 Selected from CH and C(R 4b ). On the other hand, B 2 For CH.

[0108] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein B 2 N and B 1 Selected from CH and C(R 4b ). On the other hand, B 1 For CH.

[0109] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 2b is hydrogen or -C 1-4 Alkyl, and R 3b Choose Free-C 6-10 Aryl, -(5- to 10-membered)-C 1-9 Heteroaryl, -C 3-10 Cycloalkyl and -(5- to 10-membered)-C 2-9 The group consisting of heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b ) 2, optionally 1 or 2 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the group consisting of heterocyclic groups are substituted.

[0110] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 3b is hydrogen or -C 1-4 Alkyl, and R 2b Choose Free-C 6-10 Aryl, -(5- to 10-membered)-C 1-9 Heteroaryl, -C 3-10 Cycloalkyl and -(5- to 10-membered)-C 2-9 The group consisting of heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b ) 2, optionally 1 or 2 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the group consisting of heterocyclic groups are substituted.

[0111] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 2b is hydrogen or -C 1-4 Alkyl, and R 3b is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b ) 2, optionally 1 or 2 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the heterocyclic group are substituted -C 6-10 On the other hand, R 3b For unsubstituted -C 6-10 Aryl or 1 or 2 each independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1 or 2 groups independently selected from halogen, -CN, -O(C 1-4 Alkyl), -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 6-10 On the other hand, R 3b For unsubstituted -C 6-10 In another aspect, R 3b is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 Alkyl), -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1 or 2 groups independently selected from halogen, -CN, -O(C 1-4 Alkyl), -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 6-10 On the other hand, R 3b -C 6-10 aryl, and preferably phenyl substituted by 1 or 2 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. On the other hand, R 3b In another aspect, the substituent is connected to the meta position of the phenyl group. In another aspect, the substituent is connected to the ortho position of the phenyl group. In another aspect, the substituent is connected to the para position of the phenyl group.

[0112] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 2b is hydrogen or -C 1-4 Alkyl, and R 3b is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb b 、-SRbb 、-N(Rb b ) 2, optionally 1 or 2 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 -(5- to 10-membered)-C 1-9 In another aspect, R 3b is unsubstituted -(5 to 10 members)-C 1-9 Heteroaryl or 1 or 2 independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1 or 2 groups independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 -(5 to 10 membered)-C 1-9 In another aspect, R 3b is unsubstituted -(5 or 10 member)-C 1-9 In another aspect, R 3b is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1 or 2 groups independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 -(5 or 10 membered)-C 1-9 Heteroaryl.

[0113] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 2b is hydrogen or -C 1-4 Alkyl, and R3b -C 3-10 Cycloalkyl or -(5- to 10-membered)-C 2-9 Heterocyclyl, wherein the cycloalkyl and heterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b ) 2, optionally 1 or 2 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the group consisting of heterocyclic groups are substituted.

[0114] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 3b is hydrogen or -C 1-4 Alkyl, and R 2b is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b ) 2, optionally 1 or 2 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the heterocyclic group are substituted -C 6-10 On the other hand, R 2b For unsubstituted -C 6-10 Aryl or 1 or 2 each independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1 or 2 groups independently selected from halogen, -CN, -O(C 1-4 Alkyl), -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C1-4 Alkyl group consisting of substituents substituted -C 6-10 On the other hand, R 2b For unsubstituted -C 6-10 In another aspect, R 2b is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 Alkyl), -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1 or 2 groups independently selected from halogen, -CN, -O(C 1-4 Alkyl), -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 6-10 On the other hand, R 2b -C 6-10 aryl, and preferably phenyl substituted by 1 or 2 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. On the other hand, R 2b In another aspect, the substituent is connected to the meta position of the phenyl group. In another aspect, the substituent is connected to the ortho position of the phenyl group. In another aspect, the substituent is connected to the para position of the phenyl group.

[0115] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 3b is hydrogen or -C 1-4 Alkyl, and R 2b is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b ) 2, optionally 1 or 2 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 -(5- to 10-membered)-C 1-9 In another aspect, R 2b is unsubstituted -(5 or 10 member)-C 1-9 Heteroaryl or 1 or 2 independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1 or 2 groups independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 -(5 to 10 membered)-C 1-9 In another aspect, R 3b is unsubstituted -(5 to 10 members)-C 1-9 In another aspect, R 2b is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1 or 2 groups independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 -(5 or 10 membered)-C 1-9 Heteroaryl.

[0116] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 3b is hydrogen or -C 1-4 Alkyl, and R 2b -C 3-10 Cycloalkyl or -(5- to 10-membered)-C 2-9 Heterocyclyl, wherein the cycloalkyl and heterocyclyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b) 2, optionally 1 or 2 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the group consisting of heterocyclic groups are substituted.

[0117] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 2b is hydrogen and R 3b As defined above.

[0118] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein R 3b is hydrogen and R 2b As defined above.

[0119] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts thereof, wherein R 1b -C 6-10 Aryl or -C 1-4 Alkyl-C 6-10 Aryl, wherein the aryl or alkylaryl is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b )2, optionally substituted by 1, 2 or 3 halogen atoms -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the group consisting of heterocyclic groups are substituted, wherein Rb b As defined above.

[0120] On the other hand, R 1b For unsubstituted C 6-10 Aryl or 1, 2 or 3 each independently selected from halogen, hydroxyl, -CN, -ORb b 、-SRb b 、-N(Rb b ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb b and -N(Rb b )2 substituted with a substituent group consisting of -C1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the heterocyclic group substituted C 6-10 On the other hand, R 1b For unsubstituted -C 6-10 Aryl or 1 or 2 each independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 6-10 On the other hand, R 1b For unsubstituted -C 6-10 On the other hand, R 1b unsubstituted phenyl. On the other hand, R 1b is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 6-10 Aryl.

[0121] On the other hand, R 1b For unsubstituted -C 1-4 Alkyl-C 6-10 Aryl or optionally substituted by 1, 2 or 3 each independently selected from halogen, hydroxy, -CN, -ORb b 、-SRb b 、-N(Rb b ) 2, optionally 1, 2 or 3 each independently selected from halogen, -CN, -ORb b and -N(Rb b)2 substituted with a substituent group consisting of -C 1-4 Alkyl, optionally substituted -C 6-10 Aryl, optionally substituted -(5- to 10-membered)-C 1-9 Heteroaryl and -(5- to 10-membered)-C 2-9 The substituents of the heterocyclic group are substituted -C 1-4 Alkyl-C 6-10 On the other hand, R 1b For unsubstituted -C 1-4 Alkyl-C 6-10 Aryl or 1 or 2 each independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 1-4 Alkyl-C 6-10 On the other hand, R 1 For unsubstituted -C 1-4 Alkyl-C 6-10 On the other hand, R 1b is unsubstituted benzyl or unsubstituted phenethyl. 1b is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -CN, -O(C 1-4 )alkyl, -S(C 1-4 )alkyl, -N(C 1-4 Alkyl)2, -NH(C 1-4 alkyl) and optionally substituted by 1, 2 or 3 each independently selected from halogen, -CN, -O(C 1-4 )alkyl, -N(C 1-4 Alkyl)2 and -NH(C 1-4 alkyl) substituted with a substituent consisting of -C 1-4 Alkyl group consisting of substituents substituted -C 1-4 Alkyl-C 6-10 Aryl.

[0122] In another embodiment, the compound of the present disclosure is a compound of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein Rb b is hydrogen or -C 1-4 alkyl.

[0123] In another aspect, the compound of the present disclosure is a compound of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein X is absent and Y is selected from a bond (ie, absent), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 The group consisting of alkylene-C(=O).

[0124] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein X is C 1-4 Alkylene, and Y is selected from a bond (ie, not present), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 The group consisting of alkylene-C(=O).

[0125] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein X is C(=O), and Y is selected from a bond (ie, absent), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 The group consisting of alkylene-C(=O).

[0126] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein X is C(═O)—C 1-2 Alkylene, and Y is selected from a bond (ie, not present), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 The group consisting of alkylene-C(=O).

[0127] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein X is C 1-2 Alkylene-C(=O), and Y is selected from a free bond (ie, absent), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 The group consisting of alkylene-C(=O).

[0128] In another aspect, the compound of the present disclosure is a compound of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein Y is absent and X is selected from a bond (ie, absent), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2The group consisting of alkylene-C(=O).

[0129] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein Y is C 1-4 Alkylene, and X is selected from a bond (ie, not present), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 The group consisting of alkylene-C(=O).

[0130] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein Y is C(=O), and X is selected from a bond (ie, absent), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 The group consisting of alkylene-C(=O).

[0131] In another aspect, the compound of the present disclosure is a compound of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein Y is C(=O)-C 1-2 Alkylene, and X is selected from a bond (ie, not present), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 The group consisting of alkylene-C(=O).

[0132] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts and solvates thereof, wherein Y is C 1-2 Alkylene-C(=O), and X is selected from a bond (ie, absent), C 1-4 Alkylene, C(=O), C(=O)-C 1-2 Alkylene and C 1-2 The group consisting of alkylene-C(=O).

[0133] In another aspect, the compounds of the present disclosure are compounds of formula (IB) and pharmaceutically acceptable salts thereof, wherein X and Y are each independently C 1-4 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.

[0134] In another embodiment, the present disclosure provides a compound of formula (IB) of the present disclosure selected from the group consisting of

[0135] and pharmaceutically acceptable salts and solvates thereof.

[0136] As used herein, the term "halogen" or "halo" refers to -F, -Cl, -Br, or -I.

[0137] As used herein, the term "hydroxy" refers to the group -OH.

[0138] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting of carbon atoms and hydrogen atoms, free of unsaturated groups, which is attached to the rest of the molecule by a single bond, and unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., C 1-4 Alkyl. Exemplary C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl and sec-butyl. In another embodiment, the alkyl group is C 1-2 Alkyl (methyl or ethyl).

[0139] As used herein, the term "C 1-4 "Alkoxy" refers to the C 1-4 One of the alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, and sec-butoxy) is replaced by, for example, C 1-2 A substituted oxygen in an alkyl group.

[0140] As used herein, the term "cycloalkyl" encompasses saturated carbocyclic groups, and unless otherwise specified, cycloalkyl groups typically have 3 to 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples thereof include cyclopropyl, cyclopentyl, and cyclohexyl. In another embodiment, a cycloalkyl group is C 3-10 Cycloalkyl.

[0141] As used herein, the term "alkylcycloalkyl" when used to define a substituent refers to a cycloalkyl group as defined above, which is separated by an alkylene group (such as C 1-4 For example, a cyclopentylethyl substituent is a substituent consisting of a cyclopentyl group connected to the core structure it replaces via an ethylene group.

[0142] As used herein, the term "heterocyclyl" or "heterocyclic group" generally encompasses monocyclic or polycyclic, non-aromatic, saturated or unsaturated C 2-10 A carbocyclic ring, such as a 5- to 10-membered group, wherein one or more, for example 1, 2, 3 or 4 carbon atoms (for example, 1 or 2 carbon atoms) are replaced by a heteroatom selected from N, O and S. In one embodiment, the heterocyclic group is C 3-7 Heterocyclyl, ie, a heterocycle having 3 to 7 carbon atoms and at least one heteroatom. In another embodiment, heterocyclyl is (5 to 10 membered)-C2-9 Heterocyclyl, ie, a heterocyclic ring having 5 to 10 members, 2 to 9 of which are carbon. In another embodiment, the heteroatom is N. In another embodiment, the heteroatom is O.

[0143] In another embodiment, the heterocyclyl group is saturated. The heterocyclyl group can be a single ring or two or more fused rings, at least one of which contains a heteroatom. When the heterocyclyl group carries one or more substituents, these substituents can be the same or different.

[0144] The optionally substituted heterocyclic group is typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. Examples of heterocyclic groups include piperidinyl, pyrrolidinyl, pyrrolinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazolinyl, pyrazolidinyl, quinuclidinyl, tetrazolyl, chromanyl, isochromanyl, imidazolidinyl, oxiranyl, aziridine, 4,5-dihydro-oxazolyl and 3-aza-tetrahydrofuranyl. Substituents are, for example, selected from: halogen atoms, for example, fluorine or chlorine atoms; hydroxyl groups; alkoxycarbonyl groups, wherein the alkyl portion has 1 to 4 carbon atoms; hydroxycarbonyl groups; carbamoyl groups; nitro groups; cyano groups; 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 Hydroxyalkyl groups.

[0145] As used herein, the term "alkylheterocyclyl" when used to define a substituent refers to a heterocyclyl group as defined above, which is connected to the core structure on which it replaces through an alkylene group. In one embodiment, the alkylheterocyclyl group is -C 1-4 Alkyl-(5- to 10-membered)-C 2-9 Heterocyclic group.

[0146] As used herein, the term "aryl" generally refers to a C 6-10 Monocyclic or polycyclic aromatic groups, such as phenyl and naphthyl. In another embodiment, aromatic groups are phenyl. The optionally substituted aromatic groups are typically unsubstituted or substituted by 1, 2 or 3 substituents which may be the same or different. Substituents are, for example, selected from: halogen atoms, for example, fluorine or chlorine atoms; hydroxyl groups; alkoxycarbonyl groups, in which the alkyl portion has 1 to 4 carbon atoms; hydroxycarbonyl groups; carbamoyl groups; nitro groups; cyano groups; 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 1-4When an aryl group carries two or more substituents, these substituents may be the same or different. Unless otherwise specified, the substituents on the aryl group are generally unsubstituted.

[0147] As used herein, the term "alkylaryl" when used to define a substituent refers to an aryl group as defined above, which is separated by an alkylene group (such as C 1-4 alkylene) is attached to the core structure it replaces.

[0148] As used herein, the term "heteroaryl" generally refers to a 5- to 10-membered ring system comprising at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N, typically 1, 2, 3 or 4 heteroatoms.

[0149] The heteroaryl group may contain a single ring or two or more fused rings, at least one of which contains a heteroatom. The optionally substituted heteroaryl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are, for example, selected from: halogen atoms, for example, fluorine, chlorine or bromine atoms; alkoxycarbonyl groups, in which the alkyl portion has 1 to 4 carbon atoms; carbamoyl groups; nitro groups; hydroxyl groups; C 1-4 an alkyl group, optionally substituted with one or more halogen atoms; and C 1-4 Alkoxy groups are optionally substituted with one or more halogen atoms. When a heteroaryl group carries two or more substituents, these substituents may be the same or different. Unless otherwise stated, the substituents on the heteroaryl group are typically unsubstituted.

[0150] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, tetrazolyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrrolyl, pyridyl, benzothiazolyl, indolyl, indazolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinolizinyl, cinnolinyl, triazolyl, indolizinyl, indolyl, isoindolyl, isoindolyl, imidazolidinyl, pteridinyl, thianthrenyl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, and various pyrrolopyridinyl groups.

[0151] In another embodiment, heteroaryl is a (5- to 10-membered)-C 2-9 In another embodiment, the heteroaryl group is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxy, -CN, -ORb, -SRb,

[0152] -N(Rb)2, -C optionally substituted by 1, 2 or 3 halogen atoms1-4 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted (5- to 10-membered)-C 1-9 Heteroaryl and (5- to 10-membered)-C 2-9 said cycloalkyl, alkylcycloalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, heterocyclyl and alkylheterocyclyl being optionally fused to another (second) ring.

[0153] References in the present disclosure to optionally substituted heteroaryl groups or residues are intended to encompass the N-oxides which may be obtained from these groups when they contain an N-atom.

[0154] As used herein, the term "alkylheteroaryl" when used to define a substituent refers to a heteroaryl group as defined above, which is attached to the core structure it replaces via an alkylene group. In another embodiment, the alkylheteroaryl group is -C 1-4 Alkyl-(5- to 10-membered)-C 1-9 Heteroaryl.

[0155] The term "pharmaceutically acceptable" refers to compositions and molecular entities that are physiologically tolerable and do not typically produce allergic reactions or similar adverse reactions, such as stomach problems, dizziness, etc., when administered to humans or animals. For example, the term "pharmaceutically acceptable" means that it is approved by a state or federal regulatory agency or included in the U.S. Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0156] The term "treating" refers to administering a therapy in an amount, manner, or pattern effective to improve a condition, symptom, or parameter associated with the condition, or to prevent the progression of the condition, to a statistically significant degree or to an extent detectable by one skilled in the art. The effective amount, manner, or pattern can vary depending on the subject and can be customized for the patient.

[0157] By "effective amount" or "therapeutically effective amount" of a drug or pharmacologically active agent is meant an amount of the drug or agent that is non-toxic but sufficient to provide the desired effect. An "effective" amount will vary from subject to subject, depending on the individual's age and general condition, the specific active agent or agents, and the like. Thus, it is not always possible to specify an exact "effective amount." However, an appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0158] The term "prevent" or "preventing" refers to reducing the risk of acquiring or developing a given disease or disorder, or reducing or inhibiting the recurrence of a disease or disorder.

[0159] As used herein, the term "about" in relation to a measured amount refers to the normal variation of that measured amount, as would be expected by a skilled artisan performing the measurement with a degree of care commensurate with the precision of the measurement objective and the measuring equipment. Typically, the term "about" includes ±10% of the referenced number. Thus, "about 10" means 9 to 11.

[0160] As used herein, the term "optionally substituted" refers to a group that can be unsubstituted or substituted.

[0161] The term "not more than" preceding a number or series of numbers is understood to include the numbers adjacent to the term "not more than" and all preceding numbers or integers that can be logically included, as clear from the context. When "not more than" precedes a series of numbers or a range, it should be understood that "not more than" can modify each number in the series or range.

[0162] 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. In some embodiments, the patient is a prepubertal child. In some embodiments, the patient is a teenager.

[0163] As used herein, the term "child" is a human being between birth and adolescence.

[0164] The term "puberty" refers to the process of physical changes that occur when a child's body matures into an adult body capable of sexual reproduction. On average, puberty begins around the ages of 10 to 11 for girls and ends around the ages of 15 to 17 for boys, and begins around the ages of 11 to 12 for boys and ends around the ages of 16 to 17.

[0165] As used herein, the term "infant" is a synonym for "baby" and is a very young human offspring. The term "infant" generally applies to young children under one year old.

[0166] As used herein, the term "toddler" refers to a child between 12 and 36 months old.

[0167] As used herein, the term "prepubertal child" refers to a human between the ages of 10 and 13.

[0168] As used herein, the term "adolescent" refers to a person between the ages of 10 and 19 years old.

[0169] The term "solvate" refers to any form of an active compound of the present disclosure that has another molecule (eg, a polar solvent such as water or ethanol, cyclodextrin, or dendrimer) attached thereto by a non-covalent bond. Solvation methods are known in the art.

[0170] The present disclosure also provides salts of the compounds of the present disclosure. Non-limiting examples are sulfates; hydrohalide salts; phosphates; lower alkane sulfonates; aryl sulfonates; C 1-20 Salts of aliphatic mono-, di-, or tri-protic acids, which may contain one or more double bonds, aromatic nuclei, or other functional groups such as hydroxyl, amino, or keto groups; salts of aromatic acids, wherein the aromatic nuclei may or may not be substituted with groups such as hydroxyl, lower alkoxy, amino, or mono- or di-lower alkylaminosulfonamido groups. Also included within the scope of this disclosure are quaternary salts of tertiary nitrogen atoms with lower alkyl halides or sulfates, as well as oxidized derivatives of tertiary nitrogen atoms, such as N-oxides. When preparing dosage formulations, one skilled in the art will select pharmaceutically acceptable salts.

[0171] Solvates and salts can be prepared by methods known in the art. Note that non-pharmaceutically acceptable solvates also fall within the scope of the present disclosure, as they can be used to prepare pharmaceutically acceptable salts and solvates.

[0172] 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, except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon by an isotopically enriched 11 C. 13 C or 14 C is replaced by carbon or nitrogen is enriched 15 Besides nitrogen substitution of N, compounds having the present structures are within the scope of this disclosure.

[0173] Some compounds disclosed herein may contain one or more asymmetric centers and therefore may produce enantiomers, diastereomers and other stereoisomeric forms, such as epimers. The disclosure is intended to encompass the purposes of all such possible forms, as well as their racemic and resolved forms and their mixtures. According to the disclosure, each enantiomer may be separated according to methods known to those of ordinary skill in the art. When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, unless otherwise stated, they are intended to include E and Z geometric isomers. All tautomers are also intended to be encompassed by the disclosure.

[0174] 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 with more than one chiral center that are not mirror images of each other (diastereomers).

[0175] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0176] The term "epimer" refers to a diastereomer having the opposite configuration at only one of the two or more tetrahedral centers present in the corresponding molecular entity.

[0177] The term "stereocenter" is an atom bearing groups such that interchange of any two groups produces stereoisomers.

[0178] The terms "enantiomer" and "enantiomerically" refer to molecules that are not superimposable on their mirror images and are therefore optically active, wherein an enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

[0179] The term "racemic" refers to a mixture of equal parts of enantiomers, and the mixture is optically inactive.

[0180] The term "resolution" refers to the separation or enrichment or depletion of one of the two enantiomeric forms of a molecule.

[0181] The terms "a" and "an" refer to one or more.

[0182] Some reactions for preparing 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 functional group and reacts on other functional groups or parts of the molecule. Those skilled in the art will be familiar with the selection, connection and cutting of amine protecting groups, and will understand that many different protecting groups are known in the art, and the suitability of one or another protecting group depends on the specific synthesis scheme planned. Papers on this topic are available for review, such as Wuts, PGM & Greene, TW, Greene's Protective Groups in Organic Synthesis, 4th edition (J.Wiley & Sons, 2007), which are incorporated herein by reference in their entirety. Suitable amine protecting groups include methyl carbamate, tert-butyloxycarbonyl (tert-butyl carbamate; BOC), 9-fluorenylmethylcarbamate, benzyl carbamate, 2-(trimethylsilyl)ethylcarbamate, 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).

[0183] As used herein, the term "enzyme replacement therapy" or "ERT" refers to the administration of an exogenously produced natural or recombinant enzyme or its analog to a patient in need thereof. For example, in the case of lysosomal storage diseases, due to a lack or defect in the enzyme responsible for metabolizing the substrate, or due to a lack of an enzyme activator required for proper enzymatic function, the patient accumulates harmful levels of substrate (i.e., stored material) in the lysosomes. Enzyme replacement therapy is provided to the patient to reduce the level of substrate accumulated in the affected tissue (i.e., reduction). Enzyme replacement therapy for the treatment of lysosomal storage diseases is known in the art. According to the combination therapy disclosed herein, lysosomal enzymes, such as β-glucocerebrosidase, can be used in enzyme replacement therapy to reduce the level of corresponding substrates such as β-glucocerebroside in patients with lysosomal storage diseases such as Gaucher's disease.

[0184] As used herein, the term "substrate reduction therapy" or "SRT" is a therapeutic approach for treating certain metabolic disorders, such as lysosomal storage disorders, in which the accumulation of substrates, such as glycolipids, is not counteracted by replacing the defective enzyme but by reducing substrate levels to better balance 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 unique, independent, and potentially complementary mechanisms of action in the treatment of lysosomal storage diseases and other diseases.

[0185] The general principle of SRT is to administer a substrate reducing agent to a patient to partially inhibit the biosynthesis of a substrate that accumulates in the absence of a specific lysosomal enzyme. As used herein, the term "substrate reducing agent" is a small molecule that reduces the number of substrate molecules that need to be catabolized within the lysosome, thereby helping to balance the synthesis rate with the impaired catabolism rate. Substrate reducing agents are known in the art.

[0186] As used herein, an "effective amount" of an enzyme, when administered to a subject in the combination therapy of the present disclosure, is an amount sufficient to improve the clinical course of a lysosomal storage disease, where the clinical improvement is measured by any of a variety of defined parameters well known to the skilled artisan.

[0187] As used herein, the term "small molecule chaperone" refers to a compound other than the compounds of the present disclosure that is capable of allosterically or competitively binding to a mutated enzyme, such as β-galactosidase, thereby stabilizing the enzyme to prevent degradation. In some embodiments, the small molecule chaperone promotes the correct folding and transport of the enzyme to its site of action. Small molecule chaperones for treating lysosomal storage diseases are known in the art. See, for example, US 2016 / 0207933 A1 and WO 2011 / 049737 A1.

[0188] Alpha-synuclein disease is a neurodegenerative disease characterized by the abnormal accumulation of alpha-synuclein aggregates in neurons, nerve fibers or glial cells. There is a recognized clinical association between the development of mutations in the glucocerebrosidase gene and more general multifactorial disorders (including Parkinson's disease and other synuclein diseases). See Siebert, M. et al., Brain 137:1304-1322 (2014). According to the research of Siebert et al., in synuclein diseases such as Parkinson's disease and Lewy body dementia, there is a mutual relationship between glucocerebrosidase activity (wild type and mutant) and alpha-synuclein. This mutual relationship shows that the therapy for Gaucher's disease (its goal is to increase glucocerebrosidase activity or reduce the storage of glucocerebroside) can be proved to be an effective strategy for regulating alpha-synuclein protein homeostasis and its subsequent aggregation and oligomerization.

[0189] Synthesis of Compounds of the Disclosure

[0190] The compounds of the present disclosure can be prepared using methods known to those skilled in the art according to the present disclosure or by the exemplary methods shown in the following schemes. For example, compounds of the present disclosure with formula (IA) can be prepared as shown in schemes 1-8 below, and compounds of the present disclosure with formula (IB) can be prepared as shown in schemes 9-12 below. Additional synthetic methods are described and illustrated in the working examples set forth below.

[0191] Solution 1

[0192]

[0193] R 3a As defined above for formula (IA).

[0194] Method 1

[0195] Step 1 (Reaction A)

[0196] In the first method according to the present disclosure, the compound of formula (IIA) (wherein R 3a (as defined above) is reacted with dicyandiamide (IIIA) to produce a biguanide compound of formula (IVA) as shown in reaction A of the scheme above (Scheme 1).

[0197] Reaction A is used to prepare a compound of formula (IVA) 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, hydrogen chloride, hydrogen sulfide, or a mixture thereof) and a suitable solvent (e.g., butanol, water, tetrahydrofuran, xylene, acetone, methanol, ethanol, acetonitrile, 2-propanol, dichloromethane, dimethylformamide, dimethyl sulfoxide, or a mixture thereof), and for example, at about room temperature, reflux temperature, or microwave irradiation reaction conditions.

[0198] The reaction can also be carried out in the presence of a suitable catalyst (or salt thereof) such as iron(III) chloride or copper(II) chloride, and optionally also in the presence of an additive or protecting group such as trimethylchlorosilane or trimethylsilyl trifluoromethanesulfonate.

[0199] The reaction can be carried out in the presence of protecting groups, and these protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0200] Step 2 (Reaction B)

[0201] The biguanide (hydrochloride or non-hydrochloride) compound of formula (IVA) is then mixed with a compound of formula (VA) (wherein R 4 The methyl or ethyl group) is reacted to produce a compound of formula (VIA) as shown in reaction B of the scheme above (Scheme 1).

[0202] Reaction B is carried out under standard condensation conditions, for example in the presence of a suitable base (e.g., 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 (e.g., ethanol, methanol, dimethylformamide or a mixture thereof) and for example at about room temperature or reflux temperature.

[0203] The reaction can be carried out in the presence of protecting groups, and these protecting groups can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0204] Option 2

[0205]

[0206] A 1 、A 2 、A 3 、R 1a 、R 2a and R 3a As defined above for formula (IA).

[0207] Method 2 (Reaction C)

[0208] Reaction C can be used to prepare a compound of formula (IA) by reacting a compound of formula (VIA) with a compound of formula (XIIA). The carboxylic acid or acid chloride of the compound of formula (VIA) is then converted to a substituted amide group to produce a compound of formula (IA) according to the present disclosure, as shown in reaction C of Scheme 2. Reaction C is carried out under standard amide coupling conditions, for example, in the presence of a suitable coupling agent (e.g., 1,1'-carbonyldiimidazole, N,N'-cyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or its hydrochloride), N,N'-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 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-pyrrolidinylphosphonium hexafluorophosphate, bromo-tris-pyrrolidinylphosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate). In the presence of 1-hydroxybenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazole-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, sodium hydroxide, potassium tert-butoxide and / or lithium diisopropylamide (or variants thereof)) and a suitable solvent (e.g., tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine). Such reactions can be carried out in the presence of additional additives such as 1-hydroxybenzotriazole hydrate.

[0209] The reaction mixture is stirred or heated at low temperature or room temperature until the starting material is exhausted. The reaction can be carried out in the presence of blocking groups, and these blocking groups can be removed after the reaction. Suitable blocking groups are well known to those skilled in the art (see TW Greene, " Protective Groups in Organic Synthesis ", 3rd edition, New York, 1999).

[0210] Compounds of formula (IA) may be delivered as the free base or may be converted to a salt form (eg, HCl salt) by standard salt formation procedures.

[0211] Option 3

[0212]

[0213] A 1 、A 2 、A 3 、R 1a 、R 2a and R 3a As defined above for formula (IA), and PG is a protecting group.

[0214] Method 3

[0215] Step 1 (Reaction D)

[0216] In another method according to the present disclosure, a compound of formula (VIIA) (wherein Z 2 Can be-NR 1a R 2a , -OPG, wherein PG is a protecting group, and R 1a and R 2a Each of which is defined above) is reacted with an amine source (eg, tert-octylamine) to produce a compound of formula (VIIIA) as shown in Reaction D of the scheme above (Scheme 3).

[0217] One of the chloro groups of the compound of formula (VIIIA) is subsequently replaced by reaction with an amine to form the corresponding amino group, yielding a compound of formula (XA) according to the present disclosure, as shown in reaction D of the scheme above (Scheme 3).

[0218] 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 Pd2(dba)3), a suitable base (cesium carbonate or triethylamine, etc.) and a suitable ligand (such as 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Xantphos or XPhos) in a suitable solvent (e.g., butanol, toluene, dioxane or a mixture thereof) and, for example, at about room temperature or reflux temperature.

[0219] Alternatively, the transformation can be carried out in the presence of a suitable base (eg, N,N-diisopropylethylamine or triethylamine) and an appropriate solvent (such as dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol or mixtures thereof).

[0220] The reaction can be carried out in the presence of protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0221] Step 2 (Reaction E)

[0222] Subsequently, the compound of formula (VIIIA) (wherein Z 1 Can be-NR 1a R 2a , -OPG, wherein PG is a protecting group, and R 1a and R 2a Each of the remaining chlorine groups (as defined above) and the amine groups (IXA) (wherein R 3a as defined above) to produce a compound of formula (XA) as shown in reaction E of the scheme above (Scheme 3).

[0223] Formula (XA) compound can be used as its free base or can be converted into its salt form (such as HCl salt) by standard salt formation procedure.Reaction E is carried out under standard nucleophilic substitution conditions, for example, in the presence of a suitable base (such as triethylamine, pyridine, potassium carbonate or N,N-diisopropylethylamine) or acid (such as, 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 (such as, Pd (dba) , XantPhos and cesium carbonate or 1,1'-bis (diphenylphosphino) ferrocene (Dppf), Pd (OAc) and K PO ) and a suitable solvent (such as, ethanol, water, acetonitrile, N,N-dimethylacetamide, propanol, N-methylpyrrolidine, 1-methylpiperazine, dimethylformamide, dioxane, butanol or a mixture thereof).

[0224] The reaction mixture is stirred or heated at low temperature, room temperature until the starting material is exhausted. The reaction can be carried out in the presence of blocking groups, and these blocking groups can be removed after the reaction. Suitable blocking groups are well known to those skilled in the art (see TW Greene, " Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0225] Option 4

[0226]

[0227] R 1a 、R 2a and R 3aAs defined above for formula (IA).

[0228] Method 4 (Reaction F)

[0229] In the fourth method according to the present disclosure, the compound of formula (XIA) (wherein R 3a as defined above) and an amine compound (XIIA) (wherein R 1a and R 2a Each of which is defined above) is reacted to produce an amide compound of formula (XIIA) as shown in reaction F of the scheme above (Scheme 4).

[0230] Reaction F is carried out under standard amide forming conditions, for example, the carboxylic acid or acid chloride of the compound of formula (XIA) is converted into a substituted amide group to produce the compound of formula (XIIA) according to the present invention, for example, in the presence of a suitable coupling agent (e.g., propylphosphonic anhydride, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1,1'-carbonyldiimidazole, N,N'-cyclohexylcarbodiimide imine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (or its hydrochloride), N,N'-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 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(dimethylamino)phosphonium hexafluorophosphate, -O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, bromo-tris-pyrrolidinylphosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluorocarbonate, 1-cyclohexylcarbodiimide-3-propoxymethylpolystyrene, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate In the presence of urea (e.g., uronium 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 variants)) and a suitable solvent (e.g., tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine). Such reactions can be carried out in the presence of additional additives such as 1-hydroxybenzotriazole hydrate.

[0231] When an acid chloride of compound XIA is used, it can be prepared from the corresponding carboxylic acid under standard acid chloride forming conditions, for example in the presence of thionyl chloride or oxalyl chloride.

[0232] The reaction mixture is stirred or heated at low temperature or room temperature until the starting material is exhausted. The reaction can be carried out in the presence of blocking groups, and these blocking groups can be removed after the reaction. Suitable blocking groups are well known to those skilled in the art (see TW Greene, " Protective Groups in Organic Synthesis ", 3rd edition, New York, 1999).

[0233] Option 5

[0234]

[0235] R 1a 、R 2a and R 3a As defined above for formula (IA).

[0236] Method 5 (Reaction G)

[0237] In another method according to the present disclosure, a compound of formula (XIIIA) wherein M may be -NH2 or -Cl, and N may be -CONR 1a R 2a , -COOPG or -SO2Me, wherein PG is a protecting group, and R 1a and R 2a Each of which is as defined above) and an aryl chloride of formula (IXA) (wherein R 3a as defined above) to produce a compound of formula (XIVA) as shown in reaction G of the scheme above (Scheme 5).

[0238] The aryl chloride of the compound of formula (XIIIA) is substituted by reaction with amine (IXA) to form the corresponding amino group, resulting in a compound of formula (XIVA) according to the present disclosure, as shown in reaction G of the scheme above (Scheme 5).

[0239] Reaction G is carried out under standard nucleophilic substitution conditions, for example, in the presence of a suitable base (e.g., sodium hydride, 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 (e.g., Pd(dba)2 or Pd(OAc)2), a ligand (e.g., XantPhos, BINAP or 1,1'-bis(diphenylphosphino)ferrocene (Dppf)) and a base (e.g., cesium carbonate or K3PO4) and a suitable solvent (e.g., ethanol, water, acetonitrile, N,N-dimethylacetamide, propanol, N-methylpyrrolidine, 1-methylpiperazine, dioxane, dimethylformamide, butanol or mixtures thereof).

[0240] The reaction mixture is stirred or heated at low temperature, room temperature until the starting material is exhausted. The reaction can be carried out in the presence of blocking groups, and these blocking groups can be removed after the reaction. Suitable blocking groups are well known to those skilled in the art (see TW Greene, " Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0241] Option 6

[0242]

[0243] R 1a 、R 2a and R 3a As defined above for formula (IA).

[0244] Method 6 (Reaction H)

[0245] In another method according to the present disclosure, a compound of formula (XVA) (wherein Y 1 Can be -Cl or -HNR 3a ; and Z 2 Can be-NR 1a R 2a or -OPG, wherein PG is a protecting group, and R 1a 、R 2a and R 3a Each of which is defined above) is reacted with an amine source (eg, tert-octylamine, tert-butyl carbamate, or diphenylformimine) to produce a compound of formula (XVIA) as shown in Reaction H of the above scheme (Scheme 6).

[0246] The aryl chloride of the compound of formula (XVA) is substituted by reaction with an amine to form the corresponding protected amino group, yielding a compound of formula (XVIA) according to the present disclosure, as shown in reaction H of the scheme above (Scheme 6).

[0247] 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 Pd2(dba)3), a suitable base (cesium carbonate, sodium tert-butoxide or triethylamine, etc.) 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 mixtures thereof) and, for example, at about room temperature or reflux temperature.

[0248] Alternatively, the transformation can be carried out in the presence of a suitable base (eg, N,N-diisopropylethylamine or triethylamine) and an appropriate solvent (such as dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol or mixtures thereof).

[0249] The reaction can be carried out in the presence of protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0250] Option 7

[0251]

[0252] R 1a 、R 2a and R 3a As defined above for formula (IA).

[0253] Method 7 (Reaction I)

[0254] In another method, a compound of formula (XVIA) (wherein Y 1 Can be -Cl or -HNR 3a , Z 2 Can be-NR 1a R 2a or -OPG, wherein PG is a protecting group, and R 1a 、R 2a and R 3a , each of which is defined above) to produce a compound of formula (XVIIA) as shown in Reaction I of the scheme above (Scheme 7).

[0255] The protecting group on the amine portion of the compound of formula (XVIA) (e.g., tert-octylamine, tert-butyl carbamate, or diphenylformimine) is treated to form the corresponding primary amino group of the compound of formula (XVIIA) according to the present disclosure as shown in reaction 1 of the scheme above (Scheme 7).

[0256] Compound (XVIIA) can be delivered as its free base or converted to its salt form (eg, HCl salt) by standard salt formation procedures.

[0257] 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 (for example, tetrahydrofuran, dioxane, dichloromethane or a mixture thereof).

[0258] The reaction mixture is stirred or heated at low temperature, room temperature until the starting material is exhausted. The reaction can be carried out in the presence of blocking groups, and these blocking groups can be removed after the reaction. Suitable blocking groups are well known to those skilled in the art (see TW Greene, " Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0259] Option 8

[0260]

[0261] R 1a 、R 2a and R 3a As defined above for formula (IA).

[0262] Method 8 (Reaction J)

[0263] In another method according to the present disclosure, a compound of formula (XVA) (wherein Y 1 Can be -Cl or -HNR 3a , Z 2 Can be-NR 1a R 2a , -OPG, wherein PG is a protecting group, and R 1a 、R 2a and R 3a Each of which is defined above) is reacted with an amine precursor (eg, sodium azide) to produce a compound of formula (XVIIA) as shown in Reaction H of the above scheme (Scheme 8).

[0264] The aryl chloride of the compound of formula (XVA) is substituted by reaction with an azide followed by reduction with a reducing agent to form the corresponding amino group and produce the compound of formula (XVIIA) according to the present disclosure as shown in reaction J of the scheme above (Scheme 8).

[0265] Compound (XVIIA) can be delivered as its free base or converted to its salt form (eg, HCl salt) by standard salt formation procedures.

[0266] Reaction J can be carried out under standard conditions in the presence of sodium azide in a suitable solvent (e.g., dimethylformamide) and, for example, at about room temperature or reflux temperature. Subsequently, the reaction mixture is treated with a reducing agent (e.g., sodium borohydride) in a suitable solvent (e.g., methanol).

[0267] The reaction can be carried out in the presence of protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0268] Option 9

[0269]

[0270] B 1 、B 2 、R 1b and R 3b As defined above for formula (IB).

[0271] Step 1 (Reaction A)

[0272] In another method according to the present disclosure, a compound of formula (IIB) (wherein R 1b As defined above) is reacted with an amine source to produce a biguanide compound of formula (IIIB) as shown in reaction A of the scheme above (Scheme 9).

[0273] One of the chloro groups of the compound of formula (IIB) is subsequently replaced by reaction with an amine to form the corresponding amino group, yielding a compound of formula (IIIB) according to the present disclosure, as shown in reaction A of the scheme above (Scheme 9).

[0274] Reaction A can be carried out under standard conditions in the presence of a suitable palladium catalyst (such as Pd(dba)2, palladium acetate or Pd2(dba)3), a suitable base (cesium carbonate or triethylamine, etc.) and a suitable ligand (such as 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Xantphos or XPhos) in a suitable solvent (e.g., butanol, toluene, dioxane or mixtures thereof) and, for example, at about room temperature or reflux temperature.

[0275] Alternatively, the transformation can be carried out in the presence of a suitable base (eg, N,N-diisopropylethylamine or triethylamine) and an appropriate solvent (such as dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol or mixtures thereof).

[0276] The reaction can be carried out in the presence of protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0277] Step 2 (Reaction B)

[0278] Subsequently, the compound of formula (IIIB) wherein PG is a protecting group and R 1b as defined above) with an aniline group (wherein R 3b as defined above) to produce a compound of formula (VB) as shown in reaction B of the scheme above (Scheme 9).

[0279] The remaining chlorine of the compound of formula (IIIB) is then replaced by reaction with amine (IVB) to form the corresponding amino group, resulting in a compound of formula (VB) according to the present disclosure, as shown in reaction B of the scheme above (Scheme 9).

[0280] Reaction B is carried out under standard nucleophilic substitution conditions, 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) and a suitable solvent (e.g., ethanol, water, acetonitrile, N,N-dimethylacetamide, propanol, N-methylpyrrolidine, 1-methylpiperazine, dioxane, butanol or mixtures thereof).

[0281] The reaction mixture is stirred or heated at low temperature, room temperature until the starting material is exhausted. The reaction can be carried out in the presence of blocking groups, and these blocking groups can be removed after the reaction. Suitable blocking groups are well known to those skilled in the art (see TW Greene, " Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0282] Plan 10

[0283]

[0284] R 1b 、R 2b 、B 1 and B 2 As defined above for formula (IB), and PG is a protecting group.

[0285] Step 1 (Reaction C)

[0286] In another method according to the present disclosure, a compound of formula (IIB) (wherein R 1b as defined above) with an aniline group (VIB) (wherein R 2bas defined above) to produce a biguanide compound of formula (VIIB) as shown in reaction C of the scheme above (Scheme 10).

[0287] One of the chlorines of the compound of formula (IIB) is subsequently replaced by reaction with aniline (VIB) to form the corresponding amino group, yielding a compound of formula (VIIB) according to the present disclosure, as shown in reaction C of the scheme above (Scheme 10).

[0288] Reaction C is carried out under standard nucleophilic substitution conditions, 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) and a suitable solvent (e.g., ethanol, water, acetonitrile, N,N-dimethylacetamide, propanol, N-methylpyrrolidine, 1-methylpiperazine, dioxane, butanol or mixtures thereof).

[0289] The reaction mixture is stirred or heated at low temperature, room temperature until the starting material is exhausted. The reaction can be carried out in the presence of blocking groups, and these blocking groups can be removed after the reaction. Suitable blocking groups are well known to those skilled in the art (see TW Greene, " Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0290] Step 2 (Reaction D)

[0291] Subsequently, the compound of formula (VIIB) (wherein R 1b and R 2b Each of which is defined above) is reacted with an amine source to produce a compound of formula (VIIIB) as shown in reaction D of the scheme above (Scheme 10).

[0292] The remaining chlorine of the compound of formula (VIIB) is subsequently replaced by reaction with an amine to form the corresponding amino group, yielding a compound of formula (VIIIB) according to the present disclosure, as shown in reaction D of the scheme above (Scheme 10).

[0293] 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 Pd2(dba)3), a suitable base (cesium carbonate or triethylamine, etc.) and a suitable ligand (such as 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Xantphos or XPhos) in a suitable solvent (e.g., butanol, toluene, dioxane or a mixture thereof) and, for example, at about room temperature or reflux temperature.

[0294] Alternatively, the transformation can be carried out in the presence of a suitable base (eg, N,N-diisopropylethylamine or triethylamine) and an appropriate solvent (such as dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol or mixtures thereof).

[0295] The reaction can be carried out in the presence of protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0296] Plan 11

[0297]

[0298] R 1b 、B 1 and B 2 As defined above.

[0299] Step 1 (Reaction E)

[0300] Subsequently, the hydroxyl group of the compound of formula (IXB) is converted to chloro to produce a compound of formula (IIB) according to the present disclosure, as shown in reaction E of Scheme 11 above.

[0301] Reaction E is carried out under standard chlorination conditions in the presence of a suitable chlorinating agent (such as phosphorus oxychloride, phosphorus pentachloride, cobalt chloride or bis(trichloromethyl)carbonate), 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).

[0302] The reaction mixture is stirred or heated at low temperature, room temperature until the starting material is exhausted. The reaction can be carried out in the presence of blocking groups, and these blocking groups can be removed after the reaction. Suitable blocking groups are well known to those skilled in the art (see TW Greene, " Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0303] Plan 12

[0304]

[0305] R 1b As defined above, and each n is independently 1, 2, 3 or 4.

[0306] Step 1 (Reaction F)

[0307] In another method according to the present disclosure, a compound of formula (XB) (wherein R 1b As defined above) with urea or guanidine to produce a biguanide compound of formula (XIB) as shown in reaction F of the scheme above (Scheme 12).

[0308] Reaction F is carried out under standard ring condensation conditions, for example in the presence of a suitable base (e.g., 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 (e.g., ethanol, methanol, dimethylformamide or mixtures thereof) and for example at about room temperature or reflux temperature.

[0309] The reaction can be carried out in the presence of protecting groups, which can be removed after the reaction. Suitable protecting groups are known to those skilled in the art (see TW Greene, "Protective Groups in Organic Synthesis," 3rd edition, New York, 1999).

[0310] Uses of the compounds disclosed herein

[0311] The effectiveness of the compounds of the present invention (including pharmaceutically acceptable salts or solvates) in the methods of the present invention can be demonstrated in appropriate in vitro or in vivo assays. The compounds of the present invention have the ability to increase β-glucocerebrosidase. Therefore, the compounds of the present invention can be used / administered to treat and / or prevent conditions associated with altered β-glucocerebrosidase activity in patients, such as lysosomal storage diseases and α-synuclein diseases. In one aspect, the lysosomal storage disease is Gaucher's disease. In another aspect, the α-synuclein disease 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, dementia with Lewy bodies, 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 disease, neurological Gaucher's disease, neuroaxial dystrophy, neurodegenerative diseases associated with Parkinson's disease, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and intact aging. See, e.g., Maegawa GHB 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 JR 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).

[0312] In another aspect, the present disclosure relates to a method for treating or preventing a condition associated with altered β-glucocerebrosidase activity in a patient in need thereof, comprising administering to a 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.

[0313] In another aspect, the present disclosure relates to a method of treating or preventing a lysosomal storage disease, such as Gaucher's disease, in a patient in need thereof, comprising 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.

[0314] In another aspect, the present disclosure relates to a method of treating or preventing an alpha-synuclein disease, such as Parkinson's disease, in a patient in need thereof, comprising 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.

[0315] 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's disease, Parkinson's disease, dementia with Lewy bodies, 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 disease, neurological Gaucher's disease, neuroaxial dystrophy, neurodegenerative diseases associated with Parkinson's disease, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and intact aging in a patient, 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.

[0316] In another aspect, any of the methods described herein may further comprise 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 competitively binds to the enzyme. In another aspect, the small molecule chaperone is selected from the group consisting of iminosugar alcohols, iminosugars, aminosugars, phenylthioglycosides, 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.

[0317] 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.

[0318] In another aspect, the present disclosure relates to a compound of the present disclosure as described herein for use in preventing or treating a condition associated with altered β-glucocerebrosidase activity 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.

[0319] In another aspect, the present disclosure relates to a compound of the present disclosure as described herein for use in preventing or treating lysosomal storage diseases such as Gaucher's disease. 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.

[0320] In another aspect, the present disclosure relates to a compound of the present disclosure as described herein for use in preventing or treating α-synuclein diseases such as Parkinson's disease. 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.

[0321] In another aspect, the present disclosure relates to a compound of the present disclosure as described herein for use in preventing or treating a disease or disorder selected from the group consisting of Gaucher's disease, Parkinson's disease, dementia with Lewy bodies, 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 disease, neurological Gaucher's disease, neuroaxonal dystrophy, neurodegenerative diseases associated with Parkinson's disease, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and intact aging. 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.

[0322] In another aspect, the present disclosure also relates to the use of a compound of the present disclosure as described herein for treating or preventing a condition associated with altered β-glucocerebrosidase activity (such as those described herein) 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.

[0323] In another aspect, the present disclosure relates to a compound of the present disclosure as described herein for use as a medicament. 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.

[0324] In another aspect, the present disclosure relates to the use of a compound of the present disclosure as described herein in the preparation of a medicament for preventing or treating a condition associated with altered β-glucocerebrosidase activity (such as lysosomal storage diseases and α-synucleinopathies described herein) 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.

[0325] In another aspect, the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure as described herein and at least one pharmaceutically acceptable excipient for use in treating or preventing a condition associated with altered β-glucocerebrosidase activity, such as lysosomal storage diseases and α-synucleinopathies described herein, 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.

[0326] Pharmaceutical composition

[0327] The present disclosure also relates to pharmaceutical compositions 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.

[0328] Due to their activity, the compounds of the present disclosure are useful in human medicine. As described above, the compounds of the present disclosure are useful, for example, in the treatment or prevention of 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 aforementioned conditions. As used herein, the term "patient" refers to any person who can experience the beneficial effects of the compounds of the present disclosure.

[0329] When administered to a patient, the compounds of the present disclosure may be administered as a component of a composition comprising a pharmaceutically acceptable excipient or carrier.

[0330] The compounds of the present disclosure can be administered in combination with at least one other therapeutic agent. The administration of the compounds of the present disclosure and at least one other therapeutic agent can be sequential or simultaneous. On the other hand, the compounds of the present disclosure and at least one other therapeutic agent are administered in separate dosage forms. On the other hand, the compounds of the present disclosure and at least one other therapeutic agent are administered simultaneously in the same dosage form.

[0331] The term "excipient" refers to a vehicle, diluent, or adjuvant with which the active ingredient is administered. Such pharmaceutical excipients may be sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, water or saline solutions for injections, as well as aqueous dextrose and glycerol solutions, may be used as vehicles. Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" (EW Martin, 21 st ed., 2005) or in “Handbook of Pharmaceutical Excipients” (Rowe CR, Paul JS, Marian E.Q., 6th ed.), both of which are incorporated herein by reference.

[0332] Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid composition (solutions, suspensions, or emulsions) for oral, topical, or parenteral administration.

[0333] 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, gum tragacanth, or polyvinyl pyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol, or glycine; lubricants for tablet preparation, for example, magnesium stearate; disintegrants, for example, starch, polyvinyl pyrrolidone, sodium starch glycolate, or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate.

[0334] Solid oral compositions can be prepared by conventional methods of mixing, filling or preparing tablets. Repeated blending operations can be used to distribute the active ingredient throughout the composition using large amounts of fillers. Such operations are conventional in the art. Tablets can be prepared, for example, by dry or wet granulation and optionally can be coated by methods well known in conventional pharmaceutical practice, particularly using an enteric coating.

[0335] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms. Suitable excipients, such as fillers, buffers or surfactants may be used.

[0336] The formulations mentioned can be prepared using standard methods, such as those described or referred to in the Spanish and US Pharmacopoeias and similar references.

[0337] In general, the effective amount of the compound of the present disclosure to be administered depends on the relative efficacy of the selected compound, the severity of the disease or disorder being treated, and the weight of the patient. The active compound can be administered once or more per day, for example 1, 2, 3, or 4 times per day, with a typical total daily dose ranging from about 0.01 mg / kg body weight / day to about 1000 mg / kg body weight / day. In another embodiment, the effective dose of the compound of the present disclosure is about 500 mg / kg body weight / day or less. In another embodiment, the effective dose of the compound of the present disclosure is about 100 mg / kg body weight / day or less. In another embodiment, the effective dose range is about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day of the compound of the present disclosure; in another embodiment, about 0.02 mg / kg body weight / day to about 50 mg / kg body weight / day of the compound of the present disclosure; and in another embodiment, about 0.025 mg / kg body weight / day to about 20 mg / kg body weight / day of the compound of the present disclosure.

[0338] The compositions of the present disclosure can be prepared by a method comprising mixing a compound of the present disclosure with a pharmaceutically acceptable excipient or carrier. Mixing can be accomplished using known methods for mixing compounds and pharmaceutically acceptable excipients or carriers. In another embodiment, the compound of the present disclosure is present in the composition in an effective amount.

[0339] The following examples are illustrative and non-limiting of the compounds, compositions and methods of the present disclosure. Suitable modifications and adaptations of the various conditions and parameters normally encountered in clinical therapy and obvious to those skilled in the art in view of this disclosure are within the spirit and scope of the present disclosure.

[0340] Example

[0341] General experimental conditions

[0342] Hereinafter, the term "h" means hour, "eq" means equivalent, "min" means minute, "HPLC" means high performance liquid chromatography, "TLC" means thin layer chromatography, "LC-MS" or "HPLC-MS" means liquid chromatography-mass spectrometry, "CDCl3" means deuterated chloroform, "DMSO-d6" means deuterated dimethyl sulfoxide, "DCM" means dichloromethane, "MeOH" means methanol, "ACN" means acetonitrile, "THF" means tetrahydrofuran, "DMF" means dimethylformamide, "EtOAc" means ethyl acetate, "NaHCO3" means sodium bicarbonate, "DIPE" means diisopropyl ether, "DIPEA" means N,N-diisopropylethylamine, and "HATU" means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- "-b]pyridinium 3-oxide hexafluorophosphate, "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium(0), "Pd(PPh3)4" refers to palladium-tetrakis(triphenylphosphine), "DavePhos" refers to 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, "XPhos" refers to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, "Zn(CN)2" refers to zinc(II) cyanide, "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium(0), "XantPhos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, "SnCl2" refers to tin(II) chloride, and "TBTU" refers to O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate".

[0343] The IUPAC names of the compounds given in this article were generated using ChemBioDraw Ultra 12.0 or 12.0.2. 1 H NMR spectra were generated and recorded on a Bruker (400 MHz).

[0344] HPLC spectra were recorded on Waters 2695, Agilent 1260 Infinity-2 and Waters UPLC-H class.

[0345] LC-MS analysis of the compounds was performed using one of the following methods:

[0346] Method-A1: SunFire C18 (50 mm x 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 0.5 min 10:5:85 + 4 min 10:5:85 to 95:5:0 + 4.5 min 95:5:0; Chromatographic system: Waters Alliance HT 2795 and PDA 2996; Mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0347] Method-B1: SunFire C18 (100 mm x 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 5 min 10:5:85 + 15 min 10:5:85 to 95:5:0 + 10 min 95:5:0; chromatography system: Waters Alliance HT 2795 and PDA 2996; mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0348] Method-C1: Aquity UPLC BEH C18 (50 mm x 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 (min) / % B): 0 / 95, 0.3 / 95, 2.0 / 5, 3.5 / 5, 3.6 / 95 MASS: Agilent 1290 infinity, Mass: 6150 SQD (ESI / APCI).

[0349] Method-D1: XSelect C18 (50 mm x 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: H2O 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).

[0350] Method-E1: Sunfire C18 (150mm x 19mm, 10μm); Wavelength: selected considering the UV maximum absorption of the target; Flow rate: 9mL / min-14mL / min; Column temperature: 30℃35℃; Run time: 30min; Mobile phase, A: ACN (MeOH:ACN (1:1) is sometimes 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; Chromatographic system: Dionex 3000 (PLCP001) equipped with foxy R1 fraction collector.

[0351] Method-F1: BEH C18 (50 mm x 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 0.5 min 5:80:15 + 4.5 min 5:80:15 to 10:85:5 + 4 min 10:85:5; Chromatographic system: Acquity H Class UPLC; Mass spectrometer: Acquity QDa.

[0352] Method-A2: Aquity UPLC BEH C18 (50 mm x 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 (min) / % A): 0.0 / 95, 0.3 / 95, 2.0 / 5, 3.5 / 5, 3.6 / 95, 4.2 / 95; MASS: Waters Acquity UPLC with SQD (ESI / APCI).

[0353] Method-B2: SunFire C18 (50 mm x 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 0.5 min 10:5:85 + 4 min 10:5:85 to 95:5:0 + 4.5 min 95:5:0; chromatography system: Waters Alliance HT 2795 and PDA 2996; mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0354] Method-C2: SunFire C18 (100 mm x 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 5 min 10:5:85 + 15 min 10:5:85 to 95:5:0 + 10 min 95:5:0; Chromatographic system: Waters Alliance HT 2795 and PDA 2996; Mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0355] General Procedure A

[0356]

[0357] Step 1

[0358] To a stirred solution of 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid (1.0 eq), an appropriate amine (1.5 eq) (e.g., 1-phenylpiperazine) and HATU (0.7 eq) in DMF (15 mL / mmol) was added DIPEA (1.3 eq). 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 (x3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product obtained was purified by flash column chromatography (EtOAc / hexanes 15%-30%) 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).

[0359] Step 2

[0360] To 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 equiv) in n-butanol (7.0 mL / mmol) at room temperature are added the appropriate aniline (e.g., 2-aminophenol) (1.1 equiv) and sulfuric acid (catalytic, 1 drop). The reaction mixture is stirred at 100-115°C for 18 hours. The reaction mixture is then cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer is extracted with ethyl acetate (3x), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product obtained is purified by flash column chromatography (EtOAc / hexanes 15%-30%) to give the desired amine product. (For example: (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone).

[0361] Step 3

[0362] A stirred solution of an appropriately 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 equiv) in TFA (15.0 mL / mmol) was stirred at 60° C. or at room temperature for 2-16 hours. The reaction mixture was then completely evaporated to give a residue, which was neutralized with saturated NaHCO₃. The aqueous mixture was extracted with ethyl acetate (3×), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product obtained was purified by flash column chromatography (MeOH / DCM 0%-10%) and / or by HPLC-semi-preparative (Method-D) to give the desired amine product (e.g., (6-amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone).

[0363] General Procedure A1 for the Synthesis of Example 1

[0364]

[0365] Step 11: Preparation of Intermediate 1

[0366] Methyl 2-chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate

[0367]

[0368] To a stirred mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (10 g, 48.3 mmol, 1.0 equiv), tert-octylamine (11.6 mL, 72.46 mmol, 1.5 equiv) in THF (10 mL) was added DIPEA (12.6 mL, 72.46 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 16 hours. TLC analysis (EtOAc / hexane 10%) showed complete conversion. The mixture was diluted with water and 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 methyl 2,6-dichloropyrimidine-4-carboxylate as a white solid.

[0369] Yield: (10.4 g, 72%).

[0370] ES-MS[M+H] + : 300.0, Rt=6.76 min (Method-A1).

[0371] Step 21: Preparation of Intermediate 2

[0372] 2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid

[0373]

[0374] To a stirred mixture of methyl 2,6-dichloropyrimidine-4-carboxylate (2.0 g, 6.6 mmol, 1.0 equiv) in THF:HO (1:1, 50 mL) was added lithium hydroxide (0.86 g, 35.9 mmol, 5.5 equiv). The resulting mixture was stirred at room temperature for 2 hours. TLC analysis (EtOAc / hexanes 10%) showed complete conversion. The mixture was acidified by adding concentrated HCl and 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.

[0375] Yield: (1.02 g, 54% yield).

[0376] ES-MS[M+H] + : 286.0, Rt=5.59 min (Method-A1).

[0377] Step 31: Preparation of Intermediate 3

[0378] (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

[0379]

[0380] To 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 equiv), 1-phenylpiperazine (0.32 mL, 2.09 mmol, 1.5 equiv), and HATU (0.40 g, 1.00 mmol, 0.7 equiv) in DMF (20 mL) was added DIPEA (0.32 mL, 1.84 mmol, 1.3 equiv). The resulting mixture was stirred at room temperature for 14 hours. TLC analysis (EtOAc / hexanes 50%) showed complete conversion. 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 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.

[0381] Yield: (0.206 g, 35% yield).

[0382] ES-MS[M+H] + : 430.0, Rt=7.146 min (Method-A1).

[0383] Step 41: Intermediate 4

[0384] (2-((2-Hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)

[0385]

[0386] To 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 equiv) in 1-butanol (3 mL) was added 2-aminophenol (0.060 g, 0.55 mmol, 1.1 equiv) and sulfuric acid (catalytic, 1 drop) at room temperature. The reaction mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3x), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting crude was purified by flash column chromatography (EtOAc / heptane 50-100) to afford (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone as a white solid.

[0387] Yield: (0.155 g, 65%).

[0388] ES-MS[M+H] + : 503.1, Rt=7.052 min (Method-A1).

[0389] Example 1

[0390] (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

[0391]

[0392] 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 equiv) in TFA (2.0 mL) was stirred at 60 °C for 2 hours. The reaction mixture was then completely evaporated to give a residue that was basified with saturated NaHCO3. 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 (MeOH / CHCl 10%) to give the title compound (6-amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone as a white solid.

[0393] Yield: (0.069 g, 58%).

[0394] ES-MS[MH] - : 389.1, Rt=16.93 min (Method-B1).

[0395] 1 H NMR (400MHz, DMSO-d6) δ10.14(brs,1H),8.09–7.78(m,2H),7.47–7.11(m,2H),7.08–6.92(m,4H),6.82(td,J=3.8,1.2Hz,3H ), 6.76–6.62(m,1H),6.00(s,1H),3.72(t,J=5.3Hz,2H),3.59(t,J=5.1Hz,2H),3.19(t,J=5.3Hz,2H),3.11(t,J=5.2Hz,2H).

[0396] Intermediate 5

[0397] (2-((3-methoxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

[0398]

[0399] Intermediate 5 was synthesized following the procedure described for the preparation of Intermediate 4 using m-anisidine and isolated as a light brown powder.

[0400] Yield: (0.115 g, 96%).

[0401] ES-MS[M+H] + : 517.1, Rt=7.257 min (Method-A1).

[0402] Example 2

[0403] (6-Amino-2-((3-methoxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

[0404]

[0405] The title compound was synthesized following 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.

[0406] Yield: (0.039 g, 43%).

[0407] ES-MS[M+H] + : 405.0, Rt=17.96 min (Method-B1).

[0408] 1 H NMR (400MHz, DMSO-d6) δ9.11 (s, 1H), 7.53 (t, J = 2.3Hz, 1H), 7.27 (ddd, J = 8.2, 2.0, 0 .9Hz,1H),7.23(dd,J=8.8,7.2Hz,2H),7.10(t,J=8.1Hz,1H),6.99–6.93(m,2H),6. 87–6.78(m,3H),6.46(ddd,J=8.2,2.5,0.9Hz,1H),5.99(s,1H),3.72(q,J=3.8Hz,2 H), 3.69 (s, 3H), 3.59 (t, J = 5.1Hz, 2H), 3.19 (t, J = 5.3Hz, 2H), 3.14 (d, J = 5.1Hz, 2H).

[0409] Intermediate 6

[0410] (4-Phenylpiperazin-1-yl)(2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)methanone

[0411]

[0412] The title compound was synthesized following the procedure described for the preparation of Intermediate 4 using p-toluidine and isolated as a light brown powder.

[0413] Yield: (0.094 g, 67%).

[0414] ES-MS[M+H] + : 501.2, Rt=7.458 min (Method-A1).

[0415] Example 3

[0416] (6-amino-2-(p-tolylamino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

[0417]

[0418] The title compound was synthesized following the procedure described for Preparative 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.

[0419] Yield: (0.034 g, 48%).

[0420] ES-MS[M+H] +: 389.0, Rt=18.640 min (Method-B1).

[0421] 1 H NMR(400MHz, DMSO-d6)δ9.00(s,1H),7.70–7.58(m,2H),7.23(dd,J=8.6,7.2Hz,2H),7.02(d,J=8.8Hz,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=5.1Hz,2H),3.20(d,J=5.4Hz,2H),3.16–3.08(m,2H),2.22(s,3H).

[0422] Intermediate 7

[0423] N-Benzyl-2-chloro-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0424]

[0425] The title compound was synthesized following the procedure described for the preparation of Intermediate 3 using N-methyl-1-phenylmethanamine and isolated as a light brown powder.

[0426] Yield: (0.310 g, 46%).

[0427] ES-MS[M+H] + : 389.0, Rt=7.09 min (Method-A1).

[0428] Intermediate 8

[0429] N-Benzyl-2-((2-hydroxyphenyl)amino)-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0430]

[0431] The title compound was synthesized following the procedure described for the preparation of Intermediate 4 using 2-aminophenol and isolated as a light brown powder.

[0432] Yield: (0.220 g, 60%).

[0433] ES-MS[M+H] + : 462.1, Rt=6.95 min (Method-A1).

[0434] Example 4

[0435] 6-amino-N-benzyl-2-((2-hydroxyphenyl)amino)-N-methylpyrimidine-4-carboxamide

[0436]

[0437] The title compound was synthesized following the procedure described for Preparative 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.

[0438] Yield: (0.135 g, 81%).

[0439] ES-MS[MH] - : 350.1, Rt=16.50 min (Method-B1).

[0440] 1 H NMR (400MHz, DMSO-d6) δ10.12(d,J=39.7Hz,1H),8.43–7.70(m,2H),7.48–7.35(m,1H),7.35–7.23(m,4H),6.98(d,J=8 .2Hz,2H),6.87–6.80(m,2H),6.79–6.68(m,1H),5.99(d,J=6.9Hz,1H),4.60(d,J=29.1Hz,2H),2.84(d,J=28.8Hz,3H).

[0441] Intermediate 9

[0442] 2-Chloro-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0443]

[0444] The title compound was synthesized following the procedure described for the preparation of Intermediate 3 using N-methylaniline and isolated as a light brown powder.

[0445] Yield: (0.196 g, 60%).

[0446] ES-MS[M+H] + : 375.0, Rt=6.823 min (Method-A1).

[0447] Intermediate 10

[0448] 2-((2-Hydroxyphenyl)amino)-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0449]

[0450] The title compound was synthesized following 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 light brown powder.

[0451] Yield: (0.085 g, 36%).

[0452] ES-MS[M+H] + : 448.1, Rt=6.824 min (Method-A1).

[0453] Example 5

[0454] 6-amino-2-((2-hydroxyphenyl)amino)-N-methyl-N-phenylpyrimidine-4-carboxamide

[0455]

[0456] The title compound was synthesized following the procedure described for Preparative 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.

[0457] Yield: (0.046 g, 73%).

[0458] ES-MS[MH] - : 336.0, Rt=15.46 min (Method-B1).

[0459] 1 H NMR (400MHz, DMSO-d6) δ10.10(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=6.4Hz,3H).

[0460] Intermediate 11

[0461] N-Methyl-N-phenyl-2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0462]

[0463] The title compound was synthesized following 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 light brown powder.

[0464] Yield: (0.106 g, 71% yield).

[0465] ES-MS[M+H] + : 446.1, Rt=7.189 min (Method-A1).

[0466] Example 6

[0467] 6-amino-N-methyl-N-phenyl-2-(p-tolylamino)pyrimidine-4-carboxamide

[0468]

[0469] The title compound was synthesized following the procedure described for Preparative 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.

[0470] Yield: (0.033 g, 50%).

[0471] ES-MS[M+H] + : 334.1, Rt=17.108 min (Method-B1).

[0472] 1 H NMR (400MHz, DMSO-d6) δ8.73(bs,1H),7.42–7.05(m,7H),6.96(d,J=8.2Hz,2H),6.68–6.49(m,2H),5.90(s,1H),3.34(d,J=0.4Hz,3H),2.21(s,3H).

[0473] Intermediate 12

[0474] 2-((3-methoxyphenyl)amino)-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0475]

[0476] This compound was synthesized following 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.

[0477] Yield: (0.120 g, 68%).

[0478] ES-MS[M+H] + : 462.1, Rt=6.975 min (Method-A1).

[0479] Example 7

[0480] 6-amino-2-((3-methoxyphenyl)amino)-N-methyl-N-phenylpyrimidine-4-carboxamide

[0481]

[0482] The title compound was synthesized following the procedure described for Preparative Example 1 using 2-((3-methoxyphenyl)amino)-N-methyl-N-phenyl-6-((2,4,4-trimethyl-pentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a white powder.

[0483] Yield: (0.053 g, 59%).

[0484] ES-MS[M+H] + : 350.0, Rt=16.374 min (Method-B1).

[0485] 1 H NMR(400MHz,DMSO-d6)δ8.87(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).

[0486] Intermediate 13

[0487] (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[0488]

[0489] The title compound was synthesized following the procedure described for the preparation of Intermediate 3 using isoindoline hydrochloride and isolated as a white powder.

[0490] Yield: (0.029 g, 71% yield).

[0491] ES-MS[M+H] + : 387.0, Rt=7.657 min (Method-A1).

[0492] Intermediate 14

[0493] (2-((2-Hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[0494]

[0495] The title compound was synthesized following 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.

[0496] Yield: (0.240 g, 70%).

[0497] ES-MS[M+H] + : 460.1, Rt=7.398 min (Method-A1).

[0498] Example 8

[0499] (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[0500]

[0501] The title compound was synthesized following 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.

[0502] Yield: (0.029 g, 16%).

[0503] ES-MS[M+H] + : 348.0, Rt=16.891 min (Method-B1).

[0504] 1H NMR(400MHz,DMSO-d6)δ10.06(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).

[0505] Intermediate 15

[0506] 2-Chloro-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0507]

[0508] The title compound was synthesized following 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.

[0509] Yield: (0.326 g, 55%).

[0510] ES-MS[MH] - : 429.0, Rt=7.592 min (Method-A1).

[0511] Intermediate 16

[0512] 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

[0513]

[0514] The title compound was synthesized following 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.

[0515] Yield: (0.334 g, 87%).

[0516] ES-MS[MH] - : 500.1, Rt=7.452 min (Method-A1).

[0517] Example 9

[0518] 6-amino-2-((2-hydroxyphenyl)amino)-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine-4-carboxamide

[0519]

[0520] The title compound was synthesized following 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.

[0521] Yield: (0.048 g, 19%).

[0522] ES-MS[M+H] + : 388.0, Rt=18.006 min (Method-B1).

[0523] 1 H NMR(400MHz,DMSO-d6)δ10.17(brs,1H),8.05–7.83(m,3H),7.12(s,1H),7.0 8–6.97(m,2H),6.96–6.90(m,2H),6.89–6.80(m,2H),6.80–6.67(m,1H),5.9 6-5.91(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).

[0524] Intermediate 17

[0525] 2-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0526]

[0527] The title compound was synthesized following 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.

[0528] Yield: (0.531 g, 98%).

[0529] ES-MS[M+H] +: 415.0, Rt=7.590 min (Method-A1).

[0530] Intermediate 18

[0531] 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

[0532]

[0533] The title compound was synthesized following 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-trimethyl-pentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a yellow powder.

[0534] Yield: (0.475 g, 76%).

[0535] ES-MS[M+H] + : 488.1, Rt=7.464 min (Method-A1).

[0536] Example 10

[0537] 6-amino-N-(2,3-dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)-N-methylpyrimidine-4-carboxamide

[0538]

[0539] The title compound was synthesized following the procedure described for Preparative 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.

[0540] Yield: (0.239 g, 64%).

[0541] ES-MS[M+H] + : 376.0, Rt=17.717 min (Method-B1).

[0542] 1H NMR(400MHz,DMSO-d6)δ10.18(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. 7,6.3,2.4Hz,1H),5.94(d,J=14.9Hz,1H),5.41–5.28(m,1H),4.70(p,J=7.7Hz, 1H), 3.17 (dd, J = 16.3, 8.4Hz, 1H), 3.05 (h, J = 7.5Hz, 3H), 2.77 (d, J = 16.1Hz, 3H).

[0543] Intermediate 19

[0544] 2-Chloro-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0545]

[0546] The title compound was synthesized following the procedure described for the preparation of Intermediate 3 using aniline and isolated as a yellow powder.

[0547] Yield: (0.307 g, 81%).

[0548] ES-MS[M+H] + : 361.0, Rt=7.526 min (Method-A1).

[0549] Intermediate 20

[0550] 2-((2-Hydroxyphenyl)amino)-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0551]

[0552] The title compound was synthesized following 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.

[0553] Yield: (0.220 g, 60%).

[0554] ES-MS[M+H] + : 434.1, Rt=7.571 min (Method-A1).

[0555] Example 11

[0556] 6-amino-2-((2-hydroxyphenyl)amino)-N-phenylpyrimidine-4-carboxamide

[0557]

[0558] The title compound was synthesized following the procedure described for Preparative 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.

[0559] Yield: (0.028 g, 17%).

[0560] ES-MS[M+H] + : 322.0, Rt=17.818 min (Method-B1).

[0561] 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),9.98(s,1H),8.24(dd,J=7.5,2.0Hz,1H),7.92(s,1H),7.81(d d, J=8.7, 1.2Hz, 2H), 7.38 (dd, J=8.5, 7.4Hz, 2H), 7.24–7.05 (m, 3H), 6.97–6.74 (m, 3H), 6.61 (s, 1H).

[0562] Intermediate 21

[0563] 2-Chloro-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0564]

[0565] The title compound was synthesized following the procedure described for the preparation of Intermediate 3 using 1,2,3,4-tetrahydronaphthalen-2-amine and isolated as a yellow powder.

[0566] Yield: (0.111 g, 15%).

[0567] ES-MS[M+H] + : 415.0, Rt=8.074 min (Method-A1).

[0568] Intermediate 22

[0569] 2-((2-Hydroxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0570]

[0571] The title compound was synthesized following the procedure described for the preparation of Intermediate 4 using 2-chloro-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-6-((2,4,4-trimethyl-pentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as a yellow powder.

[0572] Yield: (0.038 g, 29%).

[0573] ES-MS[M+H] + : 488.1, Rt=7.614 min (Method-A1).

[0574] Example 12

[0575] 6-amino-2-((2-hydroxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine-4-carboxamide

[0576]

[0577] The title compound was synthesized following 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.

[0578] Yield: (0.012 g, 44%).

[0579] ES-MS[MH] - : 374.0, Rt=18.723 min (Method-B1).

[0580] 1H NMR(400MHz, DMSO-d6)δ9.95(s,1H),8.30(d,J=8.2Hz,1H),8.09(dd,J=8.0,1.5Hz,1H),7.78(s,1H),7.25–6.98(m,6H),6.93–6.77(m,2H),6.71(d dd,J=8.8,6.9,2.0Hz,1H),6.55(s,1H),4.40–3.92(m,1H),3.01(dd,J=1 6.2,5.2Hz,1H),2.90–2.82(m,3H),2.17–1.95(m,1H),1.93–1.72(m,1H).

[0581] Intermediate 23

[0582] 2-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0583]

[0584] The title compound was synthesized following the procedure described for the preparation of Intermediate 3 using 2,3-dihydro-1H-inden-2-amine and isolated as a brown solid.

[0585] Yield: (0.169 g, 40%).

[0586] ES-MS[M+H] + : 401.0, Rt=7.634 min (Method-A1).

[0587] Intermediate 24

[0588] N-(2,3-Dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0589]

[0590] The title compound was synthesized following 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.

[0591] Yield: (0.100 g, 50%).

[0592] ES-MS[M+H] +: 474.1, Rt=7.296 min (Method-A1).

[0593] Example 13

[0594] 6-amino-N-(2,3-dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)pyrimidine-4-carboxamide

[0595]

[0596] The title compound was synthesized following the procedure described for the preparation of Example 1 using N-(2,3-dihydro-1H-inden-2-yl)-2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethyl-pentan-2-yl)amino)pyrimidine-4-carboxamide and isolated as an orange powder.

[0597] Yield: (0.021 g, 33%).

[0598] ES-MS[M+H] + : 362.0, Rt=18.309 min (Method-B1).

[0599] 1 H NMR (400MHz, DMSO-d6) δ9.95 (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=5.4,3.3Hz,2H),7.19–7.13(m,2H),7.09(brs, 2H),6.90–6.76(m,2H),6.70(ddd,J=8.0,6.9,2.1Hz,1H),6.53(s,1H),4.67(qt , J=7.7, 6.5Hz, 1H), 3.22 (dd, J=15.8, 7.5Hz, 2H), 2.96 (dd, J=15.8, 6.4Hz, 2H).

[0600] Intermediate 25

[0601] (2-(((1S,2S)-2-Hydroxycyclohexyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

[0602]

[0603] To 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 equiv) in DMF (1 mL) was added (1S,2S)-2-aminocyclohexan-1-ol (0.119 g, 1.03 mmol, 3.0 equiv) and KCO (96 mg, 0.69 mmol, 2.0 equiv). The reaction mixture was stirred at 120° C. for 18 hours. 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.

[0604] Yield: (0.180 g, crude product).

[0605] ES-MS[M+H] + : 509.2, Rt=7.112 min (Method-A1).

[0606] Example 14

[0607] (6-Amino-2-(((1S,2S)-2-hydroxycyclohexyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

[0608]

[0609] The title compound was synthesized following 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 light brown powder.

[0610] Yield: (0.007 g, 6%).

[0611] ES-MS[M+H] + : 397.0, Rt=16.59 min (Method-B1).

[0612] 1H NMR (400MHz, DMSO-d6) δ7.23(dd,J=8.7,7.2Hz,2H),6.98–6.92(m,2H),6.81(t,J=7.3Hz,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).

[0613] Intermediate 26

[0614] N-Benzyl-2-(((1S,2S)-2-hydroxycyclohexyl)amino)-N-methyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0615]

[0616] The title compound was synthesized following 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.

[0617] Yield: (0.10 g, 31%).

[0618] ES-MS[M+H] + : 468.1, Rt=7.046 min (Method-A1).

[0619] Example 15

[0620] 6-amino-N-benzyl-2-(((1S,2S)-2-hydroxycyclohexyl)amino)-N-methylpyrimidine-4-carboxamide

[0621]

[0622] The title compound was synthesized following the procedure described for Preparative 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.

[0623] Yield: (0.013 g, 5%).

[0624] ES-MS[M+H] +: 356.1, Rt=16.109 min (Method-B1).

[0625] 1 H NMR (400MHz, DMSO-d6) δ7.69–7.11(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=41.4Hz,3H),2.18–1.72(m,2H),1.68–1.36(m,2H),1.34–0.92(m,6H).

[0626] General Procedure B

[0627]

[0628] Step 1

[0629] At room temperature, 3M HCl (0.33 mL / mmol) is added to a mixture of the appropriate amine (e.g., 3-bromoaniline) (1.0 equivalent) and dicyandiamide (1.0 equivalent). The reaction mixture is heated to 90° C. for 18 hours. After completion of the reaction, the reaction mixture is cooled to room temperature and evaporated under reduced pressure and co-distilled twice with toluene. The crude product is washed with ether or triturated with EtOAc and dried to give the desired biguanide product (e.g., 3-bromophenylbiguanide hydrochloride).

[0630] Step 2

[0631] To a stirred solution of the appropriate biguanide compound (e.g., 3-bromophenylbiguanide hydrochloride) (1.0 equiv) and diethyl oxalate (3.0 equiv) in methanol (5.12 mL / mmol) is added a 25% methanolic solution of sodium methoxide (1.0-5 equiv). The resulting mixture is stirred at reflux for 16 hours. The reaction mixture is then cooled to room temperature and concentrated to dryness. The resulting solid is poured into water and filtered to afford a white solid, which is treated with a solution of LiOH (5 equiv) in THF:H2O (1:1, 12 mL / mmol) and stirred at room temperature for 3 hours. The mixture is then acidified with concentrated HCl, and the resulting suspension is filtered to afford the desired carboxylic acid derivative (e.g., 4-amino-6-((3-bromophenyl)amino)-1,3,5-triazine-2-carboxylic acid).

[0632] Step 3

[0633] Follow General Procedure A, step 1.

[0634] General Procedure B1-1 for the Synthesis of Example 16

[0635]

[0636] Step 11: Preparation of Intermediate 27

[0637] 3-Bromophenylbiguanide hydrochloride

[0638]

[0639] At room temperature, 3M HCl (3.84mL) is added to the mixture of 3-bromoaniline (2.0g, 11.63mmol, 1.0 equivalent) and dicyandiamide (0.978g, 11.63mmol, 1.0 equivalent). The reaction mixture is heated to 90 ℃ and kept for 18 hours. After the reaction is completed, the reaction mixture is cooled to room temperature and completely evaporated under reduced pressure, and co-distilled twice with toluene. The crude product is washed with ether and dried to obtain the required product as a white solid.

[0640] Yield: (1.79 g, 53%).

[0641] ES-MS[M+H] + : 255.9, Rt=7.149 min (Method-A1).

[0642] Step 21: Preparation of Intermediate 28

[0643] 4-Amino-6-((3-bromophenyl)amino)-1,3,5-triazine-2-carboxylic acid

[0644]

[0645] To a stirred solution of 3-bromophenyl biguanide hydrochloride (0.30 g, 1.17 mmol, 1.0 equivalent) and diethyl oxalate (0.48 mL, 3.51 mmol, 3.0 equivalent) in MeOH (6 mL) was added a solution of 25% NaOMe in MeOH (0.32 mL, 1.17 mmol, 1.0 equivalent). The resulting mixture was refluxed for 16 hours. The reaction mixture was then cooled to room temperature and concentrated to dryness. The resulting solid was poured into water and filtered to give a white solid, which was treated with a solution of LiOH (0.127 g, 5.3 mmol, 5 equivalents) in THF:HO (1:1, 14 mL) and stirred at room temperature for 3 hours. The mixture was then 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.

[0646] Yield: (0.298 g, 82% over 2 steps).

[0647] ES-MS[M+H] + : 311.9, Rt=0.648 min (Method-A1).

[0648] Step 31: Preparation of Example 16

[0649] (4-Amino-6-((3-bromophenyl)amino)-1,3,5-triazin-2-yl)(4-phenylpiperazin-1-yl)methanone

[0650]

[0651] The title compound was synthesized following the procedure described for the preparation of Intermediate 3 using 4-amino-6-((3-bromophenyl)amino)-1,3,5-triazine-2-carboxylic acid and isolated as a white powder.

[0652] Yield: (0.040 g, 18%).

[0653] ES-MS[M+H] + : 455.9, Rt=18.585 min (Method-B1).

[0654] 1 H NMR(400MHz, DMSO-d6)δ9.96(brs,1H),8.02(t,J=2.0Hz,1H),7.80-7.72(m,1H),7.53-7.45(m,2H),7.31–7.20(m,3H),7.20–7.12(m,1 H), 6.96 (d, J = 7.8Hz, 2H), 6.82 (t, J = 7.2Hz, 1H), 3.80–3.65 (m, 2H), 3.47 (t, J = 5.0Hz, 2H), 3.18 (t, J = 5.3Hz, 2H), 3.13 (t, J = 5.1Hz, 2H).

[0655] Example 17

[0656] 4-amino-N-benzyl-6-((3-bromophenyl)amino)-N-methyl-1,3,5-triazine-2-carboxamide

[0657]

[0658] This compound was synthesized following the procedure described for the preparation of 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.

[0659] Yield: (0.068 g, 34% yield).

[0660] ES-MS[M+H] + : 414.9, Rt=18.216 min (Method-B1).

[0661] 1 H NMR(400MHz, DMSO-d6)δ9.99-9.85(m,1H),8.00(dt,J=9.3,2.0Hz,1H),7.82-7.70(m,1H),7.55-7.40(m,2H),7.42–7.34(m,3H),7.31 (dq,J=7.6,1.5Hz,2H),7.24(td,J=8.0,0.9Hz,1H),7.17(ddt,J=7.9,2.0,1.0Hz,1H),4.52(d,J=68.5Hz,2H),2.80(d,J=24.2Hz,3H).

[0662] Example 18

[0663] 4-Amino-6-((3-bromophenyl)amino)-N-methyl-N-phenyl-1,3,5-triazine-2-carboxamide

[0664]

[0665] The title compound was synthesized following the procedure described for the preparation of 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.

[0666] Yield: (0.029 g, 29%).

[0667] ES-MS[M+H] + : 398.9, Rt=17.847 min (Method-B1).

[0668] 1 H NMR (400MHz, DMSO-d6) δ7.41–6.89(m,12H),3.32(s,3H).

[0669] Example 19

[0670] 4-Amino-6-((3-bromophenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3,5-triazine-2-carboxamide

[0671]

[0672] The title compound was synthesized following the procedure described for the preparation of 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.

[0673] Yield: (0.008 g, 3%).

[0674] ES-MS[M+H] + : 438.9, Rt=19.904 min (Method-B1).

[0675] 1 H NMR (400MHz, DMSO-d6) δ10.04(brs,1H),8.31(d,J=7.9Hz,1H),8.06(t,J=2.0Hz,1H),7.80(d,J=8.3Hz,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=16.5,4.6Hz,1H),2. 92–2.71(m,3H),2.08–1.93(m,1H),1.78(ddt,J=12.4,10.3,8.0Hz,1H).

[0676] General Procedure B1-2 for the Synthesis of Example 20

[0677]

[0678] Step 11: Preparation of Intermediate 29

[0679] 2-Methoxyphenylbiguanide hydrochloride

[0680]

[0681] To a mixture of o-anisidine (1.0 g, 8.13 mmol, 1.0 equiv) and dicyandiamide (0.700 g, 8.29 mmol, 0.7 equiv) was added 3 M HCl (2.84 mL) at room temperature. The reaction mixture was heated to 90° C. for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and completely evaporated under reduced pressure and co-distilled twice with toluene. The crude product was washed with ether and dried to give the desired product as a pink solid.

[0682] Yield: (1.96 g, 99%).

[0683] ES-MS[M+H] + :208.1, Rt=7.037min (Method-A1).

[0684] Step 21: Preparation of Intermediate 30

[0685] 4-Amino-6-((2-methoxyphenyl)amino)-1,3,5-triazine-2-carboxylic acid

[0686]

[0687] To a stirred solution of 2-methoxyphenyl biguanide hydrochloride (0.83 g, 3.4 mmol, 1.0 equivalent) and diethyl oxalate (1.46 mL, 10.8 mmol, 3.0 equivalents) in MeOH (18 mL) was added a 25% NaOMe solution in MeOH (0.96 mL, 16.8 mmol, 5.0 equivalents). The resulting mixture was refluxed for 16 hours. The reaction mixture was then cooled to room temperature and concentrated to dryness. The resulting solid was poured into water and filtered to give a white solid, which was treated with a THF:HO (1:1, 30 mL) solution of LiOH (0.290 g, 12.1 mmol, 5.0 equivalents) and stirred at room temperature for 3 hours. The mixture was then acidified with concentrated HCl, and the resulting suspension was filtered to give 4-amino-6-((2-methoxyphenyl)amino)-1,3,5-triazine-2-carboxylic acid as a yellow solid.

[0688] Yield: (0.517 g, 58% over 2 steps).

[0689] ES-MS[M+H] + : 261.0, Rt=0.567 min (Method-A1).

[0690] Step 31: Preparation of Example 20

[0691] 4-amino-6-((2-methoxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3,5-triazine-2-carboxamide

[0692]

[0693] The title compound was synthesized following the procedure described for the preparation of 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.

[0694] Yield: (0.028 g, 14%).

[0695] ES-MS[M+H] + : 391.0, Rt=19.011 min (Method-B1).

[0696] 1 H NMR (400MHz, DMSO-d6) δ8.52–8.35(m,1H),8.33(s,1H),8.01(d,J=7.9Hz,1H),7.346-7.29(m,2H),7.23–6.99(m,6H),6.92(td,J=7.5,1. 7Hz,1H),4.22–4.02(m,1H),3.83(s,3H),3.00(dd,J=16.2,5.3Hz,1H),2.92–2.68(m,3H),1.99(td,J=8.5,4.6Hz,1H),1.87–1.64(m,1H).

[0697] General Procedure C

[0698]

[0699] Step 1

[0700] 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 (6 mL / mmol) at room temperature are added the appropriate amine (e.g., p-toluidine) (1.2 eq.), catalytic sulfuric acid (2 drops) and heated to 100°C for 16 hours. After completion of the reaction, the reaction mixture is cooled to room temperature and slowly basified with saturated NaHCO3 and the organic product is extracted into EtOAc. The organic layer is dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure to give the crude product. The crude product is purified by column chromatography (silica gel 230-400 mesh) using 1% to 3% methanol in DCM as eluent to give the desired amine compound (e.g., methyl 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate).

[0701] Step 2

[0702] Sodium hydroxide (2 equivalents) is added to a stirred solution of the appropriate carboxylate (e.g., methyl 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate) (1 equivalent) in MeOH:water (10:1 mL) at 0°C. The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure. The residue is diluted with water and acidified with 2N HCl at 0°C. The product precipitates, is filtered, and dried under vacuum to yield 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 is used in the next step without purification.

[0703] Step 3

[0704] A 50% solution of propylphosphonic anhydride (T3P) (2 eq) in EtOAc is 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 is warmed to room temperature and stirred for 16 hours. The reaction mixture is quenched with a minimum amount of aqueous NaHCO3 solution and the organic product is extracted with DCM (3 x 25 mL). The combined organic extracts are dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to give the crude compound. The crude product was purified by column chromatography (silica gel 230-400 mesh; 2%-4% MeOH in DCM as eluent) 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).

[0705] Step 4

[0706] Follow General Procedure A, step 3.

[0707] General Procedure C1 for the Synthesis of Example 21

[0708]

[0709] Step-1: Preparation of intermediate 31

[0710] 2-(p-Tolylamino)-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxylic acid methyl ester

[0711]

[0712] To 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) was added p-toluidine (0.21 g, 2.0 mmol, 1.2 eq), catalytic H2SO4 (2 drops) and heated to 100°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to RT and slowly basified with saturated NaHCO3, and the organic product was extracted into EtOAc. The organic layer was dried over anhydrous Na2SO4, 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 eluent to give methyl 2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate as a light yellow solid (the material shown in LCMS was the trans-esterification with BuOH).

[0713] Yield: (0.35 g, 56%).

[0714] ES-MS[M+H] + : 413.32; Rt=2.40 min (Method-C1).

[0715] Step-2: Preparation of intermediate 32

[0716] 2-(p-Tolylamino)-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxylic acid

[0717]

[0718] 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:water (10:1 mL) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. 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 precipitated, which was filtered and dried under vacuum to yield 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.

[0719] Yield: (0.25 g, crude product).

[0720] ES-MS[M+H] + : 357.18; Rt=2.07 min (Method-C1).

[0721] Step-3: Preparation of intermediate 33

[0722] N-Benzyl-N-methyl-2-(p-tolylamino)-6-(2,4,4-trimethylpentan-2-ylamino)pyrimidine-4-carboxamide

[0723]

[0724] At 0 ° C, a solution of 50% propylphosphonic anhydride (T3P) (0.89 mL, 1.40 mmol, 2 equivalents) 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 equivalent), N-methyl-1-phenylmethanamine (0.17 g, 1.40 mmol, 2 equivalents) and N,N-diisopropylethylamine (0.45 g, 3.51 mmol, 5 equivalents) in DCM (10 mL). The reaction mixture was warmed to RT and stirred for 16 hours. The reaction mixture was quenched with a minimum amount of NaHCO3 aqueous solution and the organic product was extracted with DCM (3×25 mL). The combined organic extracts were dried over anhydrous Na2SO4. 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; 2%-4% MeOH in DCM as eluent) to give 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.

[0725] Yield: (0.21 g, 48% over 2 steps).

[0726] ES-MS[M+H] + : 460.82; Rt=2.32 min (Method-C1).

[0727] 1 H NMR (400MHz, DMSO-d6): δ8.91-8.87(d,J=14.8Hz,1H),7.58-7.52(m,2H),7.36-7.26(m,5H),7.02-7.00(m,2H),6.88(s,1H),6.02-6.0 0(d,J=8.4Hz,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).

[0728] Step-4: Preparation of Example 21

[0729] 6-amino-N-benzyl-N-methyl-2-(p-tolylamino)pyrimidine-4-carboxamide

[0730]

[0731] At RT, add TFA (5mL) and be heated to 60 ℃ and keep 16 hours to the stirred solution of intermediate 32 (0.21g, 0.45mmol, 1.0 equivalent) in DCM (10mL).Reactant mixture is evaporated completely, obtain residue, this residue is used saturated NaHCO alkalize, and organic product is extracted in DCM.Use anhydrous Na SO Dry organic layer, and evaporate under reduced pressure solvent.Use 2% to 5%MeOH DCM solution as eluent, by column chromatography (silica gel 230-400 order) purification of crude product, obtain 6-amino-N-benzyl-N-methyl-2-(p-tolylamino) pyrimidine-4-methane amide that is light brown colloidal liquid.

[0732] Yield: (78 mg, 49%).

[0733] ES-MS[M+H] + : 348.22; Rt=1.87 min (Method-C1).

[0734] 1 H NMR (400MHz, DMSO-d6): δ9.01-8.96 (d, J=16.4Hz, 1H), 7.65-7.56 (m, 2H), 7.38-7.25 (m, 5H), 7.02-6.9 8(m,2H),6.77(s,br,2H),5.96-5.94(d,J=8Hz,1H),4.62-4.57(m,2H),2.88-2.80(m,3H),2.22(s,3H).

[0735] Intermediate 34

[0736] N-(1,2,3,4-Tetrahydronaphthalen-2-yl)-2-(p-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0737]

[0738] The title compound was synthesized following the procedure described for the preparation of Intermediate 33.

[0739] Yield: (complete conversion, continue without purification).

[0740] ES-MS[M+H] +: 486 (raw materials).

[0741] Example 22

[0742] 6-amino-N-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-(p-tolylamino)pyrimidine-4-carboxamide

[0743]

[0744] The title compound was synthesized following the procedure described for the preparation of Example 21.

[0745] Yield: (14 mg, 21%).

[0746] ES-MS[M+H] + : 374; Rt = 3.10 min (Method-C1).

[0747] General Procedure A2 for the Synthesis of Example 23

[0748]

[0749] Step-1: Preparation of intermediate 35

[0750] 2-Amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

[0751]

[0752] In a sealed tube, NaOMe (30% in MeOH; 6.06 mL, 33.6 mmol, 5.0 equiv) was added to a stirred solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (HCl salt) (2.0 g, 6.73 mmol, 1.0 equiv) in EtOH (30 mL) and stirred for 10 minutes at RT. At RT, guanidine hydrochloride (0.96 g, 10.1 mmol, 1.5 equiv) was added to the reaction mixture. The reaction mixture was heated to 100 ° C for 16 hours under stirring. The solvent was evaporated under reduced pressure, diluted with water, and adjusted to pH ~ 6 with dilute HCl to give intermediate 1 as a pure solid, which was filtered and dried under reduced pressure.

[0753] Yield: (1.2 g, 61%).

[0754] ES-MS[M+H] + : 257.09, Rt=0.59 min (Method-A2).

[0755] 1H NMR (400MHz, DMSO-d6): δ11.11(br 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=12Hz,2H),2.25(m,2H).

[0756] Step-2: Preparation of intermediate 36

[0757] 7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

[0758]

[0759] At room temperature, N,N-dimethylaniline (0.01 mL, catalytic) was added to a solution of compound intermediate 1 (0.3 g, 1.1 mmol, 1.0 equiv) in POCl (3 mL) and 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 the crude product. The crude product was used directly in the next step without any purification.

[0760] Yield: (0.3 g, crude product).

[0761] Step-3: Preparation of Example 23

[0762] 7-Benzyl-N4-(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0763]

[0764] At RT, m-anisidine (0.27 g, 2.2 mmol, 2.0 equiv) was added to a solution of intermediate 35 (0.3 g, 1.0 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) and heated at 100°C for 16 hours. The reaction mixture was quenched with a minimal amount of aqueous NaHCO3 solution, and the organic product was extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over anhydrous Na2SO4. The solvent was distilled off under reduced pressure to obtain the crude compound. The crude compound was purified by reverse phase preparative HPLC to obtain the pure compound 7-benzyl-N4-(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine.

[0765] Yield: (0.03 g, 7.6%).

[0766] ES-MS[M+H] + : 362.26, Rt=1.49 min (Method-A2).

[0767] 1 H NMR (300MHz, DMSO-d6): δ7.87(s,1H),7.45(s,1H),7.37-7.27(m,6H),7.16-7.12(t,J=16Hz,1H),6.54-6.52 (d,J=8Hz,1H),5.88(s,2H),3.73(s,3H),3.63(s,2H),3.20(s,2H),2.71-2.68(t,J=12Hz,2H),2.50(m,2H).

[0768] Example 24

[0769] 7-Benzyl-N4-(2-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0770]

[0771] 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 equiv) in 1-butanol (3 mL) was added o-anisidine (0.179 g, 1.456 mmol, 2.0 equiv) and sulfuric acid (catalytic, 2 drops) at room temperature. The reaction mixture was stirred at 100 ° C for 18 hours. 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 (MeOH / CHCl 10%) to give 6-benzyl-N2-(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine as a white solid.

[0772] Yield: (0.131 g, 50%).

[0773] ES-MS[M+H] + : 362.15, Rt=17.26 min (Method-C2).

[0774] 1H NMR(400MHz, DMSO-d6)δ8.15(dt,J=7.9,1.0Hz,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=5.8Hz,2H),2.53(t,J=5.4Hz,2H).

[0775] Example 25

[0776] 2-((2-amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)phenol

[0777]

[0778] The title compound was synthesized following the procedure described for the preparation of Example 24, but using 2-aminophenol instead of o-anisidine in step 3, and isolated as a light yellow solid.

[0779] Yield: (0.102 g, 41% yield).

[0780] ES-MS[M+H] + : 348.1, Rt=15.236 min (Method-C2).

[0781] 1 H NMR(400MHz, DMSO-d6)δ9.96(s,1H),7.81(dd,J=8.0,1.6Hz,1H),7.44–7.31(m,5H),7.31–7.23(m,1H),6.92(ddd,J=8.0,7.2,1.6Hz,1H),6.85 (dd,J=8.0,1.6Hz,1H),6.78(ddd,J=8.0,7.2,1.7Hz,1H),6.09(s,2H),3.72(s,2H),3.39(s,2H),2.67(t,J=5.8Hz,2H),2.53(t,J=5.1Hz,2H).

[0782] Example 26

[0783] 7-Benzyl-N4-(4-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0784]

[0785] The title compound was synthesized following the procedure described for the preparation of Example 24, but using 4-methoxyaniline instead of o-anisidine in step 3, and isolated as a light yellow solid.

[0786] Yield: (0.056 g, 22% yield).

[0787] ES-MS[M+H] + : 362.1, Rt=15.734 min (Method-C2).

[0788] 1H NMR(400MHz, DMSO-d6)δ8.11(brs,1H),7.48(d,J=9.0Hz,2H),7.42–7.31(m,4H),7.32–7.13(m,1H),6.86( d,J=9.0Hz,2H),6.12(s,2H),3.76-3.79(m,5H),3.41(s,2H),2.66(t,J=5.4Hz,2H),2.53(t,J=5.5Hz,2H).

[0789] General Procedure B2 for the Synthesis of Example 27

[0790]

[0791] Step 1: Preparation of intermediate 37

[0792] 7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol

[0793]

[0794] The NaOMe 25% MeOH solution (1.92mL, 8.4mmol, 5.0 equivalents) is added to a solution of 1-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester hydrochloride (500mg, 1.68mmol, 1.0 equivalents) and urea (0.50g, 8.4mmol, 5.0 equivalents) in EtOH (10mL). The reaction mixture was stirred at reflux for 4 hours. TLC analysis (EtOAc / hexane 50%) showed that the reaction was complete. The reaction mixture was concentrated to dryness and purified by flash column chromatography (MeOH / DCM 10%-20%) to obtain 7-benzyl-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine-2,4-diol as a white solid.

[0795] Yield: (0.604 g, >theoretical yield).

[0796] ES-MS[M+H] +: 258.1, Rt=8.32 min (Method-B2).

[0797] 1 H NMR (400MHz, CDCl3): 10.96 (s, 1H), 10.64 (s, 1H), 7.41–7.21 (m, 5H), 3.20–3.09 (m, 4H), 2.60 (t, J = 5.8Hz, 2H), 2.21 (t, J = 5.7Hz, 2H).

[0798] Step 2: Preparation of intermediate 38

[0799] 7-Benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

[0800]

[0801] 7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol (4.3 g, 16.79 mmol, 1.0 equiv) was added portionwise to phosphorus oxychloride (15 mL, 1 mL / mmol). The reaction mixture was heated at 100°C for 21 hours with stirring. 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 taken up in saturated NaHCO3 and extracted with DCM (5×) and 2-methyl-THF (3×) and DCM / MeOH 5% (2×). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (EtOAc / hexanes 10-30-40-50%) to give 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine as a light yellow solid.

[0802] Yield: (2.6 g, 53% yield).

[0803] ES-MS[M+H] + : 296.1, 294.1, Rt=11.14 min (Method-B2).

[0804] Step 3: Preparation of Intermediate 39

[0805] 7-Benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

[0806]

[0807] NH3 (7N in MeOH, 0.540 mL, 3.785 mmol, 5.0 equiv) 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 equiv) in THF (8 mL). The resulting yellow suspension was warmed to 60°C and stirred at this temperature for 3 hours. TLC analysis (EtOAc / hexanes 10%) showed no reaction. More NH3 (7N in MeOH, 20 equiv) was added to the reaction mixture, and it was stirred at 60°C for another hour. TLC analysis (EtOAc / hexanes 10%) showed no reaction. More NH3 (7N in MeOH, 100 equiv) was added to the reaction mixture, and it was stirred at reflux for 5 hours. TLC analysis (EtOAc / hexanes 10%) showed the formation of two new spots. The reaction mixture was concentrated to dryness and purified by flash column chromatography (MeOH / DCM 2%-5%) to give 7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a beige solid.

[0808] Yield: (0.074 g, 27% yield).

[0809] ES-MS[M+H] + : 275.0, 277.1, Rt=9.27 min (Method-B2).

[0810] 1 H NMR (400MHz, DMSO-d6): 7.40–7.24 (m, 5H), 3.62 (s, 2H), 3.27 (s, 2H), 2.66 (d, J = 6.6Hz, 2H), 2.33 (s, 2H).

[0811] Step 4: Preparation of Example 27

[0812] 7-Benzyl-N 2 -(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0813]

[0814] At room temperature, m-anisidine (0.063 g, 0.510 mmol, 2.0 equivalents) and sulfuric acid (catalytic, 2 drops) were added to 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 equivalents) in 1-butanol (3 mL). The reaction mixture was stirred at 100 ° C for 21 hours. 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 (MeOH / DCM 3%-5%). The obtained product was slurried with a 1:1 mixture of EtOAc / hexane to give 7-benzyl-N-(2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a white solid. 2 -(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine.

[0815] Yield: (0.026 g, 30% yield).

[0816] ES-MS[M+H] + : 362.1, Rt=19.24 min (Method-C2).

[0817] 1 H NMR (400MHz, DMSO-d6): 8.70 (s, 1H), 7.51 (s, 1H), 7.41–7.32 (m, 4H), 7.26 (d, J=9.6Hz, 2H), 7.06 (t,J=8.2Hz,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).

[0818] Example 28

[0819] 7-Benzyl-N2-(2-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0820]

[0821] The title compound was synthesized from intermediate 36 following the procedure described for the preparation of Example 27 using o-anisidine and isolated as a light brown solid.

[0822] Yield: (0.072 g, 47% yield).

[0823] ES-MS[M+H] + : 362.1, Rt=19.32 min (Method-C2).

[0824] 1 H NMR(300MHz,DMSO-d6)δ7.79–7.34(m,1H),6.82–6.40(m,6H),6.23–5.91(m,3H),5.69(b rs,2H),3.00(s,3H),2.80(s,2H),2.41(s,2H),1.84(t,J=5.7Hz,2H),1.56-1.48(m,2H).

[0825] Example 29

[0826] 2-((4-amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)phenol

[0827]

[0828] The title compound was synthesized from intermediate 36 following the procedure described for the preparation of Example 27 using 2-aminophenol and was isolated as a white solid.

[0829] Yield: (0.029 g, 31% yield).

[0830] ES-MS[M+H] + : 348.0, Rt=18.068 min (Method-C2).

[0831] 1 H NMR(400MHz,DMSO-d6)δ10.74(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=5.8Hz,2H),2.38-2.30(m,2H).

[0832] Example 30

[0833] 7-Benzyl-N2-(4-methoxyphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

[0834]

[0835] The title compound was synthesized following 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.

[0836] Yield: (0.032 g, 12% yield).

[0837] ES-MS[M+H] + : 362.11, Rt=16.790 min (Method-C2).

[0838] 1 H NMR (400MHz, DMSO-d6) δ8.47(s,1H),7.61(d,J=9.1Hz,2H),7.44–7.23(m,4H),7.30–7.10(m,1H),6.77(d,J=9 .1Hz,2H),6.29(brs,2H),3.68(s,3H),3.63(s,2H),3.22(s,2H),2.67(t,J=5.8Hz,2H),2.34(t,J=6.1Hz,2H).

[0839] General Procedure C2 for the Synthesis of Example 31

[0840]

[0841] Step 1: Preparation of intermediate 40

[0842] 6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diol

[0843]

[0844] NaOMe 25% in MeOH (0.440 mL, 1.91 mmol, 5.0 equiv) was added to a solution of 1-benzyl-4-oxopiperidine-3-carboxylic acid ethyl ester (0.10 g, 0.382 mmol, 1.0 equiv) and urea (0.115 g, 1.91 mmol, 5.0 equiv) in EtOH (3 mL). The reaction mixture was stirred at reflux for 18 hours. TLC analysis (EtOAc / hexane 50%) showed that the reaction was complete. The reaction mixture was concentrated to dryness, water was added and 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 light brown solid, which was used without further purification.

[0845] Yield: (0.172 g, crude product).

[0846] ES-MS[M+H] + : 258.19, Rt=0.42 min (Method-B2).

[0847] Step 2: Preparation of Intermediate 41

[0848] 6-Benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

[0849]

[0850] 6-Benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diol (0.172 g, 0.67 mmol, 1 equivalent) was added portionwise to phosphorus oxychloride (1 mL / mmol). The reaction mixture was heated at 100°C for 18 hours with stirring. The reaction mixture was cooled to room temperature and evaporated under reduced pressure and co-distilled twice with toluene to afford 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine as a brown solid, which was used without further purification.

[0851] Yield: (0.097 g, crude product).

[0852] ES-MS[M+H] + : 296.08, 294.05, Rt=1.88 min (Method-B2).

[0853] Step 3: Preparation of intermediate 42

[0854] 6-Benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine

[0855]

[0856] NH3 (7N in MeOH, 0.145 mL, 0.996 mmol, 5.0 equiv) 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 equiv) in THF (0.7 mL). The resulting yellow suspension was stirred in a sealed tube at 60 ° C for 16 hours. TLC analysis (EtOAc / hexane 10%) showed partial conversion. Additional NH3 (7N in MeOH, 20 equiv) was added to the reaction mixture, which was stirred at 60 ° C for 3 hours. LC-MS analysis (Method-B) showed the formation of the desired product. The reaction mixture was concentrated to dryness to give 6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4-amine as a beige solid, which was used without further purification.

[0857] Yield: (0.092 g, crude product).

[0858] ES-MS[M+H] +: 277.14, 275.09, Rt=0.92 min (Method-B2).

[0859] Step 4: Preparation of Example 31

[0860] 6-Benzyl-N2-(3-methoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine hydrochloride

[0861]

[0862] 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 equiv) in 1-butanol (3 mL) at room temperature was added m-anisidine (0.082 g, 0.664 mmol, 2.0 equiv) and sulfuric acid (catalytic, 2 drops). The reaction mixture was stirred at 100° C. for 18 hours. 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 hour. 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.

[0863] Yield: (0.032 g, 27%).

[0864] ES-MS[M+H] + : 362.17, Rt=17.08 min (Method-C2).

[0865] 1 H NMR (400MHz, DMSO-d6) δ12.05(brs,1H),10.15(s,1H),8.35(brs,1H),7.76–7.61(m,2H),7.48(p,J=3.9Hz,3H),7.37–7.17(m,2H),7.10(d d,J=7.8,2.0Hz,1H),6.72(dd,J=8.2,2.5Hz,1H),4.45(s,2H),4.05-3.81(m,1H),3.77(s,3H),3.69-3.38(m,4H),3.28–3.23-2.88(m,1H).

[0866] General Procedure D2 for the Synthesis of Example 32

[0867]

[0868] Step 1: Preparation of intermediate 43

[0869] 3-Oxo-1-phenylpiperidine-4-carboxylic acid ethyl ester

[0870]

[0871] BINAP (0.239 g, 0.38 mmol, 4 mol%) and Pd(dba) (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 equiv), bromobenzene (1.1 mL, 10.54 mmol, 1.1 equiv), and NaOtBu (2.76 g, 28.74 mmol, 3.0 equiv) in toluene (20 mL). The resulting mixture was stirred at reflux for 90 minutes. TLC analysis (MeOH / CH2Cl2 5%) 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 (EtOAc / hexanes 10%-20%) to give ethyl 3-oxo-1-phenylpiperidine-4-carboxylate as a yellow oil.

[0872] Yield: (1.6 g, 63%).

[0873] ES-MS[M+H] + : 247.7, Rt=11.39 min (Method-B2).

[0874] 1 H NMR (400MHz, chloroform-d) δ12.44(s,1H),7.68(t,J=7.0Hz,2H),7.35-7.22(m,3H),4.65(qd,J=7.1,1.9Hz,2 H), 4.23 (s, 2H), 3.77 (d, J = 5.8Hz, 2H), 2.85 (ddd, J = 7.7, 3.9, 1.9Hz, 2H), 1.72 (td, J = 7.1, 1.9Hz, 3H).

[0875] Step 2: Preparation of intermediate 44

[0876] 2-Amino-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

[0877]

[0878] NaOMe (25% MeOH solution, 3.7 mL, 16.2 mmol, 5.0 equiv) was added to a solution of ethyl 3-oxo-1-phenylpiperidine-4-carboxylate (0.8 g, 3.24 mmol, 1.0 equiv) and guanidine hydrochloride (0.464 g, 4.86 mmol, 1.5 equiv) in EtOH (20 mL). The reaction mixture was stirred at reflux under nitrogen for 2 hours. The reaction mixture was cooled to room temperature and adsorbed on silica gel. The resulting crude product was purified by flash column chromatography (MeOH / CH2Cl2 10%) to give 2-amino-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol as a white solid.

[0879] Yield: (0.678 g, 83%).

[0880] ES-MS[M+H] + : 243.0 (Method-B2).

[0881] 1 H NMR(400MHz,DMSO-d6)δ9.96(brs,1H),6.36(q,J=7.9Hz,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).

[0882] Step 3: Preparation of intermediate 45

[0883] 4-Chloro-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine

[0884]

[0885] 2-Amino-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (0.68 g, 2.81 mmol, 1.0 equiv) was added to phosphorus oxychloride (1 mL / mmol) in portions. The reaction mixture was heated at 100 ° C for 2 hours under stirring. The reaction mixture was cooled to room temperature and evaporated under reduced pressure and co-distilled twice with toluene. The crude product was purified by flash column chromatography (MeOH / CHCl 10%) to give 4-chloro-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine as a brown oil.

[0886] Yield: (0.72 g, impure).

[0887] ES-MS[M+H] + : No substance detected (Method-B2).

[0888] Step 4: Preparation of Example 32

[0889] 2-((2-amino-7-phenyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)phenol

[0890]

[0891] At room temperature, 2-aminophenol (0.302 g, 2.77 mmol, 1.0 equivalent) and sulfuric acid (catalytic, 2 drops) were added 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 equivalent) in 1-butanol (20 mL). The reaction mixture was stirred at 100 ° C for 16 hours. 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 / hexane 10%-50%) to obtain 2- ((2-amino-7-phenyl-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4-yl) amino) phenol as a beige solid.

[0892] Yield: (0.023 g, 2.5%).

[0893] ES-MS[M+H] + : 334.2, Rt=17.309 min (Method-C2).

[0894] 1 H NMR (400MHz, DMSO-d6) δ10.07(brs,1H),8.01(d,J=7.9Hz,1H),7.56(s,1H),7.24(t,J=7.7Hz,2H),7.01(d,J=8.1 Hz,2H),6.96–6.85(m,2H),6.78(q,J=6.8Hz,2H),6.14(s,2H),4.02(s,2H),3.73–3.55(m,2H),2.62-2.53(s,2H).

[0895] Preparation of compounds of formula (IA) of Examples 33-141

[0896] Intermediate 46

[0897] 2-(((1S,2S)-2-Hydroxycyclohexyl)amino)-N-methyl-N-phenyl-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxamide

[0898]

[0899] 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 equiv) in DMF (1.5 mL) at room temperature was added (1S,2S)-2-aminocyclohexan-1-ol (0.150 g, 1.30 mmol, 3.0 equiv) and sulfuric acid (catalytic, 1 drop). The reaction mixture was stirred at 130 ° C for 18 hours. 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 was purified by flash column chromatography (EtOAc / heptane 50-100) to afford 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.

[0900] Yield: (0.020 g, 10%).

[0901] ES-MS[M+H] + : 454.2, Rt = 7.305 min (Method-A1)

[0902] Example 33

[0903] 6-amino-2-(((1S,2S)-2-hydroxycyclohexyl)amino)-N-methyl-N-phenylpyrimidine-4-carboxamide

[0904]

[0905] Synthesized according to General Procedure A, Step 3. Isolated as a white solid.

[0906] Yield: (0.023 g, 38%).

[0907] ES-MS[M+H] + : 342.1, Rt=15.226 min (Method-B1).

[0908] 1H NMR(400MHz,DMSO-d6)δ7.29(m,2H),7.25–7.10(m,3H),6.46(brs,2H),6.03(s,1H),5.72(s, 1H), 4.60 (s, 1H), 3.31 (d, J = 6.1Hz, 3H), 3.19 (s, 2H), 1.82 (m, 2H), 1.56 (m, 2H), 1.14 (m, 4H).

[0909] Intermediate 47

[0910] 2-Chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylic acid methyl ester

[0911]

[0912] To a stirred mixture of 2,6-dichloropyrimidine-4-methyl formate (5.0 g, 24.14 mmol, 1.0 equivalent), 2-methoxyaniline (2.73 mL, 24.14 mmol, 1.0 equivalent) in methanol (50 mL) was added sodium carbonate (2.81 g, 26.55 mmol, 1.1 equivalents). The resulting mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness, and the resulting residue was distributed between water and EtOAc. The water layer was extracted with EtOAc (x2), 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 2-chloro-6-((2-methoxyphenyl) amino) pyrimidine-4-methyl formate as a white solid.

[0913] Yield: (5.26 g, 74%).

[0914] ES-MS[M+H] + : 294.1, Rt = 6.09 min (Method-A1)

[0915] Intermediate 48

[0916] Methyl 6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylate

[0917]

[0918] To a stirred mixture of 2-chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylic acid methyl ester (0.40 g, 1.34 mmol, 1.0 equiv), tert-octylamine (1.1 mL, 6.72 mmol, 5.0 equiv) in DMF (4 mL) was added DIPEA (1.2 mL, 6.72 mmol, 5.0 equiv). The resulting mixture was stirred at 120 ° C for 16 hours. The mixture was diluted with water and extracted with ethyl acetate (x3), 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-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid methyl ester as a colorless wax.

[0919] Yield: (0.094 g, 20% yield).

[0920] ES-MS[M+H] + : 387.2, Rt = 7.57 min (Method-A1)

[0921] Intermediate 49

[0922] 6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidine-4-carboxylic acid

[0923]

[0924] To 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 equiv) in THF:HO (1:1, 3 mL) was added lithium hydroxide (0.051 g, 1.216 mmol, 5.0 equiv). The resulting mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness, acidified by the addition of concentrated HCl, and extracted with EtOAc / MeOH (x3), 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 light yellow solid which was used without further purification.

[0925] Yield: (0.084 g, 93% yield).

[0926] ES-MS[M+H] + : 373.1, Rt = 6.790 min (Method-A1).

[0927] Intermediate 50

[0928] (6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

[0929]

[0930] To 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 equiv), 1-phenylpiperazine (0.045 mL, 0.293 mmol, 1.3 equiv) and HATU (0.102 g, 0.270 mmol, 1.2 equiv) in DMF (10 mL) was added DIPEA (0.059 mL, 0.337 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (x3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The resulting crude was purified by flash column chromatography (EtOAc / heptane 50-100) to afford (6-((2-methoxyphenyl)amino)-2-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone as a yellow wax.

[0931] Yield: (0.059 g, 51% yield).

[0932] ES-MS[M+H] + : 517.2, Rt=7.707 min (Method-A1).

[0933] Example 34

[0934] (2-Amino-6-((2-methoxyphenyl)amino)pyrimidin-4-yl)(4-phenylpiperazin-1-yl)methanone

[0935]

[0936] Synthesized according to General Procedure A, Step 3. Isolated as a white solid. No further purification was performed.

[0937] Yield: (0.033 g, 72% yield).

[0938] ES-MS[MH] - : 403.3, Rt=17.701 min (Method-B1).

[0939] 1H NMR(400MHz,MeOD)δ8.02(d,J=7.9Hz,1H),7.33–7.17(m,2H),7.17–7.05(m,1H),7.05–6.91(m,4H),6.87(td,J=7.3,1.0Hz,1 H),6.19(d,J=0.5Hz,1H),3.88(s,3H),3.87–3.80(m,2H),3.71–3.61(m,2H),3.28–3.21(m,2H),3.18(dd,J=6.2,4.2Hz,2H).

[0940] Intermediate 51

[0941] (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone

[0942]

[0943] Synthesized according to general procedure A, step 1.

[0944] Yield: (0.163 g, 39%).

[0945] ES-MS[M+H] + : 401.9, Rt=7.443 min (Method-A1).

[0946] Intermediate 52

[0947] (3,4-Dihydroisoquinolin-2(1H)-yl)(2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)methanone

[0948]

[0949] Synthesized according to general procedure A, step 2.

[0950] Yield: (0.090 g, 47%).

[0951] ES-MS[M+H] + : 474.9, Rt=7.34 min (Method-A1).

[0952] Example 35

[0953] (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone

[0954]

[0955] Synthesized according to general procedure A, step 3.

[0956] Yield: (0.013 g, 29%).

[0957] ES-MS [M+H] + : 362.1, Rt = 17.016 min (Method-B1).

[0958] 1 H NMR(400MHz, DMSO-d6)δ10.13(d,J=4.3Hz,1H),8.28–7.56(m,2H),7.19(dddt,J=13.9,10.8,7.0,3.1Hz,4H),6.99(s,2H),6.92–6.78(m,2H ), 6.78–6.62(m,1H),5.98(dd,J=21.5,4.3Hz,1H),4.69(dd,J=29.8,3.9Hz,2H),3.72(dt,J=60.2,4.9Hz,2H),2.85(dt,J=16.3,5.4Hz,2H).

[0959] Intermediate 53

[0960] (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone

[0961]

[0962] Synthesized according to general procedure A, step 1.

[0963] Yield: (0.168 g, 40%).

[0964] ES-MS[M+H] + : 401.9, Rt=7.372 min (Method-A1).

[0965] Intermediate 54

[0966] (3,4-Dihydroquinolin-1(2H)-yl)(2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)methanone

[0967]

[0968] Synthesized according to general procedure A, step 2.

[0969] Yield: (0.052 g, 26%).

[0970] ES-MS[M+H] + : 474.9, Rt=7.40 min (Method-A1).

[0971] Example 36

[0972] (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone

[0973]

[0974] Synthesized according to general procedure A, step 3.

[0975] Yield: (0.010 g, 28%).

[0976] ES-MS[M+H] + : 362.0, Rt=16.970 min (Method-B1).

[0977] 1 H NMR(400MHz, DMSO-d6)δ10.24–9.84(m,1H),7.64(d,J=58.7Hz,2H),7.23–7.12(m,1H),7.07–6.86(m,4H),6.82–6.6 9(m,2H),6.70–6.58(m,1H),5.99(d,J=1.4Hz,1H),3.71(t,J=6.3Hz,2H),2.79(t,J=6.6Hz,2H),2.02–1.83(m,2H).

[0978] Intermediate 55

[0979] (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(indolin-1-yl)methanone

[0980]

[0981] Synthesized according to general procedure A, step 1.

[0982] Yield: (0.188 g, 46%).

[0983] ES-MS[M+H] + : 387.9, Rt=7.57 min (Method-A1).

[0984] Intermediate 56

[0985] (2-((2-Hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(indolin-1-yl)methanone

[0986]

[0987] BINAP (0.030 g, 0.05 mmol, 10 mol%) and Pd2(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 equiv), 2-aminophenol (0.060 g, 0.55 mmol, 1.5 equiv) and cesium carbonate (0.50 g, 1.4 mmol, 3.5 equiv) in dioxane (2.8 mL). The resulting mixture was stirred at 100 °C for 18 hours. 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 / hexanes 10%-20%) to afford (2-((2-hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(indolin-1-yl)methanone as a white solid.

[0988] Yield: (0.105 g, 62%).

[0989] ES-MS[M+H] + : 460.9, Rt=7.214 min (Method-A1).

[0990] Example 37

[0991] (6-Amino-2-((2-hydroxyphenyl)amino)pyrimidin-4-yl)(indolin-1-yl)methanone

[0992]

[0993] Synthesized according to General Procedure A, Step 3. The product was purified by HPLC-semipreparative (Method-E1)

[0994] Yield: (0.012 g, 16%).

[0995] ES-MS[M+H] + :348.1, Rt=16.999min (Method-B1).

[0996] 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),8.09(d,J=8.0Hz,1H),7.97(d,J=7.8Hz,1H),7.89(s,1H),7.29(d,J=7.4Hz,1H),7.22(t,J=7 .9Hz,1H),7.06(d,J=13.6Hz,3H),6.85–6.80(m,2H),6.79–6.65(m,1H),6.14(s,1H),4.15(t,J=8.3Hz,2H),3.10(t,J=8.3Hz,2H).

[0997] Intermediate 57

[0998] (2-Chloro-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[0999]

[1000] Synthesized according to general procedure A, step 1.

[1001] Yield: (0.535 g, 55%).

[1002] ES-MS[M+H] + : 387.9, Rt=7.614 min (Method-A1).

[1003] Intermediate 58

[1004] Isoindolin-2-yl(2-((3-methoxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)-pyrimidin-4-yl)methanone

[1005]

[1006] Synthesized according to general procedure A, step 2.

[1007] Yield: (0.078 g, 32%).

[1008] ES-MS[M+H] + : 474.3, Rt=5.571 min (Method-A1).

[1009] Example 38

[1010] (6-Amino-2-((3-methoxyphenyl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[1011]

[1012] Synthesized according to general procedure A, step 3.

[1013] Yield: (0.034 g, 49%).

[1014] ES-MS [M+H] + : 362.0, Rt = 17.882 min (Method-B1).

[1015] 1 H NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 7.51 (t, J = 2.3Hz, 1H), 7.45–7.37 (m, 1H), 7.34–7.22 (m, 4H), 7.12 (t, J = 8.1Hz, 1H), 6. 95–6.79(m,2H),6.47(ddt,J=8.2,2.5,0.7Hz,1H),6.20(d,J=0.5Hz,1H),5.04(s,2H),4.83(s,2H),3.70(d,J=0.5Hz,3H).

[1016] Intermediate 59

[1017] (2-((3-Hydroxyphenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[1018]

[1019] Synthesized according to general procedure A, step 2.

[1020] Yield: (0.094 g, 40%).

[1021] ES-MS[M+H] + : 460.2, Rt=7.138 min (Method-A1).

[1022] Example 39

[1023] (6-Amino-2-((3-hydroxyphenyl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[1024]

[1025] Synthesized according to General Procedure A, Step 3. The compound was purified by HPLC-semiprep (Method-E1).

[1026] Yield: (0.022 g, 31%).

[1027] ES-MS[M+H]+ : 348.2, Rt=15.841 min (Method-B1).

[1028] 1 H NMR(400MHz,DMSO-d6)δ9.15(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 = 8.0Hz, 1H), 6.79 (s, 2H), 6.32 (dd, J = 7.9, 2.3Hz, 1H), 6.20 (s, 1H), 5.04 (s, 2H), 4.83 (s, 2H).

[1029] Intermediate 60

[1030] Isoindolin-2-yl(2-(m-tolylamino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)methanone

[1031]

[1032] Synthesized according to general procedure A, step 2.

[1033] Yield: (0.107 g, 36%).

[1034] ES-MS[M+H] + : 457.9, Rt=3.20 min (Method-D1).

[1035] Example 40

[1036] (6-Amino-2-(m-tolylamino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[1037]

[1038] Synthesized according to general procedure A, step 3.

[1039] Yield: (0.038 g, 47%).

[1040] ES-MS[M+H] + : 346.1, Rt=18.670 min (Method-B1).

[1041] 1H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H), 7.66–7.56 (m, 1H), 7.53 (d, J = 2.3Hz, 1H), 7.49–7.36 (m, 1H), 7.34–7.26 (m, 3H), 7. 11(t,J=7.8Hz,1H),6.96–6.81(m,2H),6.72(dq,J=7.4,0.9Hz,1H),6.20(s,1H),5.05(s,2H),4.82(s,2H),2.25(s,3H).

[1042] Intermediate 61

[1043] (2-((3-chlorophenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[1044]

[1045] Synthesized according to general procedure A, step 2.

[1046] Yield: (0.070 g, 31%).

[1047] ES-MS[M+H] + : 478.1, Rt=7.918 min (Method-A1).

[1048] Example 41

[1049] (2-((3-chlorophenyl)amino)-6-((2,4,4-trimethylpentan-2-yl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[1050]

[1051] Synthesized according to general procedure A, step 3.

[1052] Yield: (0.020 g, 37%).

[1053] ES-MS[M+H] + : 366.1, Rt=19.152 min (Method-B1).

[1054] 1H NMR(400MHz, DMSO-d6)δ9.34(s,1H),7.94(t,J=2.1Hz,1H),7.69(ddd,J=8.3,2.0,0.9Hz,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=0.7Hz,1H),5.04(s,2H),4.83(s,2H).

[1055] General Procedure D-1

[1056]

[1057] Step 1

[1058] To a stirred solution of the appropriate aryl chloride derivative (e.g., 4,6-dichloro-2-(methylsulfonyl)pyrimidine) (1.0 equiv) in dioxane (2 mL / mmol) is added the appropriate amine (e.g., 2-methoxyaniline) (1.0 equiv) and DIPEA (3.71 mL, 21.3 mmol, 1.2 equiv). The resulting mixture is stirred at room temperature for 16 hours. The mixture is diluted with water and extracted with EtOAc (x3). The combined organic layers are washed with brine, dried over magnesium sulfate, filtered, and concentrated to yield the desired amine compound (e.g., 6-chloro-N-(2-methoxyphenyl)-2-(methylsulfonyl)pyrimidin-4-amine).

[1059] Step 2

[1060] To a stirred solution of the appropriate sulfonyl derivative (e.g., 6-chloro-N-(2-methoxyphenyl)-2-(methylsulfonyl)pyrimidin-4-amine) (1.0 equiv) in DMSO (4 mL / mmol) is added potassium cyanide (1.0 equiv). The resulting mixture is stirred at room temperature for 30 minutes. Water is then added and the solution is extracted with EtOAc (x3). The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting crude product is purified by flash column chromatography (EtOAc / hexane 50%) to give the desired carbonitrile derivative (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carbonitrile).

[1061] Step 3

[1062] To a stirred solution of the appropriate carbonitrile (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carbonitrile) (1.0 equiv) in water (7 mL / mmol) and ethanol (7 mL / mmol) is added KOH (10.0 equiv) at room temperature. The resulting mixture is stirred at reflux for 1 hour. The mixture is then cooled to room temperature and acidified to pH 3-4 by adding 3N HCl. EtOAc is then added and the layers are separated. The aqueous layer is extracted with EtOAc (x3). The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting crude product is purified by flash column chromatography (EtOAc / hexane 30% to 100%) to give the desired carboxylic acid compound (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxylic acid).

[1063] Intermediate 62

[1064] 6-Chloro-N-(2-methoxyphenyl)-2-(methylsulfonyl)pyrimidin-4-amine

[1065]

[1066] Synthesized according to general procedure D-1, step 1. Isolated as a white solid.

[1067] Yield: (7.0 g, 95%).

[1068] ES-MS[M+H] + : 314.0, Rt=5.78 min (Method-A1).

[1069] Intermediate 63

[1070] 4-Chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carbonitrile

[1071]

[1072] Synthesized according to general procedure D-1, step 2. Isolated as a white solid

[1073] Yield: (1.69 g, 50%).

[1074] ES-MS[M+H] + : 261.0, Rt=2.77 min (Method-D1).

[1075] Intermediate 64

[1076] 4-Chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxylic acid

[1077]

[1078] Synthesized according to general procedure D-1, step 3. Isolated as a yellow solid.

[1079] Yield: (1.31 g, 65%).

[1080] ES-MS[M+H] + : 280.0, Rt=2.42 min (Method-D1).

[1081] Intermediate 65

[1082] 2-Chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylic acid

[1083]

[1084] To a stirred mixture of methyl 2-chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylate (6.17 g, 21.00 mmol, 1.0 equiv) in THF:HO (1:1, 240 mL) was added lithium hydroxide (4.41 g, 105.03 mmol, 5.0 equiv). The resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness, acidified by adding concentrated HCl, extracted with EtOAc / MeOH (x3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford 2-chloro-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxylic acid as a yellow solid which was used without further purification.

[1085] Yield: (5.97 g, quantitative yield).

[1086] ES-MS[M+H] + : 280.0, Rt=4.53 min (Method-A1).

[1087] General Procedure D-2

[1088]

[1089] Step 1

[1090] The appropriate carboxylic acid compound (for example: 4-chloro-6-((2-methoxyphenyl)-amino)pyrimidine-2-carboxylic acid) (1.0 equivalent) is dissolved in SOCl (5mL / mmol) under N atmosphere and stirred at 90°C for 3 hours. The mixture is then cooled to room temperature and excess SOCl is removed under vacuum. The resulting crude residue is dissolved in THF (5mL / mmol) and then an appropriate amine (for example: 1-phenylpiperazine) (1.0 equivalent) and EtN (1 equivalent) are added. The mixture is stirred at room temperature for 16 hours. The mixture is then diluted with water and extracted with EtOAc (x3). The combined organic layers are washed with brine, dried over MgSO, filtered and concentrated. The resulting crude product is purified by flash column chromatography (EtOAc / hexane 50% to 100%) to obtain the desired amide (for example: (4-chloro-6-((2-methoxyphenyl) amino)pyrimidine-2-yl) (4-phenylpiperazine-1-yl) ketone).

[1091] Step 1 Alternative Procedure (Step 1B)

[1092] T3P (2.0 equiv of a 50% ethyl acetate solution) is added to a suspension of the appropriate carboxylic acid (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxylic acid) (1.0 equiv), the corresponding amine (e.g., (2-methoxyphenyl)amino) (1.5 equiv) and DIPEA (5.0 equiv) in DCM (5 mL / mmol). The resulting mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with saturated aqueous NaHCO3. The mixture is extracted with ethyl acetate (x3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The resulting crude product is purified by flash column chromatography (EtOAc / hexanes 50% to 100%) to give the desired product (e.g., 4-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxamide).

[1093] Intermediate 66

[1094] (4-Chloro-6-((2-methoxyphenyl)amino)pyrimidin-2-yl)(4-phenylpiperazin-1-yl)methanone

[1095]

[1096] Synthesized according to general procedure D-2, step 1. Isolated as a brown solid.

[1097] Yield: (0.485 g, 53%).

[1098] ES-MS[M+H] + : 424.0, Rt=6.605 min (Method-A1).

[1099] Intermediate 67

[1100] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxamide

[1101]

[1102] Synthesized according to general procedure D-2, step 1B.

[1103] Yield: (0.61 g, 66%).

[1104] ES-MS[MH] - : 395.9, Rt=6.820 min (Method-A1).

[1105] Intermediate 68

[1106] 4-Chloro-6-((2-methoxyphenyl)amino)-N-phenylpyrimidine-2-carboxamide

[1107]

[1108] Synthesized according to general procedure D-2, step 1B.

[1109] Yield: (0.65 g, 76%).

[1110] ES-MS[MH] - : 355.9, Rt=2.89 min (Method-D1).

[1111] Intermediate 69

[1112] 2-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)pyrimidine-4-carboxamide

[1113]

[1114] Synthesized according to procedure D-2, step 1B.

[1115] Yield: (0.229 g, 27% yield).

[1116] ES-MS[M+H] + : 395.1, Rt=7.078 min (Method-A1).

[1117] Intermediate 70

[1118] 2-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)-N-methylpyrimidine-4-carboxamide

[1119]

[1120] Synthesized according to general procedure D-2, step 1B.

[1121] Yield: (0.693 g, 79% yield).

[1122] ES-MS[M+H] + : 409.0, Rt=6.801 min (Method-A1).

[1123] Intermediate 71

[1124] 2-Chloro-6-((2-methoxyphenyl)amino)-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine-4-carboxamide

[1125]

[1126] Synthesized according to procedure D-2, step 1B.

[1127] Yield: (0.326 g, 47% yield).

[1128] ES-MS[M+H] + : 423.0, Rt=6.890 min (Method-A1).

[1129] Intermediate 72

[1130] 2-Chloro-6-((2-methoxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine-4-carboxamide

[1131]

[1132] Synthesized according to procedure D-2, step 1B.

[1133] Yield: (0.479 g, 76% yield).

[1134] ES-MS[M+H] + : 409.0, Rt=7.212 min (Method-A1).

[1135] Intermediate 73

[1136] (2-Chloro-6-((2-methoxyphenyl)amino)pyrimidin-4-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1137]

[1138] Synthesized according to general procedure D-2, step 1B.

[1139] Yield: (0.816 g, 96% yield).

[1140] ES-MS[M+H] + : 395.0, Rt=6.662 min (Method-A1).

[1141] Intermediate 74

[1142] (2-Chloro-6-((2-methoxyphenyl)amino)pyrimidin-4-yl)(isoindolin-2-yl)methanone

[1143]

[1144] Synthesized according to general procedure D-2, step 1B.

[1145] Yield: (0.603 g, 74% yield).

[1146] ES-MS[M+H] + : 381.0, Rt=6.823 min (Method-A1).

[1147] General Procedure D-3

[1148]

[1149] Step 1

[1150] Method 1 : To a stirred solution of 4,6-dichloropicolinic acid (1.0 eq) in DCM (3 mL / mmol) and DMF (10 drops) is added oxalyl chloride (1.5 eq) at 0°C. The resulting mixture is stirred at room temperature for 1 hour. The mixture is then concentrated to dryness and dissolved in DCM (3 mL / mmol) and DIPEA (2.0-3.0 eq). The appropriate amine (e.g., N-methylaniline) (1.2 eq) is then added, and the resulting mixture is stirred at room temperature for 4 hours. Upon completion, the mixture is concentrated to dryness, and the crude product is purified by silica gel column chromatography (hexane: EtOAc, 90:10 to 75:25) to give the desired amide product (e.g., 4,6-dichloro-N-methyl-N-phenylpicolinamide).

[1151] Method 2: T3P (2.0 equivalents of a 50% EtOAc solution) is added to a suspension of 4,6-dichloropicolinic acid (1.0 equivalent), an appropriate amine (e.g., 1-phenylpiperazine) (1.1 equivalents) and DIPEA (5.0 equivalents) in DCM (4 mL / mmol). The resulting mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with a saturated aqueous NaHCO3 solution. The mixture is extracted with ethyl acetate (x3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The resulting crude product is purified by flash column chromatography (EtOAc / heptane 50-100) to obtain the desired product (e.g., (4,6-dichloropyridin-2-yl)(4-phenylpiperazine-1-yl)methanone).

[1152] Step 2

[1153] Method 1 To a stirred solution of the appropriate amine (e.g., 2-methoxyaniline) (0.80 g, 6.5 mmol, 2.0 equiv) in DMF (7 mL) at 0°C was added NaH (0.785 g of a 60% suspension in mineral oil, 19.62 mmol, 6.0 equiv). 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 more brine and 10% HCl, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (hexane:EtOAc, 95:05 to 80:20) to give the desired product (e.g., 6-chloro-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide).

[1154] method 2: Dppf (6 mol%) and Pd(OAc)2 (3 mol%) are 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 equiv), the appropriate arylamine (e.g., 2-methylaniline) (1.0 equiv) and K3PO4 (2.0 equiv) in dioxane (5 mL / mmol). The resulting mixture is stirred at 90°C under a nitrogen atmosphere for 2 hours. The mixture is then diluted with EtOAc and water. The layers are separated. The aqueous layer is extracted with EtOAc (x2). The combined organic layers are washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (hexanes: EtOAc 60:40) to give the desired product (eg, 4-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(o-tolylamino)picolinamide).

[1155] Intermediate 75

[1156] 4,6-Dichloro-N-methyl-N-phenylpyridineamide

[1157]

[1158] Synthesized according to general procedure D-3, step 1, method 1.

[1159] Yield: (0.940 g, 63%).

[1160] ES-MS[M+H] + : 282.2, Rt=7.64 min (Method-A1).

[1161] Intermediate 76

[1162] (4,6-Dichloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[1163]

[1164] Synthesized according to General Procedure D-3, Step 1, Method 2. Isolated as a white solid.

[1165] Yield: (2.224 g, 85% yield).

[1166] ES-MS[M+H] + : 336.0, Rt=6.618 min (Method-A1).

[1167] Intermediate 77

[1168] (4,6-Dichloropyridin-2-yl)(isoindolin-2-yl)methanone

[1169]

[1170] Synthesized according to General Procedure D-3, Step 1, Method 2. Isolated as a light brown solid.

[1171] Yield: (1.271 g, 84%).

[1172] ES-MS[M+H] + : 294.1, Rt = 2.90 min (Method-D1).

[1173] Intermediate 78

[1174] (4,6-Dichloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[1175]

[1176] Synthesized according to general procedure D-3, step 1, method 2.

[1177] Yield: (2.224 g, 85% yield).

[1178] ES-MS[M+H] + : 336.0, Rt=6.618 min (Method-A1).

[1179] Intermediate 79

[1180] 4,6-Dichloro-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

[1181]

[1182] Synthesized according to General Procedure D-3, Step 1, Method 1. Isolated as a grey solid.

[1183] Yield: (0.825 g, 51%).

[1184] ES-MS[M+H] + : 308.0, Rt=7.439 min (Method-A1).

[1185] Intermediate 80

[1186] 4,6-Dichloro-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

[1187]

[1188] Synthesized according to general procedure D-3, step 1, method 2.

[1189] Yield: (3.15 g, quantitative).

[1190] ES-MS[M+H] + :308.0, Rt=7.089min (Method-A1).

[1191] Intermediate 81

[1192] (4,6-Dichloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[1193]

[1194] Synthesized according to general procedure D-3, step 1, method 2.

[1195] Yield: (3.40 g, 97% yield).

[1196] ES-MS[M+H] + : 337.9, Rt=6.771 min (Method-A1).

[1197] Intermediate 82

[1198] 4,6-Dichloro-N-phenylpyridinamide

[1199]

[1200] Synthesized according to general procedure D-3, step 1, method 2.

[1201] Yield: (3.64 g, 87%).

[1202] ES-MS[M+H] + : 267.0, Rt=6.93 min (Method-A1).

[1203] Intermediate 83

[1204] (4,6-Dichloropyridin-2-yl)(isoindolin-2-yl)methanone

[1205]

[1206] Synthesized according to general procedure D-3, step 1, method 2.

[1207] Yield: (1.271 g, 84%).

[1208] ES-MS[M+H] + : 294.1, Rt=6.943 min (Method-A1).

[1209] Intermediate 84

[1210] (4,6-Dichloropyridin-2-yl)(indolin-1-yl)methanone

[1211]

[1212] Synthesized according to General Procedure D-3, Step 1, Method 2. This compound was used without further purification.

[1213] Yield: (1.5 g, 98%).

[1214] ES-MS[M+H] + : 294.1, Rt=3.09 min (Method-D1).

[1215] Intermediate 85

[1216] 4,6-Dichloro-N-phenylpyridinamide

[1217]

[1218] Synthesized according to general procedure D-3, step 1, method 1.

[1219] Yield: (0.122 g, 83%).

[1220] ES-MS[M+H] + : 267.0, Rt=6.82 min (Method-A1).

[1221] Intermediate 86

[1222] 4,6-Dichloro-N-(1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide

[1223]

[1224] Synthesized according to general procedure D-3, step 1, method 1.

[1225] Yield: (0.720 g, 67%).

[1226] ES-MS[M+H] + : 322.1, Rt=6.443 min (Method-A1).

[1227] Intermediate 87

[1228] 4,6-Dichloro-N-phenylpyridinamide

[1229]

[1230] Synthesized according to General Procedure D-3, Step 1, Method 2. The crude product was used without further purification.

[1231] Yield: (1.25 g, 89%).

[1232] ES-MS[M+H] + : 267.0, Rt=6.82 min (Method-A1).

[1233] Intermediate 88

[1234] 4,6-Dichloro-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

[1235]

[1236] Synthesized according to general procedure D-3, step 1, method 2.

[1237] Yield: (1.08 g, 68%).

[1238] ES-MS[M+H] + : 308.0, Rt=7.04 min (Method-A1).

[1239] Intermediate 89

[1240] 4,6-Dichloro-N-(2,3-dihydro-1H-inden-2-yl)-N-methylpicolinamide

[1241]

[1242] Synthesized according to general procedure D-3, step 1, method 2.

[1243] Yield: (0.624 g, 25%).

[1244] ES-MS[M+H] + : 321.1, Rt=6.842 min (Method-A1).

[1245] Intermediate 90

[1246] 4,6-Dichloro-N-methyl-N-phenylpyridineamide

[1247]

[1248] Synthesized according to general procedure D-3, step 1, method 2.

[1249] Yield: (2.22 g, 76%).

[1250] ES-MS[M+H] + : 281.0, Rt=6.327 min (Method-A1).

[1251] Intermediate 91

[1252] 4,6-Dichloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)picolinamide

[1253]

[1254] Synthesized according to general procedure D-3, step 1, method 2.

[1255] Yield: (3.18 g, 94%).

[1256] ES-MS[M+H] +: 325.0, Rt=6.800 min (Method-A1).

[1257] Intermediate 92

[1258] 4,6-Dichloro-N-(m-tolyl)picolinamide

[1259]

[1260] Synthesized according to general procedure D-3, step 1, method 2.

[1261] Yield: (0.639 g, 87%).

[1262] ES-MS[MH] - : 279.2, Rt=7.133 min (Method-A1).

[1263] Intermediate 93

[1264] 4,6-Dichloro-N-(3,4-dimethylphenyl)picolinamide

[1265]

[1266] Synthesized according to general procedure D-3, step 1, method 2.

[1267] Yield: (0.470 g, 61%).

[1268] ES-MS[MH] - : 279.2, Rt=7.133 min (Method-A1).

[1269] Intermediate 94

[1270] (4,6-Dichloropyridin-2-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone

[1271]

[1272] Synthesized according to general procedure D-3, step 1, method 2.

[1273] Yield: (0.50 g, quantitative).

[1274] ES-MS[M+H] + : 307.0, Rt=6.76 min (Method-A1).

[1275] Intermediate 95

[1276] 6-Chloro-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide

[1277]

[1278] Synthesized according to General Procedure D-3, Step 2, Method 1. The product was isolated as a beige solid.

[1279] Yield: (0.140 g, 7%).

[1280] ES-MS[M+H] + : 368.2, Rt=6.98 min (Method-A1).

[1281] Intermediate 96

[1282] (6-Chloro-4-((2-methoxyphenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[1283]

[1284] Synthesized according to general procedure D-3, step 2, method 1.

[1285] Yield: (0.548 g, 20%).

[1286] ES-MS[M+H] + : 423.1, Rt=6.742 min (Method-A1).

[1287] Intermediate 97

[1288] (6-Chloro-4-((2-fluorophenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[1289]

[1290] Synthesized according to general procedure D-3, step 2, method 1.

[1291] Yield: (0.180 g, 34%).

[1292] ES-MS[M+H] + : 411.1, Rt=6.737 min (Method-A1).

[1293] Intermediate 98

[1294] (6-Chloro-4-((2-chlorophenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[1295]

[1296] Synthesized according to general procedure D-3, step 2, method 1.

[1297] Yield: (0.415 g, crude product after use).

[1298] ES-MS[M+H] + : 427.0, Rt=6.956 min (Method-A1).

[1299] Intermediate 99

[1300] (6-Chloro-4-((2-methoxyphenyl)amino)pyridin-2-yl)(isoindolin-2-yl)methanone

[1301]

[1302] Synthesized according to General Procedure D-3, Step 2, Method 1. The product was isolated as a green solid.

[1303] Yield: (0.228 g, 14%).

[1304] ES-MS[M+H] + : 380.1, Rt=6.998 min (Method-A1).

[1305] Intermediate 100

[1306] (6-Chloro-4-((2-methoxyphenyl)amino)pyridin-2-yl)(indolin-1-yl)methanone

[1307]

[1308] Synthesized according to General Procedure D-3, Step 2, Method 1. The product was isolated as a brown solid.

[1309] Yield: (crude product after use).

[1310] ES-MS[M+H] + : 380.1, Rt = 3.64 min (Method-C)

[1311] Intermediates 101

[1312] 6-Chloro-4-((2-methoxyphenyl)amino)-N-phenylpicolinamide

[1313]

[1314] Synthesized according to general procedure D-3, step 2, method 1.

[1315] Yield: (0.100 g, 34%).

[1316] ES-MS[M+H] + : 354.2, Rt=6.54 min (Method-A1).

[1317] Intermediate 102

[1318] 6-Chloro-4-((2-methoxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide

[1319]

[1320] Synthesized according to general procedure D-3, step 2, method 1.

[1321] Yield: (0.239 g, 80%).

[1322] ES-MS[M+H] + : 409.2, Rt=7.57 min (Method-A1).

[1323] Intermediate 103

[1324] 6-Chloro-4-((2-methoxyphenyl)amino)-N-phenylpicolinamide and 4-chloro-6-((2-methoxyphenyl)amino)-N-phenylpicolinamide

[1325]

[1326] Synthesized according to General Procedure D-3, Step 2, Method 1. Isolated as a mixture of the above compounds.

[1327] Yield: (0.81 g, 85%).

[1328] ES-MS[M+H] + : 354.0, Rt=7.084 and 7.257 min (Method-A1).

[1329] Intermediate 104

[1330] 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((2-methoxyphenyl)amino)picolinamide

[1331]

[1332] Synthesized according to general procedure D-3, step 2, method 1.

[1333] Yield: (0.327 g, 23%).

[1334] ES-MS[M+H] +: 394.9, Rt=7.216 min (Method-A1).

[1335] Intermediate 105

[1336] 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((2-methoxyphenyl)(methyl)amino)-picolinamide

[1337]

[1338] Synthesized according to general procedure D-3, step 2, method 1.

[1339] Yield: (0.200 g, 12%)

[1340] ES-MS[M+H] + : 408.0, Rt=7.27 min (Method-A1).

[1341] Intermediate 106

[1342] 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((2-fluorophenyl)amino)picolinamide and 4-chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-fluorophenyl)amino)picolinamide

[1343]

[1344] Synthesized according to General Procedure D-3, Step 2, Method 1. Isolated as a mixture of the title compounds.

[1345] Yield: (0.130 g, 80%).

[1346] ES-MS[M+H] + : 382.0, Rt = 7.120 and 7.410 min (Method-A1).

[1347] Intermediate 107

[1348] 6-Chloro-4-((2-chlorophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

[1349]

[1350] Synthesized according to general procedure D-3, step 2, method 1.

[1351] Yield: (0.270 g, 42%).

[1352] ES-MS[M+H] +: 398.1, Rt=7.268 min (Method-A1).

[1353] Intermediate 108

[1354] 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((2-methoxy-4-methylphenyl)amino)-picolinamide

[1355]

[1356] Synthesized according to general procedure D-3, step 2, method 1.

[1357] Yield: (0.150 g, 30%).

[1358] ES-MS[M+H] + : 408.1, Rt=3.50 min (Method-A1).

[1359] Intermediate 109

[1360] 6-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-4-((4-fluoro-2-methoxyphenyl)amino)picolinamide

[1361]

[1362] Synthesized according to general procedure D-3, step 2, method 1.

[1363] Yield: (0.170 g, 15%).

[1364] ES-MS[MH]-: 410.2, Rt=7.28 min (Method-A1).

[1365] Intermediate 110

[1366] 4-(Benzo[d][1,3]dioxol-4-ylamino)-6-chloro-N-phenylpyridineamide

[1367]

[1368] Synthesized according to general procedure D-3, step 2, method 1.

[1369] Yield: (0.365 g, 26%).

[1370] ES-MS[M+H] + : 368.0, Rt=3.12 min (Method-A1).

[1371] Intermediate 111

[1372] 6-Chloro-4-((2-fluorophenyl)amino)-N-phenylpicolinamide

[1373]

[1374] Synthesized according to general procedure D-3, step 2, method 1.

[1375] Yield: (0.189 g, 14%).

[1376] ES-MS[MH] - : 340.2, Rt=7.153 min (Method-A1).

[1377] Intermediate 112

[1378] 4-Chloro-6-((2-fluorophenyl)amino)-N-phenylpicolinamide

[1379]

[1380] Synthesized according to general procedure D-3, step 2, method 1.

[1381] Yield: (0.146 g, 10%).

[1382] ES-MS[MH] - : 340.2, Rt=7.270 min (Method-A1).

[1383] Intermediate 113

[1384] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(o-tolylamino)picolinamide

[1385]

[1386] Synthesized according to general procedure D-3, step 2, method 2.

[1387] Yield: (0.063 g, 24%).

[1388] ES-MS[M+H] + : 378.9, Rt=7.875 min (Method-A1).

[1389] Intermediate 114

[1390] (4-Chloro-6-((2-hydroxyphenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[1391]

[1392] Synthesized according to General Procedure D-3, Step 2, Method 2. This compound was used without further purification after work-up.

[1393] Yield: (0.243 g, crude product after use).

[1394] ES-MS[M+H] + : 409.1, Rt=2.72 min (Method-A1).

[1395] Intermediate 115

[1396] 6-(Benzo[d][1,3]dioxol-4-ylamino)-4-chloro-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

[1397]

[1398] Synthesized according to General Procedure D-3, Step 2, Method 2. This compound was used without further purification after work-up.

[1399] Yield: (0.283 g, crude product after use).

[1400] ES-MS[M+H] + : 408.1, Rt=7.155 min (Method-A1).

[1401] Intermediate 116

[1402] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-fluoro-3-methylphenyl)amino)picolinamide

[1403]

[1404] Synthesized according to General Procedure D-3, Step 2, Method 2. This compound was used without further purification after work-up.

[1405] Yield: (0.275 g, crude product after use).

[1406] ES-MS[M+H] + : 396.9, Rt=7.463 min (Method-A1).

[1407] Intermediate 117

[1408] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-hydroxy-3-methylphenyl)amino)picolinamide

[1409]

[1410] Synthesized according to General Procedure D-3, Step 2, Method 2. This compound was used without further purification after work-up.

[1411] Yield: (0.274 g, crude product after use).

[1412] ES-MS[M+H] + : 394.9, Rt=7.171 min (Method-A1).

[1413] Intermediate 118

[1414] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-fluorophenyl)amino)picolinamide

[1415]

[1416] Synthesized according to General Procedure D-3, Step 2, Method 2. This compound was used without further purification after work-up.

[1417] Yield: (0.265 g, crude product after use).

[1418] ES-MS[M+H] + : 382.9, Rt=7.331 min (Method-A1).

[1419] Intermediate 119

[1420] 4-Chloro-6-((2-methoxyphenyl)amino)-N-phenylpicolinamide

[1421]

[1422] Synthesized according to general procedure D-3, step 2, method 2.

[1423] Yield: (0.157 g, 10%).

[1424] ES-MS[M+H] + : 354.9, Rt=7.247 min (Method-A1).

[1425] Intermediate 120

[1426] 6-(Benzo[d][1,3]dioxol-4-ylamino)-4-chloro-N-phenylpyridineamide

[1427]

[1428] Synthesized according to general procedure D-3, step 2, method 2.

[1429] Yield: (0.365 g, 26%).

[1430] ES-MS[M+H] + : 368.0, Rt=3.22 min (Method-D1).

[1431] Intermediate 121

[1432] (6-(Benzo[d][1,3]dioxol-4-ylamino)-4-chloropyridin-2-yl)(isoindolin-2-yl)methanone

[1433]

[1434] Synthesized according to general procedure D-3, step 2, method 2.

[1435] Yield: (0.230 g, crude product after use).

[1436] ES-MS[M+H] + : 394.9, Rt=6.985 min (Method-A1).

[1437] Intermediate 122

[1438] (4-Chloro-6-((2-methoxyphenyl)amino)pyridin-2-yl)(isoindolin-2-yl)methanone

[1439]

[1440] Synthesized according to general procedure D-3, step 2, method 2.

[1441] Yield: (0.240 g, crude product after use).

[1442] ES-MS[M+H] + : 380.1, Rt=7.149 min (Method-A1).

[1443] Intermediate 123

[1444] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(m-tolylamino)picolinamide

[1445]

[1446] Synthesized according to general procedure D-3, step 2, method 2.

[1447] Yield: (0.696 g, crude product after use).

[1448] ES-MS[M+H] + : 378.1, Rt=7.394 min (Method-A1).

[1449] Intermediate 124

[1450] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((4-fluorophenyl)amino)picolinamide

[1451]

[1452] Synthesized according to general procedure D-3, step 2, method 2.

[1453] Yield: (0.265 g, crude product after use).

[1454] ES-MS[M+H] + : 382.0, Rt=7.212 min (Method-A1).

[1455] Intermediate 125

[1456] 4-Chloro-6-((2-cyanophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

[1457]

[1458] Synthesized according to general procedure D-3, step 2, method 2.

[1459] Yield: (0.405 g, crude product after use).

[1460] ES-MS[M+H] + : 389.1, Rt=6.895 min (Method-A1).

[1461] Intermediate 126

[1462] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-methoxyphenyl)amino)picolinamide

[1463]

[1464] Synthesized according to general procedure D-3, step 2, method 2.

[1465] Yield: (0.274 g, crude product after use).

[1466] ES-MS[M+H] +: 394.0, Rt=7.222 min (Method-A1).

[1467] Intermediate 127

[1468] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)picolinamide

[1469]

[1470] Synthesized according to General Procedure D-3, Step 2, Method 1. Isolated as a beige solid. Yield: (0.285 g, 74%).

[1471] ES-MS[M+H] + : 395.0, Rt=7.538 min (Method-A1).

[1472] Intermediate 128

[1473] (4-Chloro-6-((2-methoxyphenyl)amino)pyridin-2-yl)(isoindolin-2-yl)methanone

[1474]

[1475] Synthesized according to general procedure D-3, step 1, method 2.

[1476] Yield: (0.240 g, crude product after use).

[1477] ES-MS[M+H] + : 380.1, Rt=7.149 min (Method-A1).

[1478] Intermediate 129

[1479] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(m-tolylamino)picolinamide

[1480]

[1481] Synthesized according to general procedure D-3, step 1, method 2.

[1482] Yield: (0.696 g, crude product after use).

[1483] ES-MS[M+H] + : 378.1, Rt=7.394 min (Method-A1).

[1484] Intermediate 130

[1485] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((4-fluorophenyl)amino)picolinamide

[1486]

[1487] Synthesized according to general procedure D-3, step 1, method 2.

[1488] Yield: (0.265 g, crude product after use).

[1489] ES-MS[M+H] + : 382.0, Rt=7.212 min (Method-A1).

[1490] Intermediate 131

[1491] 4-Chloro-6-((2-cyanophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

[1492]

[1493] Synthesized according to general procedure D-3, step 1, method 2.

[1494] Yield: (0.405 g, crude product after use).

[1495] ES-MS[M+H] + : 389.1, Rt=6.895 min (Method-A1).

[1496] Intermediate 132

[1497] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-methoxyphenyl)amino)picolinamide

[1498]

[1499] Synthesized according to general procedure D-3, step 1, method 2.

[1500] Yield: (0.274 g, crude product after use).

[1501] ES-MS[M+H] + : 394.0, Rt=7.222 min (Method-A1).

[1502] Intermediate 133

[1503] (4-Chloro-6-((3-fluorophenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[1504]

[1505] Synthesized according to general procedure D-3, step 1, method 2.

[1506] Yield: (0.244 g, crude product after use).

[1507] ES-MS[M+H] + : 411.0, Rt=7.008 min (Method-A1).

[1508] Intermediate 134

[1509] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)-N-methyl-picolinamide

[1510]

[1511] Synthesized according to general procedure D-3, step 1, method 2.

[1512] Yield: (0.254 g, crude product after use).

[1513] ES-MS[M+H] + : 408.1, Rt=7.192 min (Method-A1).

[1514] Intermediate 135

[1515] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-fluorophenyl)amino)-N-methylpicolinamide

[1516]

[1517] Synthesized according to general procedure D-3, step 1, method 2.

[1518] Yield: (0.246 g, crude product after use).

[1519] ES-MS[M+H] + : 394.1, Rt=7.157 min (Method-A1).

[1520] Intermediate 136

[1521] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-fluoro-2-methylphenyl)amino)picolinamide

[1522]

[1523] Synthesized according to general procedure D-3, step 1, method 2.

[1524] Yield: (0.257 g, crude product after use).

[1525] ES-MS[M+H] + : 394.1, Rt = 7.371 min (Method-A1).

[1526] Intermediate 137

[1527] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-methoxyphenyl)amino)picolinamide

[1528]

[1529] Synthesized according to general procedure D-3, step 1, method 2.

[1530] Yield: (0.274 g, crude product after use).

[1531] ES-MS[MH] - : 394.1, Rt=7.222 min (Method-A1).

[1532] Intermediate 138

[1533] 4-Chloro-6-((2-cyanophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

[1534]

[1535] Synthesized according to general procedure D-3, step 1, method 2.

[1536] Yield: (0.405 g, crude product after use).

[1537] ES-MS[MH] - : 387.3, Rt=6.895 min (Method-A1).

[1538] Intermediate 139

[1539] 4-Chloro-6-((3,5-difluorophenyl)amino)-N-(2,3-dihydro-1H-inden-2-yl)picolinamide

[1540]

[1541] Synthesized according to general procedure D-3, step 1, method 2.

[1542] Yield: (0.260 g, crude product after use).

[1543] ES-MS[MH] - : 400.1, Rt=7.411 min (Method-A1).

[1544] Intermediate 140

[1545] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((4-fluorophenyl)amino)picolinamide

[1546]

[1547] Synthesized according to general procedure D-3, step 1, method 2.

[1548] Yield: (0.265 g, crude product after use).

[1549] ES-MS[MH] - : 380.3, Rt=7.212 min (Method-A1).

[1550] Intermediate 141

[1551] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-(m-tolylamino)picolinamide

[1552]

[1553] Synthesized according to general procedure D-3, step 1, method 2.

[1554] Yield: (0.263 g, crude product after use).

[1555] ES-MS[MH] - : 376.3, Rt=7.394 min (Method-A1).

[1556] Intermediate 142

[1557] 4-Chloro-6-((2-hydroxyphenyl)amino)-N-methyl-N-phenylpicolinamide

[1558]

[1559] Synthesized according to general procedure D-3, step 1, method 2.

[1560] Yield: (0.251 g, crude product after use).

[1561] ES-MS[MH] -: 376.3, Rt=6.383 min (Method-A1).

[1562] Intermediate 143

[1563] 4-Chloro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((2-fluorophenyl)amino)picolinamide

[1564]

[1565] Synthesized according to general procedure D-3, step 1, method 2.

[1566] Yield: (0.245 g, crude product after use).

[1567] ES-MS[M+H] + : 400.1, Rt=7.110 min (Method-A1).

[1568] Intermediate 144

[1569] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((3-hydroxyphenyl)amino)picolinamide

[1570]

[1571] Synthesized according to general procedure D-3, step 1, method 2.

[1572] Yield: (0.118 g, crude product after use).

[1573] ES-MS[MH] - : 378.4, Rt=6.718 min (Method-A1).

[1574] Intermediate 145

[1575] 4-Chloro-6-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide

[1576]

[1577] Synthesized according to general procedure D-3, step 1, method 2.

[1578] Yield: (0.262 g, crude product after use).

[1579] ES-MS[MH] - : 368.0, Rt=6.776 min (Method-A1).

[1580] Intermediate 146

[1581] 4-Chloro-6-((2-fluorophenyl)amino)-N-methyl-N-phenylpicolinamide

[1582]

[1583] Synthesized according to general procedure D-3, step 1, method 2.

[1584] Yield: (0.253 g, crude product after use).

[1585] ES-MS[MH] - : 354.3, Rt = 6.700 min (Method-A1).

[1586] Intermediate 147

[1587] 4-Chloro-6-((3-fluorophenyl)amino)-N-methyl-N-phenylpicolinamide

[1588]

[1589] Synthesized according to general procedure D-3, step 1, method 2.

[1590] Yield: (0.255 g, crude product after use).

[1591] ES-MS[MH] - : 356.1, Rt=6.733 min (Method-A1).

[1592] Intermediate 148

[1593] (4-Chloro-6-((3-fluorophenyl)amino)pyridin-2-yl)(isoindolin-2-yl)methanone

[1594]

[1595] Synthesized according to general procedure D-3, step 1, method 2.

[1596] Yield: (0.500 g, crude product after use).

[1597] ES-MS[MH] - : 368.0, Rt=6.866 min (Method-A1).

[1598] Intermediate 149

[1599] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-hydroxyphenyl)amino)-N-methyl-picolinamide

[1600]

[1601] Synthesized according to general procedure D-3, step 1, method 2.

[1602] Yield: (0.211 g, crude product after use).

[1603] ES-MS[MH] - : 394.1, Rt=6.845 min (Method-A1).

[1604] Intermediate 150

[1605] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-fluorophenyl)amino)-N-methylpicolinamide

[1606]

[1607] Synthesized according to general procedure D-3, step 1, method 2.

[1608] Yield: (0.246 g, crude product after use).

[1609] ES-MS[MH] - : 396.2, Rt=7.122 min (Method-A1).

[1610] Intermediate 151

[1611] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-methoxyphenyl)amino)picolinamide

[1612]

[1613] Synthesized according to general procedure D-3, step 1, method 2.

[1614] Yield: (unisolated, crude product used).

[1615] ES-MS[MH] - : 394.2, Rt=3.34 min (Method-D1).

[1616] Intermediate 152

[1617] 4-Chloro-6-((3-fluorophenyl)amino)-N-phenylpicolinamide

[1618]

[1619] Synthesized according to general procedure D-3, step 1, method 2.

[1620] Yield: (0.255 g, crude product after use).

[1621] ES-MS[MH] - : 342.1, Rt=7.318 min (Method-A1).

[1622] Intermediate 153

[1623] 4-Chloro-6-((3-methoxyphenyl)amino)-N-phenylpicolinamide

[1624]

[1625] Synthesized according to general procedure D-3, step 1, method 2.

[1626] Yield: (0.264 g, crude product after use).

[1627] ES-MS[MH] - : 354.1, Rt=7.271 min (Method-A1).

[1628] Intermediate 154

[1629] 4-Chloro-6-((3-fluorophenyl)amino)-N-(m-tolyl)picolinamide

[1630]

[1631] Synthesized according to general procedure D-3, step 1, method 2.

[1632] Yield: (0.252 g, crude product after use).

[1633] ES-MS[MH] - : 356.0, Rt=7.498 min (Method-A1).

[1634] Intermediate 155

[1635] 4-Chloro-N-(3,4-dimethylphenyl)-6-((3-fluorophenyl)amino)picolinamide

[1636]

[1637] Synthesized according to general procedure D-3, step 1, method 2.

[1638] Yield: (0.590 g, crude product after use).

[1639] ES-MS[MH] -: 370.0, Rt=7.573 min (Method-A1).

[1640] Intermediate 156

[1641] 4-Chloro-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-fluorophenyl)amino)picolinamide

[1642]

[1643] Synthesized according to general procedure D-3, step 1, method 2.

[1644] Yield: (3.73 g, crude product after use).

[1645] ES-MS[MH] - : 382.1, Rt=7.197 min (Method-A1).

[1646] General Procedure E

[1647]

[1648] XPhos (5 mol%-10 mol%) and Pd(dba) (3 mol%-6 mol%) are added to a degassed solution of the appropriate formamide (e.g., 4-chloro-6-((2-methoxyphenyl)amino)pyrimidine-2-carboxamide) (1.0 equiv), tert-butyl carbamate (3.0 equiv) and CsCO (3.0 equiv) in dioxane (4.0 mL / mmol). The resulting mixture is stirred at 100° C. under a nitrogen atmosphere for 18 hours. The mixture is then diluted with EtOAc and water. The layers are separated. The aqueous layer is extracted with EtOAc (x2). The combined organic layers are washed with water and brine, dried over MgSO, filtered and concentrated. The crude product was purified by flash column chromatography (EtOAc / hexanes 50% to 100%) to give the desired product (ex: tert-butyl (6-((2-methoxyphenyl)amino)-2-(4-phenylpiperazine-1-carbonyl)pyrimidin-4-yl)carbamate).

[1649] Intermediate 157

[1650] tert-Butyl (6-((2-methoxyphenyl)amino)-2-(4-phenylpiperazine-1-carbonyl)pyrimidin-4-yl)carbamate

[1651]

[1652] Synthesized according to General Procedure E.

[1653] Yield: (0.186 g, 56%).

[1654] ES-MS[M+H] + : 505.0, Rt=7.109 min (Method-A1).

[1655] Intermediate 158

[1656] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-methoxyphenyl)amino)-pyrimidin-4-yl)carbamate

[1657]

[1658] Synthesized according to General Procedure E. Isolated as a yellow solid.

[1659] Yield: (0.388 g, 67%).

[1660] ES-MS[MH] - : 476.9, Rt=6.365 min (Method-A1).

[1661] Intermediate 159

[1662] tert-Butyl (6-((2-methoxyphenyl)amino)-2-(phenylcarbamoyl)pyrimidin-4-yl)carbamate

[1663]

[1664] Synthesized according to General Procedure E.

[1665] Yield: (0.070 g, 9%).

[1666] ES-MS[MH] - : 436.9, Rt=2.054 min (Method-D1).

[1667] Intermediate 160

[1668] tert-Butyl (4-((2-methoxyphenyl)amino)-6-(4-phenylpiperazine-1-carbonyl)pyridin-2-yl)carbamate

[1669]

[1670] Synthesized according to General Procedure E.

[1671] Yield: (0.297 g, 46%).

[1672] ES-MS[M+H] + : 504.0, Rt=7.040 min (Method-A1).

[1673] Intermediate 161

[1674] tert-Butyl (4-((2-fluorophenyl)amino)-6-(4-phenylpiperazine-1-carbonyl)pyridin-2-yl)carbamate

[1675]

[1676] Synthesized according to General Procedure E.

[1677] Yield: (0.050 g, 21%).

[1678] ES-MS[M+H] + : 491.1, Rt=7.060 min (Method-A1).

[1679] Intermediate 162

[1680] tert-Butyl (6-(isoindoline-2-carbonyl)-4-((2-methoxyphenyl)amino)pyridin-2-yl)carbamate

[1681]

[1682] Synthesized according to General Procedure E. Isolated as a yellow wax.

[1683] Yield: (0.118 g, 43%).

[1684] ES-MS[M+H] + : 461.1, Rt=2.804 min (Method-D1).

[1685] Intermediate 163

[1686] tert-Butyl (6-(indoline-1-carbonyl)-4-((2-methoxyphenyl)amino)pyridin-2-yl)carbamate

[1687]

[1688] Synthesized according to General Procedure E. Isolated as a brown solid.

[1689] Yield: (0.690 g, 71%).

[1690] ES-MS[M+H] + : 461.1, Rt=7.715 min (Method-A1).

[1691] Intermediate 164

[1692] 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

[1693]

[1694] Synthesized according to General Procedure E. Isolated as a mixture of title compounds.

[1695] Yield: (0.236 g, 16%).

[1696] ES-MS[M+H] + : 435.0, Rt=6.996 and 7.416 min (Method-A1).

[1697] Intermediate 165

[1698] tert-Butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((2-methoxyphenyl)amino)pyridin-2-yl)carbamate

[1699]

[1700] Synthesized according to General Procedure E.

[1701] Yield: (0.205 g, 84%).

[1702] ES-MS [M+H] + : 475.2, Rt = 7.240 min (Method-A1).

[1703] Intermediate 166

[1704] 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

[1705]

[1706] Synthesized according to General Procedure E. Isolated as a mixture of title compounds.

[1707] Yield: (0.280 g, 96%).

[1708] ES-MS[M+H] + : 463.1, Rt=7.145 and 7.211 min (Method-A1).

[1709] Intermediate 167

[1710] tert-Butyl (4-((2-chlorophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-2-yl)carbamate

[1711]

[1712] Synthesized according to General Procedure E.

[1713] Yield: (0.050 g, 50%).

[1714] ES-MS[M+H] + : 479.1, Rt=7.424 min (Method-A1).

[1715] Intermediate 168

[1716] tert-Butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((2-methoxy-4-methylphenyl)amino)pyridin-2-yl)carbamate

[1717]

[1718] Synthesized according to General Procedure E.

[1719] Yield: (0.098 g, 55%).

[1720] ES-MS[M+H] + : 489.2, Rt=3.12 min (Method-D1).

[1721] Intermediate 169

[1722] tert-Butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((4-fluoro-2-methoxyphenyl)amino)pyridin-2-yl)carbamate

[1723]

[1724] Synthesized according to General Procedure E.

[1725] Yield: (0.250 g, 21%).

[1726] ES-MS[MH] - : 491.1, Rt=7.34 min (Method-A1).

[1727] Intermediate 170

[1728] tert-Butyl (4-(benzo[d][1,3]dioxol-4-ylamino)-6-(phenylcarbamoyl)pyridin-2-yl)carbamate

[1729]

[1730] Synthesized according to General Procedure E.

[1731] Yield: (0.372 g, 43%).

[1732] ES-MS[M+H] + : 449.1, Rt=6.948 min (Method-A1).

[1733] Intermediate 171

[1734] tert-Butyl (4-((2-fluorophenyl)amino)-6-(phenylcarbamoyl)pyridin-2-yl)carbamate

[1735]

[1736] Synthesized according to General Procedure E.

[1737] Yield: (0.147 g, 63%).

[1738] ES-MS[M+H] + : 423.2, Rt=7.247 min (Method-A1).

[1739] Intermediate 172

[1740] tert-Butyl (2-((2-fluorophenyl)amino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

[1741]

[1742] Synthesized according to General Procedure E.

[1743] Yield: (0.055 g, 31%).

[1744] ES-MS[M+H] + : 423.2, Rt=7.361 min (Method-A1).

[1745] Intermediate 173

[1746] tert-Butyl (4-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-methoxyphenyl)amino)-pyrimidin-2-yl)carbamate

[1747]

[1748] Synthesized according to General Procedure E.

[1749] Yield: (0.147 g, 89% yield).

[1750] ES-MS[M+H] + : 476.1, Rt=7.198 min (Method-A1).

[1751] Intermediate 174

[1752] tert-Butyl (4-((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((2-methoxyphenyl)amino)pyrimidin-2-yl)carbamate

[1753]

[1754] Synthesized according to General Procedure E.

[1755] Yield: (0.330 g, 40% yield).

[1756] ES-MS[M+H] + : 490.1, Rt=6.267 min (Method-A1).

[1757] Intermediate 175

[1758] tert-Butyl (4-((2-methoxyphenyl)amino)-6-(methyl(1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)pyrimidin-2-yl)carbamate

[1759]

[1760] Synthesized according to General Procedure E.

[1761] Yield: (0.062 g, 20% yield).

[1762] ES-MS[M+H] + : 504.1, Rt=6.377 min (Method-A1).

[1763] Intermediate 176

[1764] tert-Butyl (4-((2-methoxyphenyl)amino)-6-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)-pyrimidin-2-yl)carbamate

[1765]

[1766] Synthesized according to General Procedure E.

[1767] Yield: (0.301 g, 53% yield).

[1768] ES-MS[M+H] + : 490.2, Rt=7.289 min (Method-A1).

[1769] Intermediate 177

[1770] tert-Butyl (4-((2-methoxyphenyl)amino)-6-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-pyrimidin-2-yl)carbamate

[1771]

[1772] Synthesized according to General Procedure E,

[1773] Yield: (0.343 g, 45% yield).

[1774] ES-MS[M+H] + : 476.2, Rt=6.987 min (Method-A1).

[1775] Intermediate 178

[1776] tert-Butyl (4-(isoindoline-2-carbonyl)-6-((2-methoxyphenyl)amino)pyrimidin-2-yl)carbamate

[1777]

[1778] Synthesized according to General Procedure E.

[1779] Yield: (0.078 g, 21% yield).

[1780] ES-MS[M+H] + : 462.1, Rt=7.018 min (Method-A1).

[1781] Intermediate 179

[1782] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-(o-tolylamino)pyridin-4-yl)carbamate

[1783]

[1784] Synthesized according to General Procedure E.

[1785] Yield: (0.057 g, 75%).

[1786] ES-MS[M+H] + : 459.3, Rt=7.472 min (Method-A1).

[1787] Intermediate 180

[1788] tert-Butyl (2-((2-hydroxyphenyl)amino)-6-(4-phenylpiperazine-1-carbonyl)pyridin-4-yl)carbamate

[1789]

[1790] Synthesized according to General Procedure E.

[1791] Yield: (0.109 g, 85%).

[1792] ES-MS[M+H] + : 490.3, Rt=6.973 min (Method-A1).

[1793] Intermediate 181

[1794] tert-Butyl (2-(Benzo[d][1,3]dioxol-4-ylamino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-pyridin-4-yl)carbamate

[1795]

[1796] Synthesized according to General Procedure E.

[1797] Yield: (0.195 g, 58%).

[1798] ES-MS[M+H] - : 489.2, Rt=7.294 min (Method-A1).

[1799] Intermediate 182

[1800] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-fluoro-3-methylphenyl)amino)pyridin-4-yl)carbamate

[1801]

[1802] Synthesized according to General Procedure E.

[1803] Yield: (0.283 g, 86%).

[1804] ES-MS[M+H] + : 477.3, Rt=7.601 min (Method-A1).

[1805] Intermediate 183

[1806] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-hydroxy-3-methylphenyl)amino)pyridin-4-yl)carbamate

[1807]

[1808] Synthesized according to General Procedure E.

[1809] Yield: (0.251 g, 76%).

[1810] ES-MS[M+H] + : 475.3, Rt=7.329 min (Method-A1).

[1811] Intermediate 184

[1812] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-fluorophenyl)amino)pyridin-4-yl)carbamate

[1813]

[1814] Synthesized according to General Procedure E.

[1815] Yield: (0.305 g, 95%).

[1816] ES-MS[M+H] + : 463.2, Rt=7.490 min (Method-A1).

[1817] Intermediate 185

[1818] tert-Butyl (2-((2-methoxyphenyl)amino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

[1819]

[1820] Synthesized according to General Procedure E.

[1821] Yield: (0.123 g, 85%).

[1822] ES-MS[M+H] + : 435.2, Rt=3.40 min (Method-D1).

[1823] Intermediate 186

[1824] tert-Butyl (2-(benzo[d][1,3]dioxol-4-ylamino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

[1825]

[1826] Synthesized according to General Procedure E.

[1827] Yield: (0.341 g, 77%).

[1828] ES-MS[MH] - : 447.2, Rt=7.093 min (Method-A1).

[1829] Intermediate 187

[1830] tert-Butyl (2-(benzo[d][1,3]dioxol-4-ylamino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate

[1831]

[1832] Synthesized according to General Procedure E.

[1833] Yield: (0.253 g, 91%).

[1834] ES-MS[MH] - : 475.2, Rt=7.119 min (Method-A1).

[1835] Intermediate 188

[1836] tert-Butyl (2-(isoindoline-2-carbonyl)-6-((2-methoxyphenyl)amino)pyridin-4-yl)carbamate

[1837]

[1838] Synthesized according to General Procedure E.

[1839] Yield: (0.239 g, 82%).

[1840] ES-MS[M+H] + : 461.2, Rt=7.309 min (Method-A1).

[1841] Intermediate 189

[1842] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-(m-tolylamino)pyridin-4-yl)carbamate

[1843]

[1844] Synthesized according to General Procedure E.

[1845] Yield: (0.304 g, 95%).

[1846] ES-MS[M+H] + : 459.2, Rt=7.511 min (Method-A1).

[1847] Intermediate 190

[1848] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((4-fluorophenyl)amino)pyridin-4-yl)carbamate

[1849]

[1850] Synthesized according to General Procedure E.

[1851] Yield: (0.314 g, 97% over two steps).

[1852] ES-MS[M+H] + : 463.2, Rt=7.360 min (Method-A1).

[1853] Intermediate 191

[1854] tert-Butyl (2-((2-cyanophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate

[1855]

[1856] Synthesized according to General Procedure E.

[1857] Yield: (0.059 g, 12% over two steps).

[1858] ES-MS[M+H] + : 470.2, Rt=7.103 min (Method-A1).

[1859] Intermediate 192

[1860] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-methoxyphenyl)amino)pyridin-4-yl)carbamate

[1861]

[1862] Synthesized according to General Procedure E.

[1863] Yield: (0.183 g, 55% over two steps).

[1864] ES-MS[M+H] + : 475.3, Rt=7.333 min (Method-A1).

[1865] General Procedure F

[1866]

[1867] Dppf (6 mol%) and Pd (OAc) 2 (3 mol%) are added to a degassed solution of the appropriate aryl dichloride (e.g., 4,6-dichloropyridine amide) (1.0 equiv.), the appropriate arylamine (e.g., 2-chloroaniline) (1.0 equiv.) and K 3 PO 4 (2.0 equiv.) in dioxane (5 mL / mmol). The resulting mixture is stirred at 90° C. under a nitrogen atmosphere for 2 hours. Then, tert-butyl carbamate (3 equiv.) and additional dppf (6 mol%) and Pd (OAc) 2 (2 mol%) are added. The mixture is stirred at 90° C. for 18 hours. The mixture is then diluted with EtOAc and water. The layers are separated. The aqueous layer is extracted with EtOAc (x2). The combined organic layers are washed with water and brine, dried over MgSO 4 , filtered and concentrated. The crude product was purified by flash column chromatography (hexanes:EtOAc 60:40) to give the desired product (ex: tert-butyl (2-((2-chlorophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate).

[1868] Intermediate 193

[1869] tert-Butyl (2-((2-chlorophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate

[1870]

[1871] Synthesized according to General Procedure F.

[1872] Yield: (0.326 g, 85%).

[1873] ES-MS[M+H] + : 479.9, Rt=3.49 min (Method-D1).

[1874] Intermediate 194

[1875] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-(pyridin-3-ylamino)pyridin-4-yl)carbamate

[1876]

[1877] Synthesized according to General Procedure F.

[1878] Yield: (0.098 g, 32%).

[1879] ES-MS[M+H] + : 446.2, Rt=2.14 min (Method-D1).

[1880] Intermediate 195

[1881] tert-Butyl (4-((2-hydroxy-4-methylphenyl)amino)-6-(phenylcarbamoyl)pyridin-2-yl)carbamate

[1882]

[1883] Synthesized according to General Procedure F.

[1884] Yield: (0.269 g, 83%).

[1885] ES-MS[M+H] + : 435.2, Rt=3.00 min (Method-D1).

[1886] Intermediate 196

[1887] tert-Butyl (4-((4-fluoro-2-hydroxyphenyl)amino)-6-(phenylcarbamoyl)pyridin-2-yl)carbamate

[1888]

[1889] Synthesized according to General Procedure F.

[1890] Yield: (0.216 g, 64%).

[1891] ES-MS[M+H] + : 439.2, Rt=2.97 min (Method-D1).

[1892] Intermediate 197

[1893] tert-Butyl (6-(phenylcarbamoyl)-4-(pyridin-2-ylamino)pyridin-2-yl)carbamate

[1894]

[1895] Synthesized according to General Procedure F.

[1896] Yield: (0.230 g, 36%).

[1897] ES-MS[M+H] + : 406.3, Rt=7.108 min (Method-A1).

[1898] Intermediate 198

[1899] tert-Butyl (6-(phenylcarbamoyl)-4-(pyridin-3-ylamino)pyridin-2-yl)carbamate

[1900]

[1901] Synthesized according to General Procedure F.

[1902] Yield: (0.220 g, 36%).

[1903] ES-MS[M+H] + : 406.3, Rt=6.93 min (Method-A1).

[1904] Intermediate 199

[1905] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-(m-tolylamino)pyridin-4-yl)carbamate

[1906]

[1907] Synthesized according to General Procedure F.

[1908] Yield: (0.304 g, 95%).

[1909] ES-MS[M+H] + : 459.2, Rt=7.511 min (Method-A1).

[1910] Intermediate 200

[1911] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((4-fluorophenyl)amino)pyridin-4-yl)carbamate

[1912]

[1913] Synthesized according to General Procedure F.

[1914] Yield: (0.314 g, 97% over two steps).

[1915] ES-MS[M+H] + : 463.2, Rt=7.360 min (Method-A1).

[1916] Intermediate 201

[1917] tert-Butyl (2-((2-cyanophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate

[1918]

[1919] Synthesized according to General Procedure F.

[1920] Yield: (0.059 g, 12% over two steps).

[1921] ES-MS[M+H] + : 470.2, Rt=7.103 min (Method-A1).

[1922] Intermediate 202

[1923] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-methoxyphenyl)amino)pyridin-4-yl)carbamate

[1924]

[1925] Synthesized according to General Procedure F.

[1926] Yield: (0.183 g, 55% over two steps).

[1927] ES-MS[M+H] + : 475.3, Rt=7.333 min (Method-A1).

[1928] Intermediate 203

[1929] tert-Butyl (2-(isoindoline-2-carbonyl)-6-((2-methoxyphenyl)amino)pyridin-4-yl)carbamate

[1930]

[1931] Synthesized according to General Procedure F.

[1932] Yield: (0.239 g, 82% over two steps).

[1933] ES-MS[M+H] +: 461.2, Rt=7.309 min (Method-A1).

[1934] Intermediate 204

[1935] tert-Butyl (2-((3-fluorophenyl)amino)-6-(4-phenylpiperazine-1-carbonyl)pyridin-4-yl)carbamate

[1936]

[1937] Synthesized according to General Procedure F.

[1938] Yield: (0.269 g, 92% over two steps).

[1939] ES-MS[M+H] + : 492.2, Rt=7.194 min (Method-A1).

[1940] Intermediate 205

[1941] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((2-methoxyphenyl)amino)pyridin-4-yl)carbamate

[1942]

[1943] Synthesized according to General Procedure F.

[1944] Yield: (0.291 g, 96% over two steps).

[1945] ES-MS[M+H] + : 489.3, Rt=7.328 min (Method-A1).

[1946] Intermediate 206

[1947] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((3-fluorophenyl)amino)pyridin-4-yl)carbamate

[1948]

[1949] Synthesized according to General Procedure F.

[1950] Yield: (0.265 g, 89% over two steps).

[1951] ES-MS[M+H] + : 477.3, Rt=7.325 min (Method-A1).

[1952] Intermediate 207

[1953] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-fluoro-2-methylphenyl)amino)pyridin-4-yl)carbamate

[1954]

[1955] Synthesized according to General Procedure F.

[1956] Yield: (0.173 g, 56% over two steps).

[1957] ES-MS[M+H] + : 477.3, Rt=7.485 min (Method-A1).

[1958] Intermediate 208

[1959] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-methoxyphenyl)amino)pyridin-4-yl)carbamate

[1960]

[1961] Synthesized according to General Procedure F.

[1962] Yield: (0.183 g, 55% over two steps).

[1963] ES-MS[M+H] + : 475.3, Rt=7.333 min (Method-A1).

[1964] Intermediate 209

[1965] tert-Butyl (2-((2-cyanophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate

[1966]

[1967] Synthesized according to General Procedure F.

[1968] Yield: (0.59 g, 12% over two steps).

[1969] ES-MS[M+H] + : 470.2, Rt=7.103 min (Method-A1).

[1970] Intermediate 210

[1971] tert-Butyl (2-((3,5-difluorophenyl)amino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-4-yl)carbamate

[1972]

[1973] Synthesized according to General Procedure F.

[1974] Yield: (0.382 g, quantitative, over two steps).

[1975] ES-MS[M+H] + : 470.2, Rt=7.103 min (Method-A1).

[1976] Intermediate 211

[1977] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((4-fluorophenyl)amino)pyridin-4-yl)carbamate

[1978]

[1979] Synthesized according to General Procedure F.

[1980] Yield: (0.314 g, 97% over two steps).

[1981] ES-MS[M+H] + : 463.2, Rt=7.360 min (Method-A1).

[1982] Intermediate 212

[1983] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-(m-tolylamino)pyridin-4-yl)carbamate

[1984]

[1985] Synthesized according to General Procedure F.

[1986] Yield: (0.304 g, 95% over two steps).

[1987] ES-MS[M+H] + : 459.2, Rt=7.511 min (Method-A1).

[1988] Intermediate 213

[1989] tert-Butyl (2-((2-hydroxyphenyl)amino)-6-(methyl(phenyl)carbamoyl)pyridin-4-yl)carbamate

[1990]

[1991] Synthesized according to General Procedure F.

[1992] Yield: (0.189 g, 61% over two steps).

[1993] ES-MS[M+H] + : 435.2, Rt=6.638 min (Method-A1).

[1994] Intermediate 214

[1995] tert-Butyl (2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)carbamoyl)-6-((2-fluorophenyl)amino)pyridin-4-yl)carbamate

[1996]

[1997] Synthesized according to General Procedure F.

[1998] Yield: (0.176 g, 60% over two steps).

[1999] ES-MS[M+H] + : 481.2, Rt=7.217 min (Method-A1).

[2000] Intermediate 215

[2001] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((3-hydroxyphenyl)amino)pyridin-4-yl)carbamate

[2002]

[2003] Synthesized according to General Procedure F.

[2004] Yield: (0.133 g, 94% over two steps).

[2005] ES-MS[M+H] + : 461.2, Rt=6.869 min (Method-A1).

[2006] Intermediate 216

[2007] tert-Butyl (2-((2-methoxyphenyl)amino)-6-(methyl(phenyl)carbamoyl)pyridin-4-yl)carbamate

[2008]

[2009] Synthesized according to General Procedure F.

[2010] Yield: (0.310 g, 97% over two steps).

[2011] ES-MS[MH]-: 447.5, Rt=6.931 min (Method-A1).

[2012] Intermediate 217

[2013] tert-Butyl (2-((2-fluorophenyl)amino)-6-(methyl(phenyl)carbamoyl)pyridin-4-yl)carbamate

[2014]

[2015] Synthesized according to General Procedure F.

[2016] Yield: (0.240 g, 77% over two steps).

[2017] ES-MS [MH]-: 435.4, Rt=6.863 min (Method-A1).

[2018] Intermediate 218

[2019] tert-Butyl (2-((3-fluorophenyl)amino)-6-(methyl(phenyl)carbamoyl)pyridin-4-yl)carbamate

[2020]

[2021] Synthesized according to General Procedure F.

[2022] Yield: (0.304 g, 98% over two steps).

[2023] ES-MS [M+H] + : 437.2, Rt = 6.917 min (Method-A1).

[2024] Intermediate 219

[2025] tert-Butyl (2-((3-fluorophenyl)amino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate

[2026]

[2027] Synthesized according to General Procedure F.

[2028] Yield: (0.132 g, 22% over two steps).

[2029] ES-MS [M+H] + : 449.2, Rt = 7.249 min (Method-A1).

[2030] Intermediate 220

[2031] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((2-hydroxyphenyl)amino)-pyridin-4-yl)carbamate

[2032]

[2033] According to the general procedure F synthesis.

[2034] Yield: (0.155 g, 61% over two steps).

[2035] ES-MS [M+H] + : 475.3, Rt = 7.045 min (Method-A1).

[2036] Intermediate 221

[2037] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)(methyl)carbamoyl)-6-((2-fluorophenyl)amino)-pyridin-4-yl)carbamate

[2038]

[2039] Synthesized according to General Procedure F.

[2040] Yield: (0.281 g, 95% over two steps).

[2041] ES-MS [M+H] + : 477.3, Rt = 7.250 min (Method-A1).

[2042] Intermediate 222

[2043] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-methoxyphenyl)amino)pyridin-4-yl)carbamate

[2044]

[2045] Synthesized according to General Procedure F.

[2046] Yield: (0.041 g, 12% over two steps).

[2047] ES-MS [M+H] + : 475.2, Rt = 3.37 min (Method-D1).

[2048] Intermediate 223

[2049] tert-Butyl (2-((3-fluorophenyl)amino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

[2050]

[2051] Synthesized according to General Procedure F.

[2052] Yield: (0.146 g, 43% over two steps).

[2053] ES-MS [M+H] + : 423.3, Rt = 7.433 min (Method-A1).

[2054] Intermediate 224

[2055] tert-Butyl (2-((3-methoxyphenyl)amino)-6-(phenylcarbamoyl)pyridin-4-yl)carbamate

[2056]

[2057] Synthesized according to General Procedure F.

[2058] Yield: (0.261 g, 80% over two steps).

[2059] ES-MS [M+H] + : 435.1, Rt = 7.283 min (Method-A1).

[2060] Intermediate 225

[2061] tert-Butyl (2-((3-fluorophenyl)amino)-6-(m-tolylcarbamoyl)pyridin-4-yl)carbamate

[2062]

[2063] Synthesized according to General Procedure F.

[2064] Yield: (0.147 g, 47% over two steps).

[2065] ES-MS [M+H] + : 437.2, Rt = 7.600 min (Method-A1).

[2066] Intermediate 226

[2067] tert-Butyl (2-((3,4-dimethylphenyl)carbamoyl)-6-((3-fluorophenyl)amino)pyridin-4-yl)carbamate

[2068]

[2069] Synthesized according to General Procedure F.

[2070] Yield: (0.220 g, 31% over two steps).

[2071] ES-MS [M+H] + : 451.1, Rt = 7.717 min (Method-A1).

[2072] Intermediate 227

[2073] tert-Butyl (2-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-6-((2-fluorophenyl)amino)pyridin-4-yl)carbamate

[2074]

[2075] Synthesized according to General Procedure F.

[2076] Yield: (1.62 g, 36% over two steps).

[2077] ES-MS [M+H] + : 463.2, Rt = 7.319 min (Method-A1).

[2078] General Procedure G

[2079]

[2080] To a stirred solution of 2-amino-6-chloroisonicotinic acid (1.0 equiv), an appropriate amine (e.g., aniline) (1.0 equiv), and HATU (0.7 equiv) in DMF (8 mL / mmol) was added DIPEA (1.3 equiv). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (x3), 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., 2-amino-6-chloro-N-phenylisonicotinamide).

[2081] Intermediate 228

[2082] 2-Amino-6-chloro-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)isonicotinamide

[2083]

[2084] Synthesized according to General Procedure G.

[2085] Yield: (0.16 g, 29%).

[2086] ES-MS[M+H] + : 316.0, Rt=6.269 min (Method-A1).

[2087] Intermediate 229

[2088] 2-Amino-6-chloro-N-methyl-N-phenylisonicotinamide

[2089]

[2090] Synthesized according to General Procedure G.

[2091] Yield: (0.090 g, 29%).

[2092] ES-MS[M+H] + : 262.2, Rt=5.50 min (Method-A1).

[2093] Intermediate 230

[2094] 2-Amino-6-chloro-N-(2,3-dihydro-1H-inden-2-yl)-N-methylisonicotinamide

[2095]

[2096] Synthesized according to General Procedure G.

[2097] Yield: (0.290 g, 42%).

[2098] ES-MS[M+H] + : 302.0, Rt=6.13 min (Method-A1).

[2099] Intermediate 231

[2100] 2-Amino-6-chloro-N-(1,2,3,4-tetrahydronaphthalen-2-yl)isonicotinamide

[2101]

[2102] Synthesized according to General Procedure G.

[2103] Yield: (0.135 g, 39%).

[2104] ES-MS[M+H] +: 302.1, Rt = 6.201 min (Method-A1).

[2105] Intermediate 232

[2106] 2-Amino-6-chloro-N-phenylisonicotinamide

[2107]

[2108] Synthesized according to General Procedure G.

[2109] Yield: (0.130 g, 33%).

[2110] ES-MS[M+H] + : 248.1, Rt=5.66 min (Method-A1).

[2111] Intermediate 233

[2112] 2-Amino-6-chloro-N-(2,3-dihydro-1H-inden-2-yl)isonicotinamide

[2113]

[2114] Synthesized according to General Procedure G.

[2115] Yield: (0.124 g, 37%).

[2116] ES-MS[M+H] + : 288.0, Rt=5.928 min (Method-A1).

[2117] General Procedure H

[2118]

[2119] To a stirred solution of the appropriate 4,6-dichloropyridine amide (e.g., (4,6-dichloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone) (1.0 eq) in anhydrous DMF (5 mL / mmol) was added NaN3 (3.0 eq) at 0°C. The mixture was stirred at 90°C for 16 hours. The mixture was then diluted with water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was dissolved in MeOH (25 mL) and then NaBH4 (2 eq) was added at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The solvent was then evaporated and the residue was diluted with water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The resulting crude product was purified by flash column chromatography (hexanes:EtOAc, 80:20 to 0:100) to afford the desired product (ex: (4-amino-6-chloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone).

[2120] Intermediate 234

[2121] (4-Amino-6-chloropyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[2122]

[2123] Synthesized according to the general procedure H.

[2124] Yield: (0.846 g, 84%).

[2125] ES-MS[MH] - : 315.2, Rt=5.863 min (Method-A1).

[2126] Intermediate 235

[2127] (4-Amino-6-chloropyridin-2-yl)(isoindolin-2-yl)methanone

[2128]

[2129] Synthesized according to the general procedure H.

[2130] Yield: (0.925 g, 76%).

[2131] ES-MS[M+H] + : 274.9, Rt = 2.29 min (Method-D1).

[2132] General Procedure I

[2133]

[2134] Method 1

[2135] BINAP (10 mol%) and Pd(dba) (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 equiv), the appropriate aniline (e.g., 2-aminophenol) (1.1 equiv), and CsCO (2.8 equiv) in dioxane (6 mL / mmol). The resulting mixture was stirred at 100°C for 20 hours. The reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3x), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (EtOAc / hexanes 10%-20%) to give the desired product (e.g., 2-amino-6-((2-hydroxyphenyl)amino)-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)isonicotinamide).

[2136] Method 2

[2137] XantPhos (10 mol%) and Pd(OAc)2 (5 mol%) are 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 equiv), the corresponding amine (e.g., 2-fluoroaniline) (1.1 equiv), and Cs2CO3 (2.5 equiv) in dioxane (5 mL / mmol). The mixture is stirred at 100°C for 18 hours. The solvent is then evaporated under vacuum, and the resulting crude residue is 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).

[2138] Example 42

[2139] 2-Amino-6-((2-hydroxyphenyl)amino)-N-methyl-N-(1,2,3,4-tetrahydronaphthalen-2-yl)isonicotinamide

[2140]

[2141] Synthesized according to General Procedure I, Method 1.

[2142] Yield: (0.030 g, 15%).

[2143] ES-MS[MH] - : 387.2, Rt=18.135 min (Method-B1).

[2144] 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (d, J = 49.1 Hz, 1H), 8.13–7.86 (m, 1H), 7.81–7.47 (m, 1H), 7.09 (d, J = 19.4 Hz, 4H), 6.82 (d, J = 4.8 Hz, 2H), 6.72 (s, 1H), 6.10–5.88 (m, 3H), 5.73 (d, J = 2.2 Hz, 1H), 4.64 (s, 0.36H), 3.90 (s, 0.64H), 3.17–3.03 (m, 1H), 3.02–2.81 (m, 5H), 2.79–2.65 (m, 1H), 2.08–1.82 (m, 2H). Conformers exist.

[2145] Example 43

[2146] 2-Amino-6-((2-hydroxyphenyl)amino)-N-methyl-N-phenylisonicotinamide

[2147]

[2148] Synthesized according to General Procedure I, Method 1. The compound was purified by HPLC-semiprep (Method-E1).

[2149] Yield: (0.008 g, 26%).

[2150] ES-MS [M+H] + : 335.1, Rt = 19.960 min (Method-B1).

[2151] 1 H NMR (400MHz, DMSO-d6) δ10.33(brs,1H),7.73(s,1H),7.32(td,J=11.2,9.8,7.3Hz,3H),7.21(td,J=7.0,1.5Hz,3H),6. 85–6.76(m,2H),6.69(ddd,J=7.9,5.8,3.1Hz,1H),5.88(d,J=8.0Hz,3H),5.68(d,J=1.1Hz,1H),3.32(d,J=7.2Hz,3H).

[2152] Example 44

[2153] 2-Amino-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-hydroxyphenyl)amino)-N-methylisonicotinamide

[2154]

[2155] Synthesized according to General Procedure I, Method 1. The compound was purified by HPLC-semiprep (Method-E1).

[2156] Yield: (0.101 g, 28%).

[2157] ES-MS [M+H] + : 375.1, Rt = 17.825 min (Method-B1).

[2158] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.06(s,1H),7.58(d,J=7.9Hz,2H),7.41–7.07(m,9H),6.89–6.79(m,4H),6.74(ddd,J=8.5,5.6,3.2Hz ,2H),6.13–5.88(m,7H),5.75(d,J=2.5Hz,2H),5.34(s,1H),4.65(d,J=8.9Hz,2H),3.04(d,J=7.8Hz,7H),2.78(s,4H),2.72(d,J=5.6Hz,2H).

[2159] Example 45

[2160] 2-Amino-6-((2-hydroxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)isonicotinamide

[2161]

[2162] Synthesized according to General Procedure I, Method 1.

[2163] Yield: (0.019 g, 14%).

[2164] ES-MS[M+H] + : 375.2, Rt=17.799 min (Method-B1).

[2165] 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.34(d,J=7.6Hz,1H),8.02(s,1H),7.72–7.49(m,1H),7.18–7.04 (m,4H),6.83(dd,J=4.0,1.3Hz,2H),6.74(ddd,J=7.9,5.5,3.4Hz,1H),6.38(d,J=1.2Hz,1H),6.12(d,J= 1.1Hz,1H),6.05(s,2H),4.10(ddd,J=10.3,5.3,2.6Hz,1H),2.99(ddd,J=16.3,5.6,1.6Hz,1H),2.86(dd ,J=7.6,4.0Hz,2H),2.77(dd,J=16.3,10.3Hz,1H),1.99(ddt,J=9.6,3.4,1.7Hz,1H),1.84–1.63(m,1H).

[2166] Example 46

[2167] 2-Amino-6-((2-hydroxyphenyl)amino)-N-phenylisonicotinamide

[2168]

[2169] Synthesized according to Procedure 1, Method 1.

[2170] Yield: (0.011 g, 7%).

[2171] ES-MS[M+H] + : 321.1, Rt=16.299 min (Method-B1).

[2172] 1 H NMR (400MHz, DMSO-d6) δ10.41(brs,1H),10.22(s,1H),8.07(s,1H),7.85–7.70(m,2H),7.66(dt,J=7.9,1.1Hz,1H),7.45–7.27(m, 2H),7.21–6.98(m,1H),6.84(dd,J=3.9,0.9Hz,2H),6.80–6.64(m,1H),6.45(d,J=1.2Hz,1H),6.18(d,J=1.2Hz,1H),6.12(s,2H).

[2173] Example 47

[2174] 2-Amino-N-(2,3-dihydro-1H-inden-2-yl)-6-((2-hydroxyphenyl)amino)isonicotinamide

[2175]

[2176] Synthesized according to General Procedure I, Method 1.

[2177] Yield: (0.009 g, 12%).

[2178] ES-MS [M+H] + : 361.1, Rt = 17.214 min (Method-B1).

[2179] 1 H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.57(d,J=7.0Hz,1H),8.00(s,1H),7.68–7.4 7(m,1H),7.22(dd,J=5.4,3.3Hz,2H),7.18–7.07(m,2H),6.88–6.80(m,2H),6.73(d dd,J=7.8,5.3,3.6Hz,1H),6.37(d,J=1.2Hz,1H),6.11(d,J=1.1Hz,1H),6.03(s,2H ), 4.63 (h, J = 7.2Hz, 1H), 3.21 (dd, J = 15.9, 7.8Hz, 2H), 2.92 (dd, J = 15.9, 6.8Hz, 2H).

[2180] Example 48

[2181] (4-Amino-6-((2-fluorophenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[2182]

[2183] Synthesized according to General Procedure 1, Method 2.

[2184] Yield: (0.008 g, 2%).

[2185] ES-MS [MH]-: 390.3, Rt=19.100 min (Method-B1).

[2186] 1H NMR(400MHz, DMSO-d6)δ8.28(d,J=1.6Hz,1H),7.91(td,J=8.3,1.7Hz,1H),7.36–7.11(m,3H),7.07(td,J=7.7,1.5Hz,1H),7.02–6.87(m,3H) ,6.81(t,J=7.3Hz,1H),6.24(d,J=1.8Hz,1H),6.05(d,J=1.8Hz,1H),6.00(s,2H),3.67(dt,J=24.1,5.1Hz,4H),3.11(dt,J=40.0,5.2Hz,4H).

[2187] General Program J-1

[2188]

[2189] Method 1

[2190] To a stirred solution of (4-amino-6-chloropyridin-2-yl)(isoindolin-2-yl)methanone (0.925 g, 3.4 mmol, 1.0 equivalent) in dioxane (26 mL) was added di-tert-butyl dicarbonate (2.21 g, 10.1 mmol, 3.0 equivalents), DMAP (0.40 g, 3.3 mmol, 1.0 equivalents) and triethylamine (1.50 mL, 10.8 mmol, 3.2 equivalents). The resulting mixture was stirred at 100 ° C for 16 hours. 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 (x2). The combined organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The resulting crude product was purified by flash column chromatography (hexanes:EtOAc 60:40) to afford the desired product, tert-butyl (2-chloro-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate.

[2191] Method 2

[2192] Dppf (6 mol%) and Pd(OAc)2 (2 mol%) were added to a degassed solution of the corresponding 4,6-dichloropyridine amide (e.g., (4,6-dichloropyridin-2-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone) (1.0 equiv), tert-butyl carbamate (3.0 equiv), and K2CO3 (2.0 equiv) in dioxane (5 mL / mmol). The resulting mixture was stirred at 90°C under a nitrogen atmosphere for 16 hours. The mixture was then diluted with EtOAc and water. The layers were separated. The aqueous layer was extracted with EtOAc (x2). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (hexanes:EtOAc 60:40) to give the desired product (ex: tert-butyl (4-chloro-6-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyridin-2-yl)carbamate).

[2193] Intermediate 236

[2194] tert-Butyl (2-chloro-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate

[2195]

[2196] Synthesized according to general procedure J-1, method 1.

[2197] Yield: (0.900 g, 71%).

[2198] ES-MS[M+H] + : 374.9, Rt=3.17 min (Method-D1).

[2199] Intermediate 237

[2200] tert-Butyl (4-chloro-6-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyridin-2-yl)carbamate

[2201]

[2202] Synthesized according to general procedure J-1, method 2.

[2203] Yield: (0.50 g, 75%).

[2204] ES-MS[M+H] + : 388.1, Rt=7.21 min (Method-A1).

[2205] Intermediate 238

[2206] tert-Butyl (4-chloro-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)pyridin-2-yl)carbamate

[2207]

[2208] Synthesized according to general procedure J-1, method 2.

[2209] Yield: (0.370 g, 97%).

[2210] ES-MS[M+H] + : 388.1, Rt=7.41 min (Method-A1).

[2211] General Procedure J-2

[2212]

[2213] Method 1

[2214] Dppf (6 mol%) and Pd(OAc) (2 mol%) are 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 equiv), the appropriate aniline (e.g., 2-aminophenol) (3.0 equiv) and K PO (2.0 equiv) in dioxane (6.4 mL / mmol). The resulting mixture is stirred at 90° C. under a nitrogen atmosphere for 16 hours. The mixture is then diluted with EtOAc and water. The layers are separated. The aqueous layer is extracted with EtOAc (x2). The combined organic layers are washed with water and brine, dried over MgSO , filtered and concentrated. The crude product was purified by flash column chromatography (hexanes:EtOAc 60:40) to give the desired product (ex: tert-butyl (2-((2-hydroxyphenyl)amino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate).

[2215] Method 2

[2216] XPhos (5 mol%) and Pd(dba) (3 mol%) are 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 equiv), the appropriate aniline (e.g., 3-methoxyaniline) (3.0 equiv) and CsCO (3.0 equiv) in dioxane (3 mL / mmol). The resulting mixture is stirred at 100° C. under a nitrogen atmosphere for 18 hours. The mixture is then diluted with EtOAc and water. The layers are separated. The aqueous layer is extracted with EtOAc (x2). The combined organic layers are washed with water and brine, dried over MgSO, filtered and concentrated. The crude product was purified by flash column chromatography (hexanes:EtOAc 60:40) to give the desired product (ex: tert-butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((3-methoxyphenyl)amino)pyridin-2-yl)carbamate).

[2217] Intermediate 239

[2218] tert-Butyl (2-((2-fluorophenyl)amino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate

[2219]

[2220] Synthesized according to general procedure J-2, method 1.

[2221] Yield: (0.110 g, 20%).

[2222] ES-MS[M+H] + : 449.9, Rt=7.214 min (Method-A1).

[2223] Intermediate 240

[2224] tert-Butyl (2-((2-hydroxyphenyl)amino)-6-(isoindoline-2-carbonyl)pyridin-4-yl)carbamate

[2225]

[2226] Synthesized according to general procedure J-2, method 1.

[2227] Yield: (0.250 g, 47%).

[2228] ES-MS[M+H] + : 447.2, Rt=6.951 min (Method-A1).

[2229] Example 49

[2230] (6-Amino-4-((2-hydroxyphenyl)amino)pyridin-2-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone

[2231]

[2232] Synthesized according to general procedure J-2, Method 2. The compound was isolated directly after step 3 and purified by HPLC-semiprep (Method-E1).

[2233] Yield: (0.130 g, 71%).

[2234] ES-MS [MH]-: 361.2, Rt=16.433 min (Method-B1).

[2235] 1 H NMR(400MHz,DMSO-d6)δ9.49(d,J=4.8Hz,1H),7.74(d,J=7.5Hz,1H),7.37–7.10(m,4H ),7.05(d,J=6.9Hz,1H),7.02–6.85(m,2H),6.79(ddt,J=11.4,5.9,2.9Hz,1H),6.19( dd,J=12.4,1.9Hz,1H),5.86(dd,J=5.9,1.9Hz,1H),5.65(d,J=4.8Hz,2H),4.67(d,J= 18.8Hz, 2H), 3.77 (t, J = 5.9Hz, 1H), 3.65 (t, J = 5.8Hz, 1H), 2.84 (q, J = 6.6, 6.2Hz, 2H).

[2236] Intermediate 241

[2237] tert-Butyl (4-(benzo[d][1,3]dioxol-4-ylamino)-6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-pyridin-2-yl)carbamate

[2238]

[2239] Synthesized according to general procedure J-2, method 2.

[2240] Yield: (0.240 g, 50%).

[2241] ES-MS[M+H] + : 489.1, Rt=7.24 min (Method-A1).

[2242] Intermediate 242

[2243] tert-Butyl (6-((2,3-dihydro-1H-inden-2-yl)carbamoyl)-4-((3-methoxyphenyl)amino)pyridin-2-yl)carbamate

[2244]

[2245] Synthesized according to general procedure J-2, method 2.

[2246] Yield: (0.130 g, 42%).

[2247] ES-MS[M+H] + : 475.3, Rt=7.259 min (Method-A1).

[2248] General Procedure K

[2249]

[2250] Step 1

[2251] BINAP (10 mol%) and Pd(dba) (5 mol%) are added to a degassed solution of the appropriate aryl chloride (e.g., 6-chloro-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide) (1.0 equiv), diphenylmethylamine (1.2 equiv), and NaOtBu (1.4 equiv) in toluene (29 mL / mmol). The resulting mixture is stirred at reflux for 18 hours. The mixture is then diluted with EtOAc and filtered through a pad of Celite / SiO. The filtrate is concentrated to dryness and used without further purification (e.g., 6-((diphenylmethylene)amino)-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide).

[2252] Step 2

[2253] To a stirred solution of the appropriate diphenylmethyleneamine derivative (e.g., 6-((diphenylmethylene)amino)-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide) in THF (25 mL / mmol) was added HCl 1N (2 mL / mmol). The resulting mixture was stirred at room temperature for 5 hours. The mixture was then diluted with EtOAc and saturated NaHCO3 aqueous solution. The organic layer was dried over NaSO4, filtered, and concentrated to dryness under reduced pressure. The crude mixture was purified by silica gel column chromatography (hexane:EtOAc, 80:20 to 70:30) to obtain the desired amine product (e.g., 6-amino-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide).

[2254] Intermediate 243

[2255] 6-((Diphenylmethylene)amino)-4-((2-methoxyphenyl)amino)-N-methyl-N-phenyl-picolinamide

[2256]

[2257] Synthesized according to General Procedure K, Step 1.

[2258] Yield: (0.194 g, crude product after use).

[2259] ES-MS[M+H] + : 513.9, Rt=7.143 min (Method-A1).

[2260] Intermediate 244

[2261] (6-((diphenylmethylene)amino)-4-((2-methoxyphenyl)amino)pyridin-2-yl)(4-phenyl-piperazin-1-yl)methanone

[2262]

[2263] Synthesized according to General Procedure K, Step 1.

[2264] Yield: (0.682 g, crude product after use).

[2265] ES-MS[M+H] + : 569.1, Rt=6.567 min (Method-A1).

[2266] Intermediate 245

[2267] 6-Chloro-4-((2-methoxyphenyl)amino)-N-(1,2,3,4-tetrahydronaphthalen-2-yl)picolinamide

[2268]

[2269] Synthesized according to General Procedure K, Step 1.

[2270] Yield: (0.320 g, crude product after use).

[2271] ES-MS[M+H] + : 553.1, Rt=7.553 min (Method-A1).

[2272] Intermediate 246

[2273] 6-((diphenylmethylene)amino)-4-((2-methoxyphenyl)amino)-N-phenylpicolinamide

[2274]

[2275] Synthesized according to General Procedure K, Step 1.

[2276] Yield: (0.135 g, quantitative).

[2277] ES-MS[M+H] + : 499.0, Rt=6.77 min (Method-A1).

[2278] Intermediate 247

[2279] N-(2,3-Dihydro-1H-inden-2-yl)-4-((diphenylmethylene)amino)-6-((2-methoxyphenyl)amino)picolinamide

[2280]

[2281] Synthesized according to General Procedure K, Step 1.

[2282] Yield: (0.381 g, crude product after use).

[2283] ES-MS[M+H] + : 538.0, Rt=7.583 min (Method-A1).

[2284] Example 50

[2285] 6-amino-4-((2-methoxyphenyl)amino)-N-methyl-N-phenylpicolinamide

[2286]

[2287] Synthesized according to General Procedure K, Step 2. Isolated as a white solid.

[2288] Yield: (0.067 g, 36% yield over 2 steps).

[2289] ES-MS[M+H] + : 349.2, Rt=19.371 min (Method-B1).

[2290] 1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.54–8.19(m,1H),7.59–7.41(m,2H),7.38–7.19(m,3H),7.16–7.01(m,2H),6.9 4(ddd,J=8.5,6.0,2.8Hz,1H),6.78(d,J=2.2Hz,1H),5.98(d,J=2.2Hz,1H),5.70(brs,2H),3.94(s,3H),3.30(s,3H).

[2291] Example 51

[2292] (6-Amino-4-((2-methoxyphenyl)amino)pyridin-2-yl)(4-phenylpiperazin-1-yl)methanone

[2293]

[2294] Synthesized according to General Procedure K, Step 2. Isolated as a white solid.

[2295] Yield: (0.010 g, 2% over two steps).

[2296] ES-MS[M+H] + : 404.2, Rt=17.765 min (Method-B1).

[2297] 1 H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.27-7.17(m,3H),7.12-7.03(m,2H),7.00-6.89(m,3H),6.85-6.76(m,1H) ,6.24(s,1H),5.90(s,1H),5.68...

Claims

1. A compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein A 1 is N, and A 2 and A 3 Each is CH; R 1a Choose Free-C 3-10 The group consisting of cycloalkyl, phenyl and benzyl, wherein the -C 3-10 Cycloalkyl, phenyl and benzyl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a )2 and -C optionally substituted by 1, 2 or 3 halogen atoms 1-4 substituted with a substituent consisting of an alkyl group; and wherein the -C 3-10 The cycloalkyl group is optionally fused to a benzene ring and the phenyl group is optionally fused to a 5- or 6-membered heterocyclic ring having 1 or 2 oxygen atoms; and R 2a Selected from hydrogen and -C 1-4 or R 1a and R 2a Together with the nitrogen atom to which they are attached, they form a 5- to 10-membered heterocyclic ring, wherein the 5- to 10-membered heterocyclic ring optionally contains 1, 2 or 3 additional heteroatoms selected from the group consisting of N, S, O, and wherein the 5- to 10-membered heterocyclic ring is optionally fused to a benzene ring, or wherein R 1a and R 2a Together with the nitrogen atom to which they are attached, they form a 1-4 an alkyl or phenyl substituted piperazinyl ring; Each Rb a are independently hydrogen or -C 1-2 Alkyl, wherein the -C 1-2 The alkyl group is optionally substituted with 1, 2 or 3 fluorine atoms; and R 3a is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, wherein the phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl groups are optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxyl, -ORb a 、-SRb a 、-N(Rb a )2 and optionally 1, 2 or 3 each independently selected from halogen and -ORb a The substituents consisting of -C 1-4 The phenyl group is substituted by a substituent consisting of the group consisting of an alkyl group, and wherein the phenyl group is optionally condensed with a 5- or 6-membered heterocyclic ring having 1 or 2 oxygen atoms.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3a is unsubstituted phenyl or substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -O(C 1-2 )alkyl, -S(C 1-2 )alkyl, -N(C 1-2 Alkyl)2, -NH(C 1-2 alkyl) and optionally 1, 2 or 3 each independently selected from halogen, -O(C 1-2 )alkyl, -N(C 1-2 Alkyl)2 and -NH(C 1-2 alkyl)-substituted-C 1-4 The phenyl group is substituted with the alkyl group as a substituent.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 3a It is phenyl substituted by 1 or 2 substituents each independently selected from the group consisting of F, Cl, Br, I, hydroxyl, methyl and methoxy.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 3a It is a phenyl group substituted by F or hydroxyl at the ortho or meta position of the benzene ring.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3a It is an unsubstituted phenyl group condensed with a 5- or 6-membered heterocyclic ring having 1 or 2 oxygen atoms.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3a is unsubstituted pyridin-2-yl or pyridin-3-yl, or is substituted by 1 or 2 groups independently selected from halogen, hydroxyl, -O(C 1-2 ) alkyl and -C 1-2 The substituents of the group consisting of alkyl are substituted with pyridin-2-yl or pyridin-3-yl.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2a For H.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2a For -C 1-4 alkyl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a is phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted by 1, 2 or 3 groups independently selected from halogen, hydroxyl, -CN, -ORb a 、-SRb a 、-N(Rb a )2 and -C optionally substituted by 1, 2 or 3 halogen atoms 1-4 Alkyl groups consisting of groups substituted, wherein Rb a As defined in claim 1; and wherein the phenyl group is optionally fused to a 5- or 6-membered heterocyclic ring having 1 or 2 oxygen atoms.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1a is unsubstituted phenyl or unsubstituted benzyl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a It is a phenyl group fused to a 5- or 6-membered heterocyclic ring having 1 or 2 oxygen atoms.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a For -C 3-10 Cycloalkyl, wherein the -C 3-10 The cycloalkyl group is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxy, -CN, -ORb a 、-SRb a 、-N(Rb a )2 and -C optionally substituted by 1, 2 or 3 halogen atoms 1-4 The alkyl group is substituted with a substituent, wherein Rb a As defined in claim 1; and wherein said -C 3-10 The cycloalkyl group is optionally fused to a benzene ring.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 1a is an unsubstituted -C fused to a benzene ring 3-10 Cycloalkyl.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein R 1a -C fused to a benzene ring 4-7 Cycloalkyl.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Rb a is hydrogen or -C 1-2 alkyl.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a and R 2a Together with the nitrogen atom to which they are attached, they form a 5- to 10-membered heterocyclic ring, wherein the 5- to 10-membered heterocyclic ring is optionally fused to a benzene ring, or wherein R 1a and R 2a Together with the nitrogen atom to which they are attached, they form a 1-4 Alkyl or phenyl substituted piperazinyl ring.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein R 1a and R 2a Together with the nitrogen atom to which they are attached they form a 5- or 6-membered ring which is optionally fused to a benzene ring.

18. A compound selected from the group consisting of 19. The compound according to claim 1, selected from the group consisting of or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 19, which is or , or a pharmaceutically acceptable salt thereof.

21. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 1, selected from the group consisting of 23. A compound selected from the group consisting of 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

25. Use of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a condition associated with altered β-glucocerebrosidase activity in a patient.

26. Use of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a lysosomal storage disease.

27. The use according to claim 26, wherein the medicament is for the treatment or prevention of Gaucher's disease.

28. Use of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof in 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, dementia with Lewy bodies, diffuse Lewy body disease, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, anxiety disorders, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, multiple myeloma, Alzheimer's disease, amyotrophic lateral sclerosis, corticobasal degeneration, frontotemporal dementia, neuroaxial dystrophy, neurodegenerative diseases associated with Parkinson's disease, progressive supranuclear palsy, pure autonomic failure, sporadic Creutzfeldt-Jakob disease, and intact aging.

29. The use according to claim 28, wherein the Gaucher's disease is neurological Gaucher's disease and the Parkinson's disease is GBA1 Parkinson's disease.

30. The use according to claim 28, wherein at least one other therapeutic agent is also administered.

31. The use according to claim 30, wherein the therapeutic agent is an effective amount of an enzyme for enzyme replacement therapy.

32. The use according to claim 31, wherein the enzyme is β-glucocerebrosidase or an analogue thereof.

33. The use according to claim 31, wherein the enzyme is imiglucerase.

34. The use according to claim 30, wherein the therapeutic agent is an effective amount of a small molecule chaperone.

35. The use according to claim 34, wherein the small molecule chaperone competitively binds to the enzyme.

36. The use according to claim 34, wherein the small molecule chaperone is selected from the group consisting of iminosugar alcohols, iminosugars, aminosugars, phenylthioglycosides, glycosidases, sulfatases, glycosyltransferases, phosphatases and peptidase inhibitors.

37. The use according to claim 36, wherein the small molecule chaperone is selected from the group consisting of isofagomine, N-nonyl-1-deoxynojirimycin, ambroxol and miglustat.

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