Substituted indolyl compounds, compositions thereof, and therapeutic uses thereof

Abstract

The present application relates to compounds of formula (I) and salts and solvates thereof, wherein A1, A2, A3 and R1, R2, R 3a , R 3b , R4 and R5 are as defined in the description, and their use for the treatment and / or prevention of disorders and conditions associated with an altered activity of β-galactosidase, in particular galactoside β-1 or GLB1, including GM1 gangliosidosis and Morquio syndrome B.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to European Patent Application No. EP23383116.3, filed on 2 November 2023, the entire contents of which are incorporated herein by reference.

[0003] open field

[0004] This disclosure provides the use of the compounds and their use in the treatment and / or prevention of conditions and disorders (including GM1 ganglioside storage disease and Mochio syndrome type B) associated with altered β-galactosidase (particularly galactosidase β-1 or GLB1) activity.

[0005] Public background

[0006] GM1 ganglioside storage disease and Mociotti type B are both caused by a deficiency of β-galactosidase (GLB1) and are extremely rare lysosomal storage diseases with a live birth rate of approximately 1 in 100,000 to 1 in 200,000 worldwide (Caciotti A). et al. , Biochim Biophys Acta 1812(7):782-890 (July 2011). These conditions are caused by mutations in the GLB1 gene, which lead to a deficiency of β-galactosidase.

[0007] β-galactosidase is responsible for removing β-galactose from various substrates, such as gangliosides and oligosaccharides with terminal β-linked galactose, like ganglioside GM1 and glycosaminoglycans, like keratin sulfate. Insufficient activity of β-galactosidase can lead to the toxic accumulation of these substrates in patients with conditions associated with GLB1 activity, such as GM1 ganglioside storage disease and IVB type mucopolysaccharidosis (MPSIVB) (Mochio syndrome type B, Mochio type B, Mochio syndrome).

[0008] GM1 ganglioside storage disease is a neurodegenerative disorder, while Mochio type B is characterized by skeletal involvement without neurological manifestations.

[0009] Suzuki et al. ( Cell. Mol. Life Sci. (65:351-353 (2008)) reported that mutations in the GLB1 gene can lead to mutations in the β-galactosidase protein, resulting in either insufficient catalytic activity or normal or near-normal catalytic function, but instability under neutral pH conditions. These mutant enzymes are unstable in the endoplasmic reticulum / Golgi apparatus and rapidly degrade due to molecular misfolding, which is the cause of their impaired activity. The authors reported that using a competitive inhibitor that binds to the misfolded mutant protein as a molecular chaperone (i.e., a small molecule that interacts with the misfolded protein to restore its activity) can stabilize the mutant enzyme and enhance its biological activity.

[0010] Therefore, small molecules (molecular chaperones) that bind to mutated β-galactosidases in an allosteric or competitive manner, thereby stabilizing the enzyme from degradation, constitute important therapeutic targets for diseases related to altered β-galactosidase activity (especially galactosidase β-1 or GLB1).

[0011] Currently, there is no cure for either Mochio type B or GM1 ganglioside storage disease, and treatment options mainly focus on symptom control and supportive care.

[0012] There is a need to develop compounds that exhibit improving properties in the treatment or prevention of conditions associated with altered activity of β-galactosidase, and particularly galactosidase β-1 or GLB1, including GM1 ganglioside storage disease and Mochio syndrome type B.

[0013] Public brief

[0014] On the one hand, this disclosure provides compounds represented by formulas (I), (II), (III) and (IV) below, as well as pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as “compounds of this disclosure” (each of which is referred to as “compounds of this disclosure”).

[0015] On the other hand, this disclosure provides a pharmaceutical composition comprising the disclosed compound and at least one pharmaceutically acceptable excipient.

[0016] On the other hand, this disclosure provides a method for treating or preventing diseases or conditions associated with altered GLB1 activity in patients in need, comprising administering an effective amount of the disclosed compound to the patient in need.

[0017] On the other hand, this disclosure provides a method for treating or preventing mochio type B or GM1 ganglioside storage disease in patients in need, comprising administering an effective amount of the disclosed compound to the patient.

[0018] On the other hand, the method described herein also includes administering at least one other therapeutic agent to the patient.

[0019] On the other hand, the method described herein for treating patients with GM1 ganglioside storage disease or Mochio type B also includes administering an effective amount of an enzyme for enzyme replacement therapy to the patient. In one embodiment, said enzyme is β-galactosidase or an analogue thereof.

[0020] On the other hand, the method further includes administering a small molecule molecular chaperone to the patient. In one embodiment, the small molecule molecular chaperone competitively binds to an enzyme. In another embodiment, the small molecule molecular chaperone is selected from iminoglycosides, imino sugars, amino sugars, thiophene glycosides, glycosidases, sulfatases, glycosyltransferases, phosphoesterases, and peptidase inhibitors.

[0021] On the other hand, this disclosure provides a method for increasing the β-galactosidase activity of a patient in need, comprising administering to the patient an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt or solvate thereof.

[0022] On the other hand, this disclosure provides compounds for the prevention or treatment of conditions associated with altered GLB1 activity.

[0023] On the other hand, this disclosure provides the use of the disclosed compounds in the preparation of medicaments for the prevention or treatment of conditions associated with altered GLB1 activity.

[0024] On the other hand, this disclosure provides compounds as described herein, which are used as pharmaceuticals.

[0025] Other aspects and advantages of the invention will become apparent from the following detailed description of the invention. Embodiments and advantages of the invention will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims.

[0026] It should be understood that the above overview and the following detailed description are merely exemplary and explanatory, and do not limit the disclosure of the claims.

[0027] Public details

[0028] The inventors have discovered that certain compounds disclosed herein can reduce the accumulation of exogenous GM1 gangliosides in in vitro cell models. Therefore, these compounds hold promise for the treatment or prevention of diseases or conditions associated with altered GLB1 activity, including Mochio type B and GM1 ganglioside storage disorders.

[0029] The compound disclosed herein is of formula (I) for use in this regard:

[0030] (I),

[0031] and its pharmaceutically acceptable salts and solvates, wherein:

[0032] A1, A2, and A3 are each independently N or CH, provided that one of A1, A2, and A3 is N, and two of A1, A2, and A3 are CH.

[0033] R1, R2, and R5 are each independently selected from hydrogen, halogens, -ORa, and -C. 1-4 Alkyl, -C 3-6 cycloalkyl and -(5- to 10-membered)-C 3-7 Heterocyclic groups, wherein the -C 1-4 Alkyl, -C 3-6 cycloalkyl and -(5- to 10-membered)-C 3-7 The heterocyclic group is optionally substituted by one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-;

[0034] Ra is -C 1-4 Alkyl groups, which are optionally substituted with one, two or three halogen atoms;

[0035] R 3a It is -NR6R7, where

[0036] R6 is hydrogen or -C 1-4 Alkyl, and

[0037] R7 is selected from hydrogen, -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-;

[0038] R 3b Selected from hydrogen, halogens and C 1-4 alkyl;

[0039] R4 is -NR8R9, where

[0040] R8 is hydrogen or -C 1-4 Alkyl, and

[0041] R9 is selected from -C 6-10Aryl and -(5- to 10-yuan)-C 1-9 Heteroaryl, wherein the -C 6-10 Aryl and -(5- to 10-yuan)-C 1-9 The heteroaryl group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -Orc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl; and

[0042] Rb and Rc are each independently selected from hydrogen and C, which are optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl, wherein

[0043] R 3a R 3b R4 and R5 each replace a ring that would originally exist in equation (I), R 3a R 3b Hydrogen atoms at any position connected to R4 and R5.

[0044] In another embodiment, the disclosed compound is a compound of formula (I) wherein A1 is N and A2 and A3 are both CH, having the structure of formula (II):

[0045] (II),

[0046] and its pharmaceutically acceptable salts and solvates, wherein R1, R2, R 3a R 3b R1, R4, and R5 are as defined in equation (I). In another embodiment, R2... 3a It is attached to the 5th or 6th position of the 2-pyridyl ring.

[0047] In another embodiment, the disclosed compound is a compound of formula (I) wherein A2 is N and A1 and A3 are both CH, having the structure of formula (III):

[0048] (III),

[0049] and its pharmaceutically acceptable salts and solvates, wherein R1, R2, R 3a R 3b R4 and R5 are as defined above for equation (I).

[0050] In another embodiment, the disclosed compound is a compound of formula (I) wherein A3 is N and A1 and A2 are both CH, having the structure of formula (IV):

[0051] (IV)

[0052] and its pharmaceutically acceptable salts and solvates, wherein R1, R2, R 3a R 3b R4 and R5 are as defined above for equation (I).

[0053] In some embodiments, the disclosed compounds are any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R4 is attached to the 4-position of the indole ring. In some embodiments, R5 is hydrogen.

[0054] In some embodiments, the disclosed compounds are any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R4 is attached to the 5-position of the indole ring. In some embodiments, R5 is hydrogen.

[0055] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R1, R2 and R5 are each independently selected from hydrogen, halogen, -ORa, -C 1-4 Alkyl and -C 3-6 cycloalkyl, wherein the -C 1-4 Alkyl and -C 3-6 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-, wherein Ra is a -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

[0056] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R1, R2 and R5 are each independently selected from hydrogen, halogen, -C 1-4 Alkoxy and -C 1-4 Alkyl, wherein the -C 1-4 The alkyl group is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4)alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-. In some embodiments, R1, R2, and R5 are each independently selected from hydrogen, halogen, and unsubstituted -C. 1-2 alkyl.

[0057] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R5 is hydrogen and R1 and R2 are each independently selected from hydrogen, halogens and unsubstituted -C. 1-2 Alkyl group. In some embodiments, R1 and R5 are each hydrogen and R2 is an unsubstituted -C group. 1-2 Alkyl group. In some embodiments, R2 and R5 are each hydrogen and R1 is an unsubstituted -C group. 1-2 alkyl.

[0058] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R1, R2 and R5 are each hydrogen.

[0059] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R6 is hydrogen and R 3a It is -NHR7, where R7 is selected from hydrogen, -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-. In some embodiments, the compounds disclosed herein are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R 3a It is -NHR7, where R7 is -C 1-4 Alkyl groups, such as methyl or ethyl.

[0060] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R6 and R7 are each hydrogen and R 3a It is -NH2.

[0061] In some embodiments, the disclosed compound is a compound of any one of formulas (I)-(IV) and its pharmaceutically acceptable salts and solvates, wherein R6 is -C 1-4 Alkyl and R 3a -N(C) 1-4 Alkyl)R7, wherein R7 is selected from -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-. In some embodiments, R6 is -C 1-2 Alkyl group. In some embodiments, R6 is methyl. In some embodiments, the compounds disclosed herein are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R7 is -C 1-4 Alkyl group, optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from halogen, hydroxyl, -C 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-. In some embodiments, R7 is an unsubstituted -C 1-4 Alkyl group. In some embodiments, R 7 It is an unsubstituted methyl or unsubstituted ethyl group. In some embodiments, R7 is a -C group substituted with one or two substituents. 1-4 Alkyl group, each substituent independently selected from halogen, hydroxyl, -C 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4)alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-. In some embodiments, R7 is a -C substituted with one or two substituents. 1-2 Alkyl group, each substituent independently selected from halogen, hydroxyl, -C 1-2 Alkoxy, monohalogenated (C 1-2 )alkyl-, dihalogenated (C 1-2 )alkyl-, trihalogenated (C 1-2 )alkyl-, monohalogenated (C 1-2 )alkoxy-, dihalo (C 1-2 )alkoxy- and trihalo (C 1-2 )alkoxy-.

[0062] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R7 is -C 3-10 Cycloalkyl group, optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, hydroxyl, -C 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-. In some embodiments, R7 is an unsubstituted -C 3-10 Cycloalkyl. In some embodiments, R7 is an unsubstituted -C 3-6 Cycloalkyl. In some embodiments, R7 is -C 3-10 Cycloalkyl groups, which are substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-. In some embodiments, R7 is -C 3-6 Cycloalkyl groups, which are substituted with one or two substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-2 Alkoxy, monohalogenated (C 1-2 )alkyl-, dihalogenated (C 1-2)alkyl-, trihalogenated (C 1-2 )alkyl-, monohalogenated (C 1-2 )alkoxy-, dihalo (C 1-2 )alkoxy- and trihalo (C 1-2 )alkoxy-.

[0063] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R7 is -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-. In some embodiments, R7 is an unsubstituted -C 1-4 Alkyl-C 3-10 Cycloalkyl. In some embodiments, R7 is an unsubstituted -C 1-2 Alkyl-C 3-6 Cycloalkyl. In some embodiments, R7 is -C 1-4 Alkyl-C 3-10 Cycloalkyl groups, which are substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-. In some embodiments, R7 is -C 1-2 Alkyl-C 3-6 Cycloalkyl groups, which are substituted with one or two substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-2 Alkoxy, monohalogenated (C 1-2 )alkyl-, dihalogenated (C 1-2 )alkyl-, trihalogenated (C 1-2 )alkyl-, monohalogenated (C 1-2 )alkoxy-, dihalo (C 1-2)alkoxy- and trihalo (C 1-2 )alkoxy-.

[0064] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R 3a -NHR7 or -N(C 1-4 Alkyl)R7, wherein R7 is selected from hydrogen, -C 1-4 Alkyl, -C 3-6 cycloalkyl and -C 1-4 Alkyl-C 3-6 cycloalkyl, wherein the -C 1-4 Alkyl, -C 3-6 cycloalkyl and -C 1-4 Alkyl-C 3-6 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogen, hydroxyl, methoxy, monohalogen (C-H2O), and hydroxyl, methoxy, monohalogen (C-H2O). 1-2 )alkyl-, dihalogenated (C 1-2) Alkyl-, trihalogenated (C 1-2 )alkyl-, monohalomethoxy-, dihalomethoxy-, and trihalomethoxy-. In some embodiments, R7 is hydrogen, methyl, or ethyl.

[0065] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R6 and R7 are each -C 1-4 Alkyl and R 3a -N(C) 1-4 Alkyl)2. In some embodiments, the compounds disclosed herein are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R 3a -N(C) 1-2 Alkyl)2. In some embodiments, R 3a It is -N(CH3)2.

[0066] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R 3a It can be -NH2, -NH(CH3) or -N(CH3)2.

[0067] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R 3b It is hydrogen.

[0068] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R 3b It is a halogen.

[0069] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R 3b -C 1-4 alkyl.

[0070] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R8 is hydrogen and R4 is -NHR9, wherein R9 is selected from -C 6-10 Aryl and -(5- to 10-yuan)-C 1-9 Heteroaryl, wherein the -C 6-10 Aryl and -(5- to 10-yuan)-C 1-9 The heteroaryl group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl group; and Rb and Rc are each independently selected from hydrogen and -C, optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

[0071] In some embodiments, the disclosed compound is a compound of any one of formulas (I)-(IV) and its pharmaceutically acceptable salts and solvates, wherein R8 is -C 1-4 Alkyl and R4 is -N(C) 1-4 Alkyl)R9, wherein R9 is selected from -C 6-10 Aryl and -(5- to 10-yuan)-C 1-9 Heteroaryl, wherein the -C 6-10 Aryl and -(5- to 10-yuan)-C 1-9 The heteroaryl group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl group; and Rb and Rc are each independently selected from hydrogen and -C, optionally substituted with 1, 2 or 3 halogen atoms. 1-4 Alkyl group. In some embodiments, R8 is -C 1-2Alkyl group. In some embodiments, R8 is methyl.

[0072] In some embodiments, the disclosed compound is a compound of any one of formulas (I)-(IV) and its pharmaceutically acceptable salts and solvates, wherein R9 is -C 6-10 The aryl group, optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -Orc, -N(Rc)2, and -C optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 Alkyl group. In some embodiments, R9 is an unsubstituted -C group. 6-10 Aryl. In some embodiments, R9 is an unsubstituted phenyl group. In some embodiments, R9 is an unsubstituted naphthyl group. In some embodiments, R9 is -C. 6-10 Aryl group, which is substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 Alkyl group. In some embodiments, R9 is a phenyl group substituted with one, two, or three substituents, each substituent independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C groups optionally substituted with one, two, or three halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from -C atoms in which hydrogen is optionally substituted by 1, 2, or 3 halogen atoms. 1-2 Alkyl group. In some embodiments, both Rb and Rc are hydrogen. In some embodiments, R9 is a phenyl group substituted with one or two substituents, each substituent independently selected from halogens, -CN, -OH, and -O(C). 1-2 )alkyl, unsubstituted -C 1-4 Alkyl groups and -C atoms substituted with 1, 2, or 3 halogen atoms 1-4 alkyl.

[0073] In some embodiments, the disclosed compound is a compound of any one of formulas (I)-(IV) and its pharmaceutically acceptable salts and solvates, wherein R9 is Where m is 1 or 2 and R 10 Selected from halogens, -CN, -OH, -C 1-4 Alkyl and -C 1-4 Alkyl group.

[0074] In some embodiments, the disclosed compound is a compound of any one of formulas (I)-(IV) and its pharmaceutically acceptable salts and solvates, wherein R9 is R 9a : or R 9b : , where R 10 Selected from halogens, -CN, -O(C) 1-2 )alkyl and -C 1-4 alkyl.

[0075] In some embodiments, the disclosed compound is a compound of any one of formulas (I)-(IV) and its pharmaceutically acceptable salts and solvates, wherein R9 is , , , , , or .

[0076] In some embodiments, the disclosed compounds are compounds of any one of formulas (I)-(IV) and their pharmaceutically acceptable salts and solvates, wherein R9 is -(5- to 10-benzene)-C 1-9 Heteroaryl, wherein the -(5- to 10-aryl)-C 1-9 The heteroaryl group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl group; and Rb and Rc are each independently selected from hydrogen and -C, optionally substituted with 1, 2 or 3 halogen atoms. 1-4 Alkyl group. In some embodiments, R9 is an unsubstituted -(5- to 10-membered)-C 1-9 Heteroaryl. In some embodiments, R9 is an unsubstituted 5- or -6-membered heteroaryl group having 1, 2, or 3 heteroatoms. In some embodiments, R9 is -(5- to 10-membered)-C. 1-9A heteroaryl group, which is substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 Alkyl group. In some embodiments, R9 is a 5- or -6-membered heteroaryl group having 1, 2, or 3 heteroatoms, wherein the 5- or -6-membered heteroaryl group is substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -Orc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl group; and Rb and Rc are each independently selected from hydrogen and -C, optionally substituted with 1, 2 or 3 halogen atoms. 1-4 Alkyl group. In some embodiments, both Rb and Rc are hydrogen.

[0077] In some embodiments, the disclosed compounds are compounds of formula (I) and their pharmaceutically acceptable salts and solvates, wherein for , , , , or .

[0078] In some embodiments, the disclosed compound is a compound of any one of formulas (I)-(IV) and its pharmaceutically acceptable salts and solvates, wherein R4 is R 4a : or R 4b : , where m and R 10 As defined above. In some implementations, R 4a and R 4b It is attached to the 4th or 5th position of the indole ring.

[0079] In some embodiments, the disclosed compound is a compound of any one of formula (I) or (II) and its pharmaceutically acceptable salt and solvate, wherein R 3a As defined above and attached to the 5-position of the 2-pyridine ring, R 3b R4 is hydrogen, as defined above, and is attached to the 4-position of the indole ring. R5 is hydrogen, and R1 and R2 are each independently selected from hydrogen, halogen, and -C. 1-2Alkyl group. In some embodiments, R1 is hydrogen and R2 is methyl or ethyl. In some embodiments, R1 is methyl or ethyl and R2 is hydrogen. In some embodiments, both R1 and R2 are hydrogen. In some embodiments, R... 3a It is -NH2 or -N(Me)2.

[0080] In some embodiments, the disclosed compound is a compound of any one of formula (I) or (II) and its pharmaceutically acceptable salt and solvate, wherein R 3a As defined above and attached to the 6-position of the 2-pyridine ring, R 3b R4 is hydrogen, as defined above, and is attached to the 4-position of the indole ring. R5 is hydrogen, and R1 and R2 are each independently selected from hydrogen, halogen, and -C. 1-2 Alkyl group. In some embodiments, R1 is hydrogen and R2 is methyl or ethyl. In some embodiments, R1 is methyl or ethyl and R2 is hydrogen. In some embodiments, both R1 and R2 are hydrogen. In some embodiments, R... 3a It is -NH2 or -N(Me)2.

[0081] In some embodiments, the disclosed compound is a compound of any one of formula (I) or (II) and its pharmaceutically acceptable salt and solvate, wherein R 3a As defined above and attached to the 5-position of the 2-pyridine ring, R 3b R4 is hydrogen, as defined above, and is attached to the 5-position of the indole ring. R5 is hydrogen, and R1 and R2 are each independently selected from hydrogen, halogen, and -C. 1-2 Alkyl group. In some embodiments, R1 is hydrogen and R2 is methyl or ethyl. In some embodiments, R1 is methyl or ethyl and R2 is hydrogen. In some embodiments, both R1 and R2 are hydrogen. In some embodiments, R... 3a It is -NH2 or -N(Me)2.

[0082] In some embodiments, the disclosed compound is a compound of any one of formula (I) or (II) and its pharmaceutically acceptable salt and solvate, wherein R 3a As defined above and attached to the 6-position of the 2-pyridine ring, R 3b R4 is hydrogen, as defined above, and is attached to the 5-position of the indole ring. R5 is hydrogen, and R1 and R2 are each independently selected from hydrogen, halogen, and -C. 1-2 Alkyl group. In some embodiments, R1 is hydrogen and R2 is methyl or ethyl. In some embodiments, R1 is methyl or ethyl and R2 is hydrogen. In some embodiments, both R1 and R2 are hydrogen. In some embodiments, R... 3a It is -NH2 or -N(Me)2.

[0083] In some embodiments, the disclosed compounds are provided in the form of pharmaceutically acceptable salts. In some embodiments, the pharmaceutically acceptable salt of the disclosed compounds is a hydrochloride salt (HCl salt).

[0084] In another embodiment, the compounds disclosed herein are selected from one or more compounds in Table 1 or their pharmaceutically acceptable salts or solvates.

[0085] Table 1

[0086]

[0087]

[0088]

[0089]

[0090] Optional substituents attached to aryl (e.g., phenyl) and heteroaryl (e.g., pyridyl) rings each replace hydrogen atoms that would otherwise be present at any position on the aryl or heteroaryl ring.

[0091] The term “halogen” or “halogenated” as used herein, either on its own or as part of another group, refers to fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I).

[0092] The term “hydroxyl” or “hydroxyl” as used in this article, either on its own or as part of another group, refers to the group -OH.

[0093] The term "cyano" as used in this article, either on its own or as part of another group, refers to the group -CN.

[0094] As used herein, the term "alkyl" or as part of another group refers to a straight-chain or branched hydrocarbon group consisting of carbon and hydrogen atoms, without any degree of unsaturation, which is connected to the rest of the molecule by a single bond, and unless otherwise stated, alkyl groups typically have 1 to 4 carbon atoms, i.e., -C. 1-4 Alkyl group. Exemplary -C 1-4 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or sec-butyl. In another embodiment, the alkyl group is -C. 1-2 Alkyl (methyl or ethyl).

[0095] As used herein, the term "alkoxy" refers, either on its own or as part of another group, to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl group is a -C1-C6 alkyl group. In another embodiment, the alkyl group is a -C1-C4 alkyl group. In yet another embodiment, the alkyl group is a -C1-C2 alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy groups.

[0096] The term "C" used in this article 1-4 "Alkoxy" itself, or as part of another group, refers to the group consisting of the -C group mentioned above. 1-4 A substituted oxygen in one of the alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, and sec-butoxy), for example, is substituted by -C 1-2 One of the alkyl groups is substituted.

[0097] As used herein, the term "halogenated alkyl" refers, either itself or as part of another group, to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl group is substituted with one, two, or three fluorine and / or chlorine atoms. In another embodiment, the alkyl group is substituted with one, two, or three fluorine atoms. In another embodiment, the alkyl group is a -C1-C6 alkyl group. In another embodiment, the alkyl group is a -C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. In some embodiments, the halogenated alkyl group is a monohalogenated (C1-C2 alkyl group). 1-4 )alkyl- (i.e., -C replaced by a halogen atom) 1-4 Alkyl), dihalogenated (C) 1-4 )alkyl- (i.e., -C replaced by two halogen atoms) 1-4 Alkyl) or trihalogen (C) 1-4 alkyl (i.e., -C replaced by three halogen atoms) 1-4 Alkyl group). In some embodiments, the haloalkyl group is a monohalogenated (C1-C2 ... 1-2 )alkyl-, dihalogenated (C 1-2 )alkyl- or trihalogenated (C 1-2 Alkyl groups. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl.

[0098] As used herein, the term "haloalkoxy" refers, either on its own or as part of another group, to a haloalkyl group attached to a terminal oxygen atom. In one embodiment, the haloalkyl group is a C1-C4 haloalkyl group. In some embodiments, the haloalkoxy group is a monohaloalkyl group (C1-C4). 1-4)alkoxy- (i.e., -C replaced by a halogen atom) 1-4 alkoxy), dihalo (C 1-4 )alkoxy- (i.e., -C replaced by two halogen atoms) 1-4 alkoxy) or trihalo (C 1-4 )alkoxy group (i.e., -C replaced by three halogen atoms) 1-4 Alkoxy group). In some embodiments, the haloalkoxy group is a monohalogenated (C6H2O) alkoxy group. 1-2 )alkoxy-, dihalo (C 1-2 )alkoxy- or trihalo (C 1-2 Alkyl groups. A non-limiting exemplary haloalkoxy group is -OCF3.

[0099] As used herein, the term "cycloalkyl" refers, either on its own or as part of another group, to a saturated carbocyclic group, and unless otherwise stated, cycloalkyl typically has 3 to 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. For example, it is cyclopropyl, cyclopentyl, and cyclohexyl. In another embodiment, the cycloalkyl group is -C 3-10 Cycloalkyl.

[0100] As used herein, the term "alkylcycloalkyl" in the definition of substituents refers to a cycloalkyl group as described above, wherein the cycloalkyl group is alkylene (e.g., C10). 1-4 The alkylene group is linked to its substituted core structure. As an example, a cyclopentylethyl substituent is a substituent consisting of a cyclopentyl group connected to its substituted core structure via an ethylene group. In another embodiment, the alkylcycloalkyl group is -C. 1-4 Alkyl-C 3-10 Cycloalkyl. In another embodiment, the alkylcycloalkyl group is -C. 1-2 Alkyl-C 3-6 Cycloalkyl.

[0101] The term “heterocyclic group” or “heterocyclic group” as used herein, either on its own or as part of another group, generally refers to a monocyclic or polycyclic, non-aromatic, saturated or unsaturated C14 group. 2-10 A carbocyclic ring, such as a 5- to 10-membered group, wherein one or more, such as 1, 2, 3, or 4 carbon atoms, such as 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 A heterocyclic group is a heterocycle having 3-7 carbon atoms and at least one heteroatom. In another embodiment, the heterocyclic group is (5- to 10-membered)-C. 2-9A heterocyclic group, i.e., a heterocycle having 5 to 10 members, wherein 2 to 9 members are carbon. In another embodiment, the heteroatom is N. In another embodiment, when a hydrogen atom is attached to the heteroatom N, the hydrogen atom can be converted to carbon. 1-4 Alkyl (e.g., CH3) substitution. In another embodiment, the heteroatom is O. In some embodiments, the heterocyclic group is -(5- to 6-membered)-C. 2-5 Heterocyclic group.

[0102] In another embodiment, the heterocyclic group is saturated. The heterocyclic group can be a monocyclic ring or two or more fused rings, wherein at least one ring contains a heteroatom. When the heterocyclic group carries one or more substituents, the substituents can be the same or different.

[0103] The optionally substituted heterocyclic group is typically unsubstituted or substituted with one, two, or three identical or different substituents. Examples of heterocyclic groups include piperidinyl, pyrrolyl, pyrrololinyl, piperazine, morpholinyl, thiomorpholinyl, pyrazololinyl, pyrazolylylene, quininecycloyl, tetrazolyl, chromanyl, isochoryl, imidazoalkyl, oxacyclopropane, azaridinyl, 4,5-dihydro-oxazolyl, and 3-aza-tetrahydrofuranyl. The substituents are selected, for example, from halogen atoms (e.g., fluorine or chlorine atoms), hydroxyl, alkoxycarbonyl (wherein the alkyl moiety has 1 to 4 carbon atoms), hydroxycarbonyl, carbamoyl, nitro, cyano, C 1-4 Alkyl groups (optionally substituted with one or more halogen atoms), C 1-4 Alkoxy groups (optionally substituted with one or more halogen atoms) and C 1-4 Hydroxyalkyl.

[0104] In another embodiment, the heterocyclic group is -(5- to 10-benzene)-C 3-7 A heterocyclic group, optionally substituted with one, two, or three substituents, each substituent independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-.

[0105] The term "aryl" as used in this article, either on its own or as part of another group, refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C6-C. 14 Aryl group. Non-limiting exemplary aryl groups are typically C6-C. 10Monocyclic or polycyclic aryl groups, such as phenyl and naphthyl. In another embodiment, the aryl group is phenyl. The optionally substituted aryl group is typically unsubstituted or substituted by 1, 2, or 3 identical or different substituents. For example, the substituents are selected from halogen atoms (e.g., fluorine or chlorine atoms), hydroxyl, alkoxycarbonyl (wherein the alkyl moiety has 1 to 4 carbon atoms), hydroxycarbonyl, carbamoyl, nitro, cyano, C 1-4 Alkyl groups (optionally substituted with one or more halogen atoms), C 1-4 Alkoxy groups (optionally substituted with one or more halogen atoms) and C 1-4 Hydroxyalkyl. When the aryl group has two or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on the aryl group are generally not substituted themselves.

[0106] As used herein, the term "heteroaryl" refers, either on its own or as part of another group, to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring members, i.e., 5- to 14-membered heteroaryls containing one, two, three, or four heteroatoms. In some embodiments, the heteroaryl is a 5- to 10-membered ring system containing at least one heteroaromatic ring and at least one heteroatom selected from O, S, and N (typically 1, 2, 3, or 4 heteroatoms). In some embodiments, the heteroaryl is a 5- or -6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from O, S, and N.

[0107] The heteroaryl group may comprise one monocyclic ring or two or more fused rings, wherein at least one ring contains a heteroatom. The optionally substituted heteroaryl group is typically unsubstituted or substituted with one, two, or three substituents, which may be the same or different. For example, the substituents are optionally selected from halogen atoms (e.g., fluorine, chlorine, or bromine atoms), alkoxycarbonyl groups (wherein the alkyl moiety has one to four carbon atoms), carbamoyl groups, nitro groups, hydroxyl groups, C6 groups, etc. 1-4 Alkyl groups (optionally substituted with one or more halogen atoms) and C 1-4 The alkoxy group (optionally substituted with one or more halogen atoms). When the heteroaryl group has two or more substituents, the substituents may be the same or different. Unless otherwise specified, the substituents on the heteroaryl group are generally not substituted themselves.

[0108] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, tetrazolyl, benzofuranyl, oxadiazolyl, oxazolyl, isoxazolyl, benzooxazolyl, imidazolyl, benzimidazolyl, thiazolyl, thiadiazolyl, thienyl, pyrroleyl, pyridyl, benzothiazolyl, indoleyl, indazoleyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphridinyl, quinoxolinyl, quinazolinyl, quinolinyl, quinolinylazinyl, cyclolinyl, triazolyl, indoleazinyl, indolelinyl, isoindolelinyl, isoindoleyl, imidazoalkyl, pteridinyl, thiaanthryl, pyrazolyl, 2H-pyrazolo[3,4-d]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidinyl, thienolo[2,3-d]pyrimidinyl and various pyrrolopyridyl groups.

[0109] In another embodiment, the heteroaryl group is (5- to 10-benzene)-C 1-9 Heteroaryl. In another embodiment, the heteroaryl group is optionally substituted with 1, 2, or 3 groups, said groups being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl group. In another embodiment, the heteroaryl group is optionally substituted with one, two, or three groups, said groups being independently selected from halogens, hydroxyl groups, -CN, -ORc, -N(Rc)2, and -C groups optionally substituted with one, two, or three halogen atoms. 1-4 alkyl.

[0110] The optional substituted heteroaryl or other groups mentioned in this disclosure are intended to cover N-oxides that are available from these groups (when they contain N atoms).

[0111] The term "trifluoromethanesulfonate" refers to the trifluoromethanesulfonate group, which is a functional group represented by the formula -OS(=O)2CF3.

[0112] Xantphos is an organophosphorus compound derived from heterocyclic xanthannaphthol.

[0113] XPhos is a phosphine ligand derived from biphenyl. It is particularly efficient and versatile when used as a precatalyst complex of (2-aminobiphenyl)-cyclometalated palladium methanesulfonate (Buchwald third-generation precatalyst system) XPhos-G3-Pd, and it is commercially available and stable at room temperature.

[0114] The term "pharmaceutical acceptable" refers to compositions and molecular entities that are physiologically well tolerated and generally do not cause allergic reactions or similar adverse reactions (such as gastrointestinal upset, dizziness, etc.) when used in humans or animals. For example, the term "pharmaceutical acceptable" means that it has been approved by state or federal regulatory agencies or is listed in the US Pharmacopeia or other recognized pharmacopoeias for use in animals, and especially in humans.

[0115] The term "treatment" or "treating" refers to the administration of a therapy in an effective amount, manner, or modality to improve a condition, symptom, or parameter associated with a disease or to prevent the progression of the disease, to a statistically significant degree or to a degree detectable by a person skilled in the art. The effective amount, manner, or modality may vary from person to person and may be adjusted according to the patient's condition.

[0116] The “effective” or “therapeutic effective” amount of a drug or pharmacologically active ingredient refers to a non-toxic amount of the drug or agent sufficient to provide the desired effect. The “effective” amount varies from person to person, depending on individual age and general condition, the specific active agent used, and other factors. Therefore, a precise “effective” amount cannot always be determined. However, in any individual case, a suitable “effective” amount can be determined by those skilled in the art using routine experiments.

[0117] The term "prevention" or "to prevent" refers to reducing the risk of developing or preventing a disease or disorder, or reducing or suppressing the recurrence of a disease or disorder.

[0118] In this document, the term "about" to describe a measured quantity refers to the fluctuation of that quantity within a normal range, which is expected by those skilled in the art after performing the measurement and taking precautions commensurate with the accuracy of the measurement target and the measuring equipment. Typically, the term "about" includes ±10% of the referenced number. Therefore, "about 10" refers to 9 to 11.

[0119] The term “optionally substituted” as used in this article refers to groups that may be unsubstituted or substituted.

[0120] As used herein, the term "patient" refers to a person. 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 juvenile patient. In some embodiments, the patient is an adolescent.

[0121] The term "child" used in this article refers to people between birth and adolescence.

[0122] The term "puberty" refers to the process of physical change through which a child's body matures into an adult body capable of sexual reproduction. On average, girls begin puberty around 10-11 years of age and end it around 15-17 years of age; boys begin it around 11-12 years of age and end it around 16-17 years of age.

[0123] The term "infant" as used in this article is a synonym for "toddler," referring to the youngest offspring of humankind. The term "infant" is generally used to refer to children under one year old.

[0124] The term "infant" as used in this article refers to children aged 12 to 36 months.

[0125] The term "teenager" used in this article refers to people aged 10-13.

[0126] The term “teenager” used in this article refers to people aged 10 to 19.

[0127] The term "solvate" refers to any form of the active compound of this disclosure having another molecule (e.g., a polar solvent such as water or ethanol, a cyclodextrin, or a dendritic polymer) connected to it by a non-covalent bond. Methods of solvation are known in the art.

[0128] This disclosure also provides salts of the compounds disclosed herein. Non-limiting examples include sulfates; hydrohalides; phosphates; lower alkane sulfonates; aryl sulfonates; C 1-20 Salts of aliphatic mono-, di-, or tri-carboxylic acids, which may contain one or more double bonds, aryl nuclei, or other functional groups such as hydroxyl, amino, or ketone groups; salts of aromatic acids, wherein the aromatic nucleus may or may not be substituted by hydroxyl, lower alkoxy, amino, mono- or di-lower alkylaminosulfonamide groups, etc. The scope of this disclosure also includes quaternary ammonium salts formed from tertiary nitrogen atoms and lower alkyl halides or sulfates, and oxygen-containing derivatives of tertiary nitrogen atoms, such as N-oxides. In preparing dosage forms, those skilled in the art will select pharmaceutically acceptable salts.

[0129] Solvents and salts can be prepared by methods known in the prior art. It should be noted that non-pharmaceutically acceptable solvates are also included within the scope of this disclosure, as they can be used to prepare pharmaceutically acceptable salts and solvates.

[0130] The disclosed compounds also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which hydrogen is replaced by deuterium or tritium, and carbon is enriched... 11 C 13 C or 14 C carbon substitution or nitrogen enrichment 15 Compounds whose structures are identical to those of existing structures, except for nitrogen substitution with N, are all within the scope of this disclosure.

[0131] Some of the compounds disclosed herein may contain one or more asymmetric centers, and thus may produce enantiomers, diastereomers, and other stereoisomers, such as epimers. This disclosure is intended to cover the use of all such possible forms, as well as their racemic, resolved forms, and mixtures thereof. According to this disclosure, the individual enantiomers can be separated according to methods known to those skilled in the art. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, they should contain E and Z geometrical isomers unless otherwise stated. All tautomers should also be included in this disclosure.

[0132] As used in this article, the term "stereoisomer" refers to all isomers of a single molecule that differ only in the spatial orientation of their atoms. It includes enantiomers as well as isomers of compounds with multiple chiral centers that are not mirror images of each other (diastereomers).

[0133] The term "chiral center" as used in this article refers to a carbon atom connected to four different groups.

[0134] The term “diastereomer” as used in this article refers to a diastereomer in which only one of the two or more tetrahedral stereocenters present in the corresponding molecular entity has an opposite configuration.

[0135] The term "stereoisomer center" refers to an atom with a group, where the interchange of any two groups will result in the formation of a stereoisomer.

[0136] The terms “enantiomer” and “enantiomeric” refer to molecules that cannot be superimposed on their mirror image and therefore have optical activity, where the enantiomer rotates the plane of polarized light in one direction, while its mirror compound rotates the plane of polarized light in the opposite direction.

[0137] The term "racemic" refers to a mixture of equal amounts of enantiomers that is not optically active.

[0138] The term "split" refers to the separation, concentration, or consumption of one of the two enantiomers of a molecule.

[0139] The terms "an" and "a kind" refer to one (species) or more (species).

[0140] As used herein, the term "enzyme replacement therapy" (ERT) refers to the administration of exogenously produced natural or recombinant enzymes or analogues thereof to patients in need. For example, in lysosomal storage disorders, harmful levels of substrates (i.e., storage substances) accumulate in the lysosomes of patients due to a deficiency or defect of enzymes responsible for metabolizing substrates or due to a lack of enzymatic activators. Enzyme replacement therapy aims to reduce (i.e., clear) the levels of substrates accumulated in the affected tissues. Enzyme replacement therapies for treating lysosomal storage disorders are known in the art. According to the combination therapy disclosed herein, lysosomal enzymes (e.g., β-galactosidase) can be used in enzyme replacement therapy to reduce the levels of corresponding substrates (e.g., GM1 gangliosides, glycoproteins, keratin sulfate) in patients with GM1 ganglioside storage disorders or Mochio type B.

[0141] As used herein, the term “effective amount” of enzyme means an amount sufficient to improve the clinical course of lysosomal storage disease when administered to a subject in combination therapy of the present disclosure, wherein the clinical improvement can be measured by any of a variety of established parameters well known to those skilled in the art.

[0142] As used herein, the term "small molecule chaperone" refers to compounds other than those disclosed herein that are capable of binding to mutant enzymes (e.g., β-galactosidase) in an allosteric or competitive manner, thereby stabilizing the enzyme and preventing its degradation. In some embodiments, the small molecule chaperone promotes the proper folding and transport of the enzyme to its site of action. Small molecule chaperones for the treatment of lysosomal storage diseases are known in the art. See, for example, US2016 / 0207933A1 and WO2011 / 049737A1.

[0143] Some reactions used to prepare the compounds disclosed herein involve the use of an amino protecting group. As used herein, an "amino protecting group" is a group that blocks (i.e. protects) the amine functional group when reacting with other functional groups or portions of the molecule. Those skilled in the art will be familiar with the selection, attachment, and removal of amino protecting groups and will understand that many different protecting groups are known in the art, and the choice of which protecting group depends on the specific synthetic scheme planned. Monographs on this subject are available for reference, such as Wuts, PGM & Greene, TW. Greene ' s Protective Groups in Organic Synthesis ,4th Ed. (J. Wiley & Sons, 2007), the entire text of which is incorporated herein by reference. Suitable amine protecting groups include methyl carbamate, tert-butyl carbamate (tert-butyl carbamate; BOC), 9-fluorenyl methyl carbamate, benzyl carbamate, 2-(trimethylsilyl)ethyl carbamate, trifluoroacetamide, benzylamine, allylamine, triphenylmethylamine, trichloroacetyl, trifluoroacetyl, p-toluenesulfonyl, and allyl carbamate. In another embodiment, the protected amino group may be a phthalimide-protected amino group (NPhth).

[0144] The “effective amount” of another therapeutic agent used herein, when administered to a subject in combination therapy of the present disclosure, refers to an amount sufficient to improve the clinical course of a disease or condition associated with altered GLB1 activity, wherein the clinical improvement is measured by any of a variety of defined parameters well known to those skilled in the art.

[0145] Synthesis of publicly disclosed compounds

[0146] The compounds disclosed herein can be prepared using methods known to those skilled in the art or using exemplary methods as shown in the following embodiments. For example, the methods described in embodiments 1-5 below can be used to prepare compounds having formula (I). Other synthetic methods will be described and illustrated in the following working examples.

[0147] Option 1

[0148]

[0149] Reaction A

[0150] In one method, a compound of formula (V) (where L1 represents a suitable leaving group, such as a halogen, trifluoromethanesulfonate, toluenesulfonate, or methanesulfonate group, and R1, R2, and R5 are each as defined above for formula (I)) is reacted with a compound of formula (VI) (where M can be NO2, NR6R7, or NH-PG, where PG is an amino protecting group, L2 is a leaving group, and A1, A2, and A3 are each as defined above for formula (I)) to obtain a compound of formula (VII), as shown in reaction A in the above scheme (Scheme 1).

[0151] Reaction A can be carried out under standard conditions in the presence of a suitable base (such as pyridine, triethylamine, dimethylaminopyridine, diisopropylamine, potassium hydroxide or mixtures thereof) and a suitable solvent (such as pyridine, dichloromethane, chloroform, tetrahydrofuran, toluene, dimethylformamide, dimethyl sulfoxide, water or mixtures thereof), and for example at or above room temperature or under microwave irradiation reaction conditions.

[0152] The reaction can also be carried out in the presence of a suitable metal catalyst (or its salt or complex), such as Cu, Cu(OAc)2, CuI (or CuI / diamine complex), tris(triphenylphosphine)copper bromide, Pd(OAc)2, tris(dibenzylideneacetone)dipalladium(O)(Pd2(dba)3) or NiCl2, and optionally with additives, such as Ph3P, 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, xantphos, (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine, NaI or suitable The reaction is carried out in the presence of a crown ether, such as 18-crown-6-benzene, in a suitable base, such as sodium hydride, triethylamine, pyridine, N,N'-dimethylethylenediamine, imidazole, sodium carbonate, potassium carbonate, tripotassium phosphate, potassium phosphate, cesium carbonate, sodium tert-butoxide or potassium tert-butoxide (or mixtures thereof, optionally in the presence of a 4 Å molecular sieve), in a suitable solvent (e.g., dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidone or tetrahydrofuran) or mixtures thereof. The reaction can be carried out under microwave irradiation. The reaction mixture can be stirred or heated at room temperature until the starting material is completely consumed.

[0153] Compounds of formulas (V) and (VI) are commercially available or can be obtained by methods described in the literature known to those skilled in the art.

[0154] The reaction can be carried out in the presence of protecting groups, and those protecting groups can be removed after the reaction is complete. Suitable protecting groups are known to those skilled in the art (see TW Greene, “Protective Groups in Organic Synthesis”, 3rd ed., New York, 1999).

[0155] Option 2

[0156]

[0157] Reaction B

[0158] According to another method of the present invention, a compound of formula (VII) (where L1 is a leaving group, such as a halogen, trifluoromethanesulfonate, p-toluenesulfonate or methanesulfonate group, M can be NO2, NR6R7 or NH-PG, where PG is a protecting group, and A1, A2, A3, R1, R2, R5, R6 and R7 are each as defined above for formula (I)) is reacted with an amine compound of formula (VIII) (where R8 and R9 are each as defined above) to obtain a compound of formula (IX), as shown in reaction B in the above scheme (scheme 2).

[0159] Reaction B can be carried out under standard conditions, in the presence of a suitable palladium catalyst, such as Pd(dba)2, palladium acetate, XantPhos PdG3, tBuXPhos Pd G3 or Pd2(dba)3, a suitable base (such as cesium carbonate or triethylamine), and a suitable ligand, such as 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene, Xantphos or XPhos, in a suitable solvent (such as butanol, toluene, dioxane or mixtures thereof), and for example at around room temperature or at reflux temperature.

[0160] Alternatively, the conversion can be performed at a suitable base (e.g., N , N The process is carried out in the presence of diisopropylethylamine or triethylamine and a suitable solvent (e.g., dimethyl sulfoxide, tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, methanol, ethanol or mixtures thereof).

[0161] Compounds of formula (VIII) are commercially available or can be obtained by methods described in the literature known to those skilled in the art.

[0162] The reaction can be carried out in the presence of protecting groups, and those protecting groups can be removed after the reaction is complete. Suitable protecting groups are known to those skilled in the art (see TW Greene, “Protective Groups in Organic Synthesis”, 3rd ed., New York, 1999).

[0163] Option 3

[0164]

[0165] Reaction C

[0166] In Scheme 2, M is the nitro group of compound (IX) of NO2, which can subsequently be reduced to a primary amine group. Therefore, as shown in reaction C of Scheme 3 above, compound (X) is reduced to compound (XI), where R... 3aThe compound is of formula (I) with -NH2. Reaction C is carried out using a suitable reducing agent (e.g., Fe, SnCl2) and hydrogen in the presence of a hydrogenation catalyst (e.g., Raney nickel, palladium, or PtO2). The reaction can be carried out in the presence of an acid (e.g., acetic acid, hydrochloric acid, or sulfuric acid) and in a suitable solvent (e.g., ethyl acetate, water, methanol, ethanol, and / or tetrahydrofuran). Other known reducing agents or acids may also be used by those skilled in the art. The reaction mixture is stirred or heated at room temperature until the starting material is completely consumed. The reaction can be carried out in the presence of protecting groups, and those protecting groups can be removed after the reaction is complete. Suitable protecting groups are known to those skilled in the art (see TW Greene, “Protective Groups in Organic Synthesis”, 3rd ed., New York, 1999).

[0167] Option 4

[0168]

[0169] Reaction D

[0170] According to another method of the present invention, a compound of formula (XII) (wherein PG is a protecting group, and A1, A2, A3, R1, R2, R5, R8 and R9 are each as defined above for formula (I)) is reacted to generate a compound of formula (XI), i.e., wherein R 3a The compound of formula (I) is -NH2, as shown in reaction D in scheme (scheme 4) above.

[0171] Treating the protecting group PG (e.g., tert-octylamine, tert-butyl carbamate, or diphenylmethylimine) of the amine moiety of compound (XII) forms the corresponding primary amino group.

[0172] Compounds of formula (XI) can be provided as free bases or converted to their salt forms (e.g., HCl salts) via standard salting procedures.

[0173] Reaction D can be carried out under standard deprotection conditions, such as in the presence of HCl, trifluoroacetic acid, or boron tribromide. Such reactions can also be carried out in suitable solvents such as tetrahydrofuran, dioxane, dichloromethane, or mixtures thereof.

[0174] The reaction mixture is stirred or heated at low temperature or room temperature until the starting material is completely consumed. The reaction can be carried out in the presence of protecting groups, and those protecting groups can be removed after the reaction is complete. Suitable protecting groups are known to those skilled in the art (see TW Greene, “Protective Groups in Organic Synthesis”, 3rd ed., New York, 1999).

[0175] Option 5

[0176]

[0177] Reaction E

[0178] According to another method of the present invention, the intermediate of formula (X) can be prepared from the compound of formula (XIII), wherein A1, A2, A3, R1, R2, R5 and R9 are each as defined above, by reacting with a suitable aldehyde of formula (XIV), wherein R8' is as defined in scheme 5 above, by a reductive amination reaction to generate the compound of formula (X), as shown in reaction E in scheme (scheme 5) above.

[0179] Reaction E is carried out under standard reducing amination conditions, such as in the presence of a reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride), or in the presence of a suitable acid (e.g., acetic acid) and a suitable solvent (e.g., acetonitrile, dichloromethane, methanol, ethanol, ethyl acetate, chloroform, dimethylformamide, toluene, or mixtures thereof). The reaction mixture is stirred or heated at room temperature until the starting material is completely consumed.

[0180] Compounds of formula (XIV) are commercially available or can be obtained by methods described in the literature known to those skilled in the art.

[0181] The reaction can be carried out in the presence of protecting groups, and those protecting groups can be removed after the reaction is complete. Suitable protecting groups are known to those skilled in the art (see TW Greene, “Protective Groups in Organic Synthesis”, 3rd ed., New York, 1999).

[0182] Where R 3b It's not hydrogen but halogen or -C 1-4 Alkyl compounds of formula (I) can be prepared using the methods described above and the following working examples using suitable starting compounds.

[0183] Compounds of formula (I) can be provided as free bases or converted to their salt form (e.g., HCl salts) by a standard salting procedure.

[0184] Starting materials and reactants can be purchased or synthesized, as shown in the working examples below.

[0185] Uses of the compounds disclosed herein

[0186] The efficacy of the disclosed compounds (including pharmaceutically acceptable salts or solvates) in the methods described herein can be demonstrated by suitable in vitro or in vivo tests. Suitable in vivo tests include, for example, those described in the following literature: 1) Takai, T., et al. , “A bicyclic 1-deoxygalactonojirimycin derivative as anovel pharmacological chaperone for GM1 gangliosidosis,” Mol. Ther. 21: 526-532 (2013); 2) Suzuki, Y., et al. , “Chemical chaperone therapy: clinical effect in murine G(M1)-gangliosidosis,” Ann. Neurol. 62(6) :671-675 (2007); and 3) Yoshiyuki, S., et al. , “Therapeutic chaperone effect of N-Octyl 4-Epi-β-valienamine on murine GM1-gangliosidosis,” Molecular Genetics and Metabolism 106(1):92-98 (2012).

[0187] The disclosed compounds are capable of allosterically binding to mutated β-galactosidases, thereby stabilizing the enzyme and preventing its denaturation. Therefore, the disclosed compounds can be used / administered for the treatment and / or prevention of conditions associated with altered β-galactosidase (particularly galactosidase β-1 or GLB1) activity, including GM1 ganglioside storage disease and Mochio syndrome type B.

[0188] Therefore, this disclosure relates to a method for treating or preventing a patient’s condition associated with altered GLB1 activity, the method comprising administering to a patient in need an effective amount of a compound of any one of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof.

[0189] This disclosure also relates to a method for treating GM1 ganglioside storage disease or Mochio type B, the method comprising administering to a patient in need an effective amount of a compound of any one of formulas (I), (II), (III), or (IV) or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the method for treating GM1 ganglioside storage disease or Mochio type B further comprises administering to the patient an effective amount of an enzyme for enzyme replacement therapy. In another embodiment, the enzyme is β-galactosidase or an analogue thereof. In another embodiment, the method further comprises administering to the patient a small molecule molecular chaperone. In one embodiment, the small molecule molecular chaperone competitively binds to the enzyme. In another embodiment, the small molecule molecular chaperone is selected from iminoglycosides, iminosugars, aminosugars, thiophene glycosides, glycosidases, sulfatases, glycosyltransferases, phosphoesterases, and peptidase inhibitors. In another embodiment, suitable small molecule chaperones are selected from 1-deoxygalactosinosin (DGJ), N-nonyldeoxygalactosin (NN-DNJ), N-butyldeoxygalactosinosin (NB-DGJ), galactose, fluoroiminotol, and epi-isofagomine.

[0190] This disclosure also relates to a method for increasing the β-galactosidase activity of a patient in need, the method comprising administering to the patient an effective amount of a compound of any one of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof.

[0191] This disclosure also relates to the use of any compound of formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment and / or prevention of conditions associated with altered β-galactosidase (particularly galactosidase β-1 or GLB1) activity, including GM1 ganglioside storage disease and Mochio syndrome type B.

[0192] This disclosure also relates to a compound of any one of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, for the treatment of a patient with GM1 ganglioside storage disease or Mochio type B. In one embodiment, a compound of any one of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, is combined with an effective amount of an enzyme for enzyme replacement therapy. In another embodiment, the enzyme is β-galactosidase or an analogue thereof. In another embodiment, a compound of any one of formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient in combination with a small molecule molecular chaperone. In one embodiment, the small molecule molecular chaperone competitively binds to the enzyme. In another embodiment, the small molecule molecular chaperone is selected from iminoglycosides, iminosugars, aminosugars, thiophene glycosides, glycosidases, sulfatases, glycosyltransferases, phosphoesterases, and peptidase inhibitors. In another embodiment, suitable small molecule chaperones are selected from 1-deoxygalactosinosin (DGJ), N-nonyldeoxygalactosin (NN-DNJ), N-butyldeoxygalactosinosin (NB-DGJ), galactose, fluoroiminotol, and episifagomin.

[0193] As shown in Table 2 below, the compounds disclosed herein can reduce the accumulation of GM1 gangliosides in p.R60H / p.R60H-β-Gal canine fibroblasts at concentrations of 1.56 µM and 0.05 µM. Therefore, the compounds disclosed herein show efficacy in treating and / or preventing conditions associated with altered β-galactosidase (particularly galactosidase β-1 or GLB1) activity because they reduce the accumulation of GM1 gangliosides.

[0194] Pharmaceutical Composition

[0195] The present invention also relates to pharmaceutical compositions comprising an effective amount of the compound disclosed herein and at least one pharmaceutically acceptable excipient. Alternatively, the composition comprises an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient. Alternatively, the composition comprises an effective amount of the compound of formula (I), (II), (III), or (IV) herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0196] Due to their activity, the compounds disclosed herein can be used in human medicine. As stated above, the compounds disclosed herein can be used to treat or prevent conditions associated with altered GLB1 activity. The compounds disclosed herein can be used to treat any patient suffering from the aforementioned conditions. As used herein, the term "patient" refers to any human being capable of experiencing the beneficial effects of the compounds disclosed herein.

[0197] When used on patients, the disclosed compounds can be administered as a component of a composition comprising a pharmaceutically acceptable excipient or carrier.

[0198] The disclosed compounds can be used in combination with at least one other therapeutic agent. The combination of the disclosed compounds with at least one other therapeutic agent can be sequential or simultaneous. Alternatively, the compounds of the present invention and at least one other therapeutic agent can be administered in different dosage forms. Conversely, the compounds of the present invention and at least one other therapeutic agent can be administered simultaneously in the same dosage form.

[0199] The term “excipient” refers to a medium, diluent, or adjuvant that is administered co-administered with the active ingredient. Pharmaceutically acceptable excipients can be sterile liquids, such as water, and oils, including petroleum, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. For example, aqueous solutions or physiological saline, as well as aqueous solutions of glucose and glycerol, can be used as media in injections. Suitable pharmaceutically acceptable media can be found in EW Martin’s “Remington’s Pharmaceutical Sciences” (21st edition, 2005) or Rowe CR; Paul JS; Marian EQ’s “Handbook of Pharmaceutical Excipients” (6th edition), which are incorporated herein by reference.

[0200] Examples of pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid composition (solution, suspension, or emulsion) for oral, topical, or parenteral administration.

[0201] In another embodiment, the pharmaceutical composition is an oral formulation. Oral pharmaceutical formulations may be tablets and capsules and may contain conventional excipients known in the art, such as binders (e.g., syrup, gum arabic, gelatin, sorbitol, tragacanth gum, or polyvinylpyrrolidone); fillers (e.g., lactose, sugar, corn starch, calcium phosphate, sorbitol, or glycine); lubricants for tablet preparation (e.g., magnesium stearate); disintegrants (e.g., starch, polyvinylpyrrolidone, sodium carboxymethyl starch, or microcrystalline cellulose); or pharmaceutically acceptable wetting agents (e.g., sodium dodecyl sulfate).

[0202] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For compositions using a large amount of filler, repeated mixing operations can be used to ensure uniform distribution of the active ingredient throughout the composition. Such operations are routine in the art. Tablets can be prepared by, for example, dry or wet granulation and optionally coated using methods commonly used in conventional pharmaceutical practice, particularly enteric coating.

[0203] The pharmaceutical composition may also be suitable for parenteral administration, for example, as a sterile solution, suspension, or lyophilized product in a suitable unit dose form. Suitable excipients, such as fillers, buffers, or surfactants, may be used.

[0204] The above-mentioned preparations can be prepared using standard methods, such as those described or mentioned in the Spanish Pharmacopoeia, the United States Pharmacopoeia, and similar references.

[0205] Typically, the effective dosage of the disclosed compounds depends on the relative efficacy of the selected compound, the severity of the disease or condition being treated, and the patient's weight. The active compound can be administered once or more daily, for example, 1, 2, 3, or 4 times daily, with a typical total daily dose range of about 0.01 mg / kg body weight / day to about 1000 mg / kg body weight / day. In another embodiment, the effective dose of the disclosed compound is about 500 mg / kg body weight / day or less. In another embodiment, the effective dose of the disclosed compound is about 100 mg / kg body weight / day or less. In another embodiment, the effective dose ranges from about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day; in another embodiment, it is about 0.02 mg / kg body weight / day to about 50 mg / kg body weight / day; and in yet another embodiment, it is about 0.025 mg / kg body weight / day to about 20 mg / kg body weight / day.

[0206] The compositions disclosed in this invention can be prepared by a method comprising mixing the disclosed compound with a pharmaceutically acceptable excipient or carrier. The mixing can be accomplished using known methods for mixing compounds with pharmaceutically acceptable excipients or carriers. In another embodiment, the disclosed compound is present in the composition in an effective amount.

[0207] The following examples are for illustrative purposes only and are not intended to limit the compounds, compositions, and methods disclosed herein. Appropriate modifications and adjustments to various conditions and parameters commonly encountered in clinical treatment will be apparent to those skilled in the art based on the content of this disclosure and are all within the spirit and scope of this disclosure.

[0208] Example

[0209] General experimental conditions for Examples 1-23

[0210] In the following, the terms "h" represent hours, "eq" represent equivalents, "RT" represent room temperature, "LC-MS" represent liquid chromatography-mass spectrometry, "UPLC" represent ultra-high performance liquid chromatography, "Rt" represent retention time, "DMSO-d6" represents deuterated dimethyl sulfoxide, "NH4OAc" represents ammonium acetate, "DCM" represents dichloromethane, "ACN" represents acetonitrile, "EtOAc" represents ethyl acetate, "DMSO" represents dimethyl sulfoxide, "EtOH" represents ethanol, "MeOH" represents methanol, "Pd2(dba)3" represents tris(dibenzylideneacetone)dipalladium(O), "Boc" represents tert-butyloxycarbonyl, "XantPhos" represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthionate, and "XantPhos Pd "G3" represents [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate and " t "BuXPhos Pd G3" represents [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0211] 1 H NMR spectra were recorded on a Variant (400 MHz).

[0212] The compound was analyzed by LC-MS using one of the following methods:

[0213] Method A: 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: 9 min; Mobile phase A: 50 mM ammonium formate solution, pH adjusted to 4 with formic acid; B: water; C: ACN; Gradient: A:B:C 0.5 min, 5:85:10 + from 5:85:10 to 5:10:85, 4.5 min + 4 min, 5:10:85; Chromatographic system: Acquity H Class UPLC; Mass spectrometer: Acquity QDa.

[0214] Method B: Luna C18 (50 mm x 2.0 mm, 5 µm); Wavelength: PDA MaxPlot 210.0 - 400 nm; Flow rate: 0.50 mL / min; Column temperature: 40 °C; Run time: 5 min; Mobile phase A: 10 mM ammonium formate buffer, pH 4, containing HCOOH; B: water; C: ACN; Gradient: A:B:C 0.3 min, 5:85:10 + from 5:85:10 to 5:10:85, 1.7 min + 3.0 min, 5:10:85; Chromatographic system: Waters Alliance HT 2795 and PDA 2996; Mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0215] Method C: SunFire C18 (100mm x 2.1mm, 3.5µm); Wavelength: PDA MaxPlot 210.0 -400nm; Flow rate: 0.50mL / min; Column temperature: 40℃; Run time: 20min; Mobile phase A: 10mM ammonium formate buffer, pH 4, containing HCOOH; B: water; C: ACN; Gradient: A:B:C 3min, 5:85:10 + 5:85:10 to 5:10:85, 9min + 8min, 5:10:85; Chromatographic system: Waters Alliance HT 2795 and PDA 2996; Mass spectrometer: Micromass ZQ2000 single quadrupole (ESI).

[0216] General Method A

[0217]

[0218] Method 1

[0219] 1,2-Dimethylethylenediamine (0.2 eq) was added to a stirred solution of a suitable bromoindole derivative (e.g., 5-bromoindole) (1 eq), a suitable substituted bromopyridine (e.g., 2-bromo-5-nitropyridine) (1.3 eq), K3PO4 (2.6 eq), and CuI (0.1 eq) in toluene (3 mL / mmol). The solution was purged with argon and stirred at 110 °C for 16 h. After cooling the reaction mixture to RT, water and EtOAc were added. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography using hexane / EtOAc to give the desired bromoindole intermediate (e.g., 5-bromo-1-(5-nitropyridine-2-yl)-1-). H -Indole.

[0220] Method 2

[0221] Use a suitable bromoindole derivative (e.g., 4-bromo-1) H 1 eq of 4-bromo-1-(5-nitropyridin-2-yl)-1-indole, a suitable bromonitropyridine (e.g., 2-bromo-5-nitropyridine) (1.5 eq), and 2.5 eq of KOH were mixed in DMSO (1.3 mL / mmol), and the solution was purged with argon and stirred at 140 °C for 16 h. After cooling the reaction mixture to RT, NH4Cl and EtOAc were added. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were washed with water (x2) and brine, dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography using hexane / EtOAc to give the desired indole intermediate (e.g., 4-bromo-1-(5-nitropyridin-2-yl)-1-indole). H -Indole.

[0222] Intermediate 1

[0223] 5-Bromo-1-(5-nitropyridin-2-yl)-1 H -Indole

[0224]

[0225] The product was synthesized using 5-bromoindole and 2-bromo-5-nitropyridine according to General Method A, Method 1. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–50%) and separated as a yellow solid.

[0226] Yield: 68 mg (42%).

[0227] 1 H NMR (400 MHz, DMSO-d6): δ 9.38 (dd, J = 2.8, 0.6 Hz, 1H), 8.72 (dd, J = 9.2, 2.8 Hz, 1H), 8.64 - 8.59 (m, 1H), 8.29 (d, J = 3.7 Hz, 1H), 8.06 (dd, J = 9.3, 0.6 Hz, 1H), 7.91 - 7.88 (m, 1H), 7.49 (dd, J = 8.9, 2.1 Hz, 1H), 6.89 (dd, J = 3.6, 0.8 Hz, 1H).

[0228] Intermediate 2

[0229] 6-(5-bromo-1) H -Indol-1-yl)pyridin-3-yl)tert-butyl carbamate

[0230]

[0231] The product was synthesized using 5-bromoindole and tert-butyl (6-bromopyridin-3-yl)carbamate according to General Method A, Method 1. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–20%) and separated into an off-white solid.

[0232] Yield: 500 mg (50%).

[0233] LC-MS [M+H] + : 388.0 / 390.0, Rt = 3.98min (Method-B).

[0234] Intermediate 3

[0235] 5-Bromo-1-(6-nitropyridin-2-yl)-1 H -Indole

[0236]

[0237] The product was synthesized using 5-bromoindole and 2-bromo-6-nitropyridine according to General Method A, Method 1. The reaction mixture was stirred at 110 °C for 72 h. The crude product was purified by silica gel column chromatography using hexane / DCM (0%–100%) and separated as a yellow solid.

[0238] Yield: 666 mg (82%).

[0239] 1 H NMR (400 MHz, DMSO-d6): δ 8.77 (d, J = 8.9 Hz, 1H), 8.38 (t, J =8.0 Hz, 1H), 8.32 - 8.27 (m, 2H), 8.16 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 2.0Hz, 1H), 7.51 (dd, J = 8.9, 2.1 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H).

[0240] Intermediate 4

[0241] 4-Bromo-1-(5-nitropyridin-2-yl)-1 H -Indole

[0242]

[0243] Following the general method A, method 2, using 4-bromo-1 H -Indole and 2-bromo-5-nitropyridine were synthesized. The crude product was purified by silica gel column chromatography using hexane / DCM (0%-60%) and separated into a yellow solid.

[0244] Yield: 446 mg (55%).

[0245] 1 H NMR (400 MHz, DMSO-d6): δ 9.40 (dd, J = 2.8, 0.6 Hz, 1H), 8.74 (dd, J = 9.2, 2.8 Hz, 1H), 8.66 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 3.7 Hz, 1H), 8.09 (dd, J = 9.3, 0.7 Hz, 1H), 7.50 (dd, J = 7.7, 0.8 Hz, 1H), 7.34 - 7.27(m, 1H), 6.86 (dd, J = 3.7, 0.8 Hz, 1H).

[0246] Intermediate 5

[0247] (6-(4-bromo-1) H -Indol-1-yl)pyridin-3-yl)tert-butyl carbamate

[0248]

[0249] Following the general method A, Method 1, using 4-bromo-1 H Synthesized from indole and tert-butyl (6-bromopyridin-3-yl)carbamate. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–30%) and separated into an off-white solid.

[0250] Yield: 101 mg (51%).

[0251] LC-MS [M+H] + : 387.8 / 389.9, Rt = 3.98min (Method-B).

[0252] Intermediate 6

[0253] 4-Bromo-1-(6-nitropyridin-2-yl)-1 H -Indole

[0254]

[0255] Following the general method A, Method 1, using 4-bromo-1 H -Indole and 2-bromo-6-nitropyridine were synthesized. The reaction mixture was stirred at 110 °C for 96 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-50%) and separated as a yellow solid.

[0256] Yield: 330 mg (68%).

[0257] 1 H NMR (400 MHz, DMSO-d6): δ 8.84 (d, J = 8.4 Hz, 1H), 8.44 - 8.32 (m,3H), 8.20 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 8.1 Hz, 1H), 6.84 (d, J = 3.6 Hz, 1H).

[0258] Intermediate 7

[0259] 6-(5-bromo-1) H -indol-1-yl)- N,N -Dimethylpyridine-3-amine

[0260]

[0261] Following the general method A, Method 1, 5-bromoindole and 6-bromo- N , N Synthesis of 3-dimethylpyridine-3-amine. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-20%) and separated as an orange oil.

[0262] Yield: 280 mg (58%).

[0263] LC-MS [M+H] + : 316.0 / 318.0, Rt = 3.89min (Method-B).

[0264] Intermediate 8

[0265] 5-Bromo-3-methyl-1-(5-nitropyridin-2-yl)-1 H -Indole

[0266]

[0267] Following general method A, method 1, using 5-bromo-3-methyl-1 H -Indole and 2-bromo-5-nitropyridine were synthesized. The reaction mixture was stirred at 110 °C for 72 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-20%) and separated as a yellow solid.

[0268] Yield: 94 mg (15%).

[0269] LC-MS [M+H] + Rt = 4.07min (Method-B).

[0270] Intermediate 9

[0271] 5-Bromo-2-methyl-1-(5-nitropyridin-2-yl)-1 H -Indole

[0272]

[0273] The product was synthesized using 5-bromo-2-methylindole and 2-bromo-5-nitropyridine according to General Method A, Method 1. The reaction mixture was stirred at 110 °C for 72 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–20%) and separated as an orange solid.

[0274] Yield: 190 mg (42%).

[0275] LC-MS [M+H] + Rt = 3.83min (Method-B).

[0276] General Method B

[0277]

[0278] Method 1

[0279] In a sealed tube, a suitable indole derivative after degassing (e.g., intermediate 1: 5-bromo-1-(5-nitropyridin-2-yl)-1) is introduced. HPd2(dba)3 (0.11 eq) and XantPhos (0.23 eq) were added to a dioxane solution (5 mL / mmol) of indole (1 eq), a suitable amine (e.g., p-toluidine) (1.35 eq), and Cs2CO3 (2.09 eq). The solution was degassed again and stirred at 140 °C for 3 h.

[0280] After cooling the reaction mixture to RT, water and EtOAc were added. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure.

[0281] The crude product was purified by silica gel column chromatography using hexane / EtOAc to obtain the desired indole intermediate (e.g., intermediate 10: 1-(5-nitropyridin-2-yl)- N -(p-Tolyl)-1 H -indole-5-amine).

[0282] Method 2

[0283] To a suitable indole derivative (e.g., intermediate 3: 5-bromo-1-(6-nitropyridin-2-yl)-1) H XantPhos Pd G3 (0.1 eq) was added to a solution of 4-indole (1 eq), a suitable amine (e.g., 4-chloroaniline (1.3 eq) and Cs2CO3 (2.6 eq)) in dioxane (3 mL / mmol). The solution was degassed again and stirred at 100 °C for 16 h.

[0284] After cooling the reaction mixture to RT, water and EtOAc were added. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure.

[0285] The crude product was purified by silica gel column chromatography using hexane / EtOAc to obtain the desired indole intermediate (e.g., intermediate 16). N -(4-Chlorophenyl)-1-(6-nitropyridin-2-yl)-1 H -indole-5-amine).

[0286] Intermediate 10

[0287] 1-(5-nitropyridin-2-yl)- N -(p-Tolyl)-1 H -Indole-5-amine

[0288]

[0289] Following general method B, method 1, 5-bromo-1-(5-nitropyridin-2-yl)-1 H -Indole (intermediate 1) and p-toluidine were synthesized. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-20%) and separated into a red solid.

[0290] Yield: 40 mg (46%).

[0291] 1 H NMR (400 MHz, DMSO-d6): δ 9.34 (d, J = 2.6 Hz, 1H), 8.65 (dd, J =9.3, 2.8 Hz, 1H), 8.53 (d, J = 9.0 Hz, 1H), 8.14 (d, J = 3.7 Hz, 1H), 7.97(s, 2H), 7.29 (d, J = 2.2 Hz, 1H), 7.08 - 6.96 (m, 4H), 6.79 (dd, J = 3.6, 0.7 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 2.23 (s, 3H).

[0292] Intermediate 11

[0293] N -(3-methoxyphenyl)-1-(5-nitropyridin-2-yl)-1 H -Indole-5-amine

[0294]

[0295] Following general method B, method 1, 5-bromo-1-(5-nitropyridin-2-yl)-1 H -Indole (intermediate 1) and m-anesanthine were synthesized. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-10%) and separated as a red solid.

[0296] Yield: 30 mg (41%).

[0297] 1 H NMR (400 MHz, DMSO-d6): δ 9.35 (dd, J = 2.8, 0.6 Hz, 1H), 8.66 (dd, J= 9.3, 2.8 Hz, 1H), 8.56 (d, J = 8.9 Hz, 1H), 8.17 (d, J = 3.7 Hz, 1H), 8.13 (s, 1H), 7.99 (dd, J = 9.4, 0.6 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.15- 7.07 (m, 2H), 6.82 (dd, J = 3.7, 0.7 Hz, 1H), 6.69 - 6.62 (m, 1H), 6.60 (t, J = 2.2 Hz, 1H), 6.36 (ddd, J = 8.2, 2.5, 0.8 Hz, 1H), 3.71 (s, 3H).

[0298] Intermediate 12

[0299] 1-(5-nitropyridin-2-yl)- N -(m-Tolyl)-1 H -Indole-5-amine

[0300]

[0301] Following general method B, method 1, 5-bromo-1-(5-nitropyridin-2-yl)-1 H -Indole (intermediate 1) and m-toluidine were synthesized. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-20%) and separated into a red solid.

[0302] Yield: 30 mg (28%).

[0303] 1 H NMR (400 MHz, DMSO-d6): δ 9.33 (dd, J = 2.8, 0.6 Hz, 1H), 8.63 (dd, J = 9.3, 2.8 Hz, 1H), 8.53 (dt, J = 9.0, 0.7 Hz, 1H), 8.14 (d, J = 3.7 Hz,1H), 8.04 - 7.92 (m, 2H), 7.33 (d, J= 2.1 Hz, 1H), 7.10 - 7.04 (m, 2H), 6.88- 6.82 (m, 2H), 6.79 (dd, J = 3.7, 0.7 Hz, 1H), 6.60 - 6.56 (m, 1H), 2.22 (s, 3H).

[0304] Intermediate 13

[0305] (6-(5-((4-chlorophenyl)amino)-1 H -Indol-1-yl)pyridin-3-yl)tert-butyl carbamate

[0306]

[0307] Following the general method B, method 2, (6-(5-bromo-1) H Synthesized from 1-indolyl)pyridinyl)tert-butyl)carbamate (intermediate 2) and 4-chloroaniline. Also added... t BuXPhos Pd G3 (0.1 eq) was added, and the solution was degassed and stirred at 100 °C for an additional 24 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–40%) and separated into a colorless oil.

[0308] Yield: 65 mg (25%).

[0309] LC-MS [M+H] + : 435.1 / 437.0, Rt = 4.00min (Method-B).

[0310] Intermediate 14

[0311] (6-(5-((3-chlorophenyl)amino)-1 H -Indol-1-yl)pyridin-3-yl)tert-butyl carbamate

[0312]

[0313] Following the general method B, method 2, (6-(5-bromo-1) H Synthesized from tert-butyl indol-1-yl)pyridin-3-yl)carbamate (intermediate 2) and 3-chloroaniline. Also added... t BuXPhos Pd G3 (0.1 eq) was added, and the solution was degassed and stirred at 100 °C for 32 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–40%) and separated into an off-white solid.

[0314] Yield: 40 mg (16%).

[0315] LC-MS [M+H] + : 435.1 / 437.0, Rt = 4.01min (Method-B).

[0316] Intermediate 15

[0317] (6-(5-((4-cyanophenyl)amino)-1 H -Indol-1-yl)pyridin-3-yl)tert-butyl carbamate

[0318]

[0319] Following the general method B, method 2, (6-(5-bromo-1) H The product was synthesized from tert-butyl carbamate (intermediate 2) and 4-aminobenzonitrile. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-100%) and separated into a colorless oil.

[0320] Yield: 40 mg (15%).

[0321] LC-MS [M+H] + : 426.1, Rt = 3.68min (Method-B).

[0322] Intermediate 16

[0323] N -(4-Chlorophenyl)-1-(6-nitropyridin-2-yl)-1 H -Indole-5-amine

[0324]

[0325] Following general method B, method 2, 5-bromo-1-(6-nitropyridin-2-yl)-1 H Synthesized from indole (intermediate 3) and 4-chloroaniline. The crude product was purified by silica gel column chromatography using hexane / DCM (0%–100%) and separated as a yellow solid.

[0326] Yield: 48 mg (21%).

[0327] 1 H NMR (400 MHz, DMSO-d6): δ 8.77 - 8.71 (m, 1H), 8.32 (dd, J = 8.3,7.6 Hz, 1H), 8.28 - 8.19 (m, 2H), 8.17 (d, J= 3.6 Hz, 1H), 8.09 (dd, J =7.6, 0.6 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.10 (dd, J = 8.9, 2.3 Hz, 1H), 7.05 - 7.00 (m, 2H), 6.77 (dd, J = 3.6, 0.8 Hz, 1H).

[0328] Intermediate 17

[0329] N -(3-Methoxyphenyl)-1-(6-Nitropyridin-2-yl)-1 H -Indole-5-amine

[0330]

[0331] Following general method B, method 2, 5-bromo-1-(6-nitropyridin-2-yl)-1 H -Indole (intermediate 3) and m-anesanthine were synthesized. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-100%) and separated into a pale yellow solid.

[0332] Yield: 129 mg (57%).

[0333] 1 H NMR (400 MHz, DMSO-d6): δ 8.75 - 8.69 (m, 1H), 8.35 - 8.21 (m, 2H), 8.16 (d, J = 3.6 Hz, 1H), 8.10 - 8.06 (m, 2H), 7.37 (d, J = 2.1 Hz, 1H), 7.13- 7.04 (m, 2H), 6.77 (dd, J = 3.6, 0.8 Hz, 1H), 6.63 (ddd, J = 8.1, 2.1, 0.9Hz, 1H), 6.57 (t, J = 2.2 Hz, 1H), 6.33 (ddd, J = 8.2, 2.4, 0.8 Hz, 1H), 3.69(s, 3H).

[0334] Intermediate 18

[0335] N -(4-methoxyphenyl)-1-(5-nitropyridin-2-yl)-1 H -Indole-4-amine

[0336]

[0337] Following general method B, method 2, 4-bromo-1-(5-nitropyridin-2-yl)-1 H Synthesized from indole (intermediate 4) and p-anesinamine. Using... t BuXPhos Pd G3 (0.1 eq) was used instead of XantPhos Pd G3. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–20%) and separated into a red solid.

[0338] Yield: 40 mg (16%).

[0339] LC-MS [M+H] + : 360.9, Rt = 3.71min (Method-B).

[0340] 1 H NMR (400 MHz, DMSO-d6): δ 9.37 (d, J = 2.8 Hz, 1H), 8.69 (dd, J =9.2, 2.8 Hz, 1H), 8.06 (d, J = 3.7 Hz, 1H), 8.01 (t, J = 7.9 Hz, 2H), 7.91(s, 1H), 7.17 - 7.06 (m, 4H), 6.94 - 6.88 (m, 2H), 6.80 (d, J = 7.8 Hz, 1H), 3.74 (s, 3H).

[0341] Intermediate 19

[0342] N -(4-Chlorophenyl)-1-(5-Nitropyridin-2-yl)-1 H -Indole-4-amine

[0343]

[0344] Following general method B, method 2, 4-bromo-1-(5-nitropyridin-2-yl)-1 H Synthesized from indole (intermediate 4) and 4-chloroaniline. Using... tBuXPhos Pd G3 (0.1 eq) was used instead of XantPhos Pd G3. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–20%) and separated into a red solid.

[0345] Yield: 90 mg (36%).

[0346] 1 H NMR (400 MHz, DMSO-d6): δ 9.39 (d, J = 2.8 Hz, 1H), 8.77 - 8.64 (m,1H), 8.33 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 3.7 Hz, 1H), 8.02(d, J = 9.2 Hz, 1H), 7.31 - 7.20 (m, 3H), 7.16 - 7.08 (m, 2H), 7.05 (d, J =7.8 Hz, 1H), 6.97 (d, J = 3.7 Hz, 1H).

[0347] Intermediate 20

[0348] (6-(4-(p-Tolylamino)-1) H -Indol-1-yl)pyridin-3-yl)tert-butyl carbamate

[0349]

[0350] Following the general method B, method 2, (6-(4-bromo-1) H Synthesized from 1-indolyl)pyridinyl)tert-butyl carbamate (intermediate 5) and p-toluidine. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–20%) and separated as a yellow solid.

[0351] Yield: 26 mg (35%).

[0352] LC-MS [M+H] + : 415.3, Rt = 3.97min (Method-B).

[0353] Intermediate 21

[0354] (6-(4-((3-methoxyphenyl)amino)-1 H -Indol-1-yl)pyridin-3-yl)tert-butyl carbamate

[0355]

[0356] Following the general method B, method 2, (6-(4-bromo-1) H Synthesized using 1-indol-1-yl)pyridin-3-yl)tert-butyl carbamate (intermediate 5) and m-anisidine. t BuXPhos Pd G3 (0.1 eq) was used instead of XantPhos Pd G3. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–20%) and separated as an orange oil.

[0357] Yield: 120 mg (60%).

[0358] LC-MS [M+H] + : 431.2, Rt = 3.82min (Method-B).

[0359] Intermediate 22

[0360] (6-(4-(m-Tolylamino)-1) H -Indol-1-yl)pyridin-3-yl)tert-butyl carbamate

[0361]

[0362] Following the general method B, method 2, (6-(4-bromo-1) H Synthesized using 1-indol-1-yl)pyridin-3-yl)tert-butyl carbamate (intermediate 5) and m-toluidine. t BuXPhos Pd G3 (0.1 eq) was used instead of XantPhos Pd G3. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–20%) and separated as an orange oil.

[0363] Yield: 120 mg (62%).

[0364] LC-MS [M+H] + : 415.2, Rt = 3.99min (Method-B).

[0365] Intermediate 23

[0366] (6-(4-((3-chlorophenyl)amino)-1 H -Indol-1-yl)pyridin-3-yl)tert-butyl carbamate

[0367]

[0368] Following the general method B, method 2, (6-(4-bromo-1) H Synthesized using 1-indol-1-yl)pyridin-3-yl)tert-butyl carbamate (intermediate 5) and 3-chloroaniline. t BuXPhos Pd G3 (0.1 eq) was used instead of XantPhos Pd G3. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–10%) and separated into a yellow oil.

[0369] Yield: 110 mg (38%).

[0370] LC-MS [M+H] + : 435.2 / 437.0, Rt = 4.06min (Method-B).

[0371] Intermediate 24

[0372] 1-(6-nitropyridin-2-yl)- N -(p-Tolyl)-1 H -Indole-4-amine

[0373]

[0374] Following General Method B, Method 2, 4-bromo-1-(6-nitropyridin-2-yl)-1 H Synthesized from indole (intermediate 6) and p-toluidine. Using... t BuXPhos Pd G3 (0.1 eq) was used instead of XantPhos Pd G3. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–50%) and separated as an orange solid.

[0375] Yield: 92 mg (26%).

[0376] LC-MS [M+H] + : 345.1, Rt = 3.83min (Method-B).

[0377] Intermediate 25

[0378] N -(4-Chlorophenyl)-1-(6-nitropyridin-2-yl)-1 H -Indole-4-amine

[0379]

[0380] Following General Method B, Method 2, 4-bromo-1-(6-nitropyridin-2-yl)-1 H Synthesized from indole (intermediate 6) and 4-chloroaniline. Using...t BuXPhos Pd G3 (0.3 eq) was used instead of XantPhos Pd G3. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–50%) and separated into a brown solid.

[0381] Yield: 120 mg (42%).

[0382] 1 H NMR (400 MHz, DMSO-d6): δ 8.42 - 8.26 (m, 4H), 8.16 (s, 1H), 8.15 -8.11 (m, 1H), 7.31 - 7.22 (m, 3H), 7.15 - 7.08 (m, 2H), 7.05 (d, J = 7.7 Hz,1H), 6.96 - 6.92 (m, 1H).

[0383] Example 1

[0384] 1-(5-(dimethylamino)pyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-5-amine

[0385]

[0386] Following the general method B, method 2, 6-(5-bromo-1- H -indol-1-yl)- N,N Synthesized using dimethylpyridine-3-amine (intermediate 7) and p-anisidine. t BuXPhos Pd G3 (0.2 eq) was used instead of XantPhos Pd G3. The crude product was purified by silica gel column chromatography with hexane / EtOAc (0%–10%), followed by reversed-phase rapid column chromatography (C18, NH4OAc (aq) 10 mM (pH 7) / ACN 0%–100%), and the off-white solid was separated.

[0387] Yield: 38 mg (12%).

[0388] LC-MS [M+H] + : 359.5, Rt = 11.90min (Method-C).

[0389] 1 H NMR (400 MHz, DMSO-d6): δ 8.04 (d, J= 3.1 Hz, 1H), 8.03 - 7.96 (m,1H), 7.75 (d, J = 3.3 Hz, 1H), 7.57 (s, 1H), 7.51 (dd, J = 9.0, 0.6 Hz, 1H), 7.34 (dd, J = 9.0, 3.2 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 7.02 - 6.96 (m,2H), 6.90 (dd, J = 8.9, 2.2 Hz, 1H), 6.86 - 6.80 (m, 2H), 6.51 (dd, J = 3.4,0.8 Hz, 1H), 3.70 (s, 3H), 2.97 (s, 6H).

[0390] Intermediate 26

[0391] N -(4-methoxyphenyl)-3-methyl-1-(5-nitropyridin-2-yl)-1 H -Indole-5-amine

[0392]

[0393] Following general method B, method 2, 5-bromo-3-methyl-1-(5-nitropyridin-2-yl)-1 H -Indole (intermediate 8) and p-anisidine were synthesized. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-40%) and separated as an orange solid.

[0394] Yield: 51 mg (48%).

[0395] LC-MS [M+H] + : 374.8, Rt = 3.83min (Method-B).

[0396] Intermediate 27

[0397] N -(4-methoxyphenyl)-2-methyl-1-(5-nitropyridin-2-yl)-1 H -Indole-5-amine

[0398]

[0399] Following general method B, method 2, 5-bromo-2-methyl-1-(5-nitropyridin-2-yl)-1H -Indole (intermediate 9) and p-anisidine were synthesized. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-40%) and separated as an orange solid.

[0400] Yield: 94 mg (44%).

[0401] LC-MS [M+H] + : 374.8, Rt = 3.71min (Method-B).

[0402] Intermediate 28

[0403] N -(4-Methoxyphenyl)-1-(6-Nitropyridin-2-yl)-1 H -Indole-5-amine

[0404]

[0405] Following General Method B, Method 1, 5-bromo-1-(6-nitropyridin-2-yl)-1 H -Indole (intermediate 3) and p-anisidine were synthesized. The crude product was used in the next step without further purification.

[0406] Yield: 117 mg (quantitative).

[0407] Intermediate 29

[0408] N -(4-Methoxyphenyl)-1-(6-Nitropyridin-2-yl)-1 H -Indole-4-amine

[0409]

[0410] Following general method B, method 1, 4-bromo-1-(6-nitropyridin-2-yl)-1 H -Indole (intermediate 6) and p-anisidine were synthesized. The crude product was used in the next step without further purification.

[0411] Yield: 170 mg (quantitative).

[0412] Intermediate 30

[0413] N -(4-methoxyphenyl)-1-(5-nitropyridin-2-yl)-1 H -Indole-5-amine

[0414]

[0415] Following general method B, method 1, 5-bromo-1-(5-nitropyridin-2-yl)-1 H -Indole (intermediate 1) and p-anisidine were synthesized. The crude product was used in the next step without further purification.

[0416] Yield: 170 mg (quantitative).

[0417] Intermediate 31

[0418] N -(3-Methoxyphenyl)- N -Methyl-1-(5-nitropyridin-2-yl)-1 H -Indole-5-amine

[0419]

[0420] Will N -(3-methoxyphenyl)-1-(5-nitropyridin-2-yl)-1 H Indole-5-amine (intermediate 11, 80 mg, 0.22 mmol, 1 eq) and 37% CH2O aqueous solution (35 µL, 0.44 mmol, 2 eq) were mixed in 1.5 mL of ACN. The solution was stirred at RT for 30 min, and then NaBH3CN (18 mg, 0.29 mmol, 1.3 eq) was added. The reaction mixture was stirred at RT for 16 h, and the solvent was removed under reduced pressure. The dried residue was dissolved in EtOAc and washed with water. After extraction with EtOAc (x3), the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–30%) to give the desired indole as an orange solid.

[0421] Yield: 40 mg (48%).

[0422] LC-MS [M+H] + : 375.0, Rt = 3.99min (Method-B).

[0423] General Method C

[0424]

[0425] Method 1

[0426] To a suitable nitro-substituted intermediate (e.g., intermediate 11: N -(3-methoxyphenyl)-1-(5-nitropyridin-2-yl)-1 H1-Indole-5-amine) was added to a solution of 10% (wet) Pd / C (0.1 eq) in ethanol (25 mL / mmol). The solution was stirred at RT for 16 h under H2 atmosphere. The reaction mixture was filtered through a diatomaceous earth column and washed with MeOH. The filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using hexane / EtOAc to give the desired indole compound (e.g., Example 3: 1-(5-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -indole-5-amine).

[0427] Method 2

[0428] Use a suitable nitro-substituted intermediate (e.g., intermediate 31). N -(4-Methoxyphenyl)-1-(6-Nitropyridin-2-yl)-1 H A mixture of 1-(6-aminopyridin-2-yl)-indole-5-amine and SnCl2·H2O (4 eq) in EtOAc (12 mL / mmol) was refluxed overnight. After cooling, the reaction mixture was filtered through a short silica gel column. The resulting solution was washed with saturated aqueous sodium bicarbonate solution and extracted with EtOAc (x3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the volatiles were removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography using DCM / MeOH to give the desired indole compound (e.g., Example 14: 1-(6-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -indole-5-amine).

[0429] Example 2

[0430] 1-(5-aminopyridin-2-yl)-N-(p-tolyl)-1 H -Indole-5-amine

[0431]

[0432] Following the general method C, method 1, 1-(5-nitropyridin-2-yl)- N -(p-Tolyl)-1 H Synthesized 5-indoleamine (intermediate 10). The crude product was purified by preparative HPLC (water / ACN containing 0.2% HCOOH, 45%-65%) and separated into a gray solid.

[0433] Yield: 5.8 mg (16%).

[0434] LC-MS [M+H] + : 315.2, Rt = 4.21min (Method-A).

[0435] 1 H NMR (400 MHz, DMSO-d6): δ 7.96 - 7.86 (m, 2H), 7.76 - 7.62 (m, 2H),7.36 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.19 - 7.11 (m, 1H), 7.03- 6.87 (m, 5H), 6.55 - 6.46 (m, 1H), 5.34 (s, 2H), 2.20 (s, 3H).

[0436] Example 3

[0437] 1-(5-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -Indole-5-amine

[0438]

[0439] Following the general method C, method 1, use N -(3-methoxyphenyl)-1-(5-nitropyridin-2-yl)-1 H Synthesis of 5-indole-5-amine (intermediate 11). The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–50%) and separated as a brown solid.

[0440] Yield: 9 mg (34%).

[0441] LC-MS [M+H] + : 331.4, Rt = 10.18min (Method-C).

[0442] 1 H NMR (400 MHz, DMSO-d6): δ 7.94 (d, J = 8.8 Hz, 1H), 7.92 - 7.87 (m,2H), 7.71 (d, J = 3.3 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.15 (dd, J = 8.7, 2.9 Hz, 1H), 7.06 (t, J= 8.1 Hz, 1H), 6.99 (dd, J =8.9, 2.2 Hz, 1H), 6.60 - 6.48 (m, 3H), 6.28 (dd, J = 8.0, 2.4 Hz, 1H), 5.35(s, 2H), 3.68(s, 3H). .

[0443] Example 4

[0444] 1-(5-aminopyridin-2-yl)- N -(m-Tolyl)-1 H -Indole-5-amine

[0445]

[0446] Following the general method C, method 1, 1-(5-nitropyridin-2-yl)- N -(m-Tolyl)-1 H -Indole-5-amine (intermediate 12) was synthesized. The crude product was purified by silica gel column chromatography with hexane / EtOAc (0%-20%), followed by preparative HPLC (10 mM NH4HCO3 (pH 7, using HCOOH) / ACN, 50-70%), and separated as a gray solid.

[0447] Yield: 8 mg (29%).

[0448] LC-MS [M+H] + : 315.2, Rt = 4.19min (Method-A).

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.83 (m, 2H), 7.77 (s, 1H), 7.69(d, J = 3.3 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.13(dd, J = 8.7, 2.9 Hz, 1H), 7.06 - 6.91 (m, 2H), 6.81 - 6.72 (m, 2H), 6.54 -6.46 (m, 2H), 5.33 (s, 2H), 2.19 (s, 3H).

[0450] Example 5

[0451] 1-(5-aminopyridin-2-yl)- N -(3-Methoxyphenyl)- N -Methyl-1 H -Indole-5-amine

[0452]

[0453] Following the general method C, method 1, use N -(3-Methoxyphenyl)- N -Methyl-1-(5-nitropyridin-2-yl)-1 H Synthesis of 5-indole-5-amine (intermediate 31). The reaction was carried out under H2 atmosphere and stirred at RT for 2 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-100%) and separated as a brown solid.

[0454] Yield: 4 mg (11%).

[0455] LC-MS [M+H] + : 345.5, Rt = 11.34min (Method-C).

[0456] 1 H NMR (400 MHz, DMSO-d6): δ 8.02 - 7.96 (m, 1H), 7.92 - 7.89 (m, 1H),7.77 (d, J = 3.3 Hz, 1H), 7.41 - 7.37 (m, 2H), 7.16 (dd, J = 8.6, 2.9 Hz,1H), 7.06 - 6.97 (m, 2H), 6.62 - 6.59 (m, 1H), 6.29 (dd, J = 8.2, 2.4 Hz, 2H), 6.24 (t, J = 2.3 Hz, 1H), 5.39 (s, 2H), 3.64 (s, 3H), 3.26 (s, 3H).

[0457] Example 6

[0458] 1-(6-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -Indole-5-amine

[0459]

[0460] Following the general method C, method 1, use N -(4-Chlorophenyl)-1-(6-nitropyridin-2-yl)-1 H Synthesis of 5-indole-5-amine (intermediate 16). PtO2 (0.1 eq) was used instead of Pd / C 10% (wet), and the reaction was stirred at RT for 3 h under H2 atmosphere. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–50%), followed by preparative HPLC (10 mM NH4HCO3 (pH 7, using HCOOH) / ACN, 60%–80%), and separated as a white solid.

[0461] Yield: 17 mg (39%).

[0462] LC-MS [M+H] + : 335.2 / 337.1, Rt = 4.65min (Method-A).

[0463] 1 H NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 8.9 Hz, 1H), 8.09 (s, 1H), 7.86 (d, J = 3.5 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H),7.22 - 7.15 (m, 2H), 7.01 - 6.95 (m, 3H), 6.75 (d, J = 7.7 Hz, 1H), 6.60 -6.55 (m, 1H), 6.30 (d, J = 8.0 Hz, 1H), 6.21 (s, 2H).

[0464] Example 7

[0465] 1-(6-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -Indole-5-amine

[0466]

[0467] Following the general method C, method 1, use N -(3-Methoxyphenyl)-1-(6-Nitropyridin-2-yl)-1 HSynthesis of 5-indole-5-amine (intermediate 17). The reaction was carried out under H2 atmosphere and stirred at RT for 3 h. The crude product was purified by silica gel column chromatography with hexane / EtOAc (0%-50%), followed by reversed-phase rapid column chromatography (C18, HCOONH4 (aq) 10mM (pH 4) / ACN 0%-100%), and separated into an off-white solid.

[0468] Yield: 52 mg (44%).

[0469] LC-MS [M+H] + : 331.1, Rt = 11.00min (Method-C).

[0470] 1 H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 8.8 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J = 3.4 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.07 (t, J = 8.1 Hz, 1H), 7.00 (dd, J = 8.9, 2.2 Hz, 1H), 6.75 (d, J = 7.3Hz, 1H), 6.62 - 6.56 (m, 2H), 6.54 (t, J = 2.2 Hz, 1H), 6.33 - 6.27 (m, 2H), 6.21 (s, 2H), 3.69 (s, 3H).

[0471] Example 8

[0472] 1-(5-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-4-amine

[0473]

[0474] Following the general method C, method 1, use N -(4-methoxyphenyl)-1-(5-nitropyridin-2-yl)-1 HSynthesis of 4-indole-18 (intermediate 18). The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–100%) and separated as a brown solid.

[0475] Yield: 7 mg (19%).

[0476] LC-MS [M+H] + : 331.1, Rt = 10.32min (Method-C).

[0477] 1 H NMR (400 MHz, DMSO-d6): δ 7.90 (dt, J = 2.9, 0.7 Hz, 1H), 7.75 (s,1H), 7.58 (d, J = 3.5 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.18 - 7.10 (m, 3H), 6.97(t, J = 8.0 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.79 (dt, J = 3.4, 0.8 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 5.38 (s, 2H), 3.73 (s, 3H).

[0478] Example 9

[0479] 1-(5-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -Indole-4-amine

[0480]

[0481] Following the general method C, method 1, use N -(4-Chlorophenyl)-1-(5-Nitropyridin-2-yl)-1 H -Indole-4-amine (intermediate 19) was synthesized. PtO2 (0.1 eq) was used instead of Pd / C 10% (wet). The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–100%) and separated into a brown solid.

[0482] Yield: 25 mg (30%).

[0483] LC-MS [M+H] + : 335.1 / 337.0, Rt = 11.35min (Method-C).

[0484] 1 H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.91 (dd, J = 2.9, 0.7 Hz, 1H), 7.64 (d, J = 3.4 Hz, 1H), 7.53 (dt, J = 8.3, 0.8 Hz, 1H), 7.36 (dd, J =8.6, 0.7 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.16 (dd, J = 8.6, 2.9 Hz, 1H), 7.13 -7.04 (m, 3H), 6.90 (d, J = 7.6 Hz, 1H), 6.68 (dt, J = 3.5, 0.7 Hz, 1H), 5.41(s, 2H).

[0485] Example 10

[0486] 1-(6-aminopyridin-2-yl)- N -(p-Tolyl)-1 H -Indole-4-amine

[0487]

[0488] Following the general method C, method 1, 1-(6-nitropyridin-2-yl)- N -(p-Tolyl)-1 H Synthesis of 4-indole-indoleamine (intermediate 24). The reaction was carried out under H2 atmosphere and stirred at RT for 3 h. The crude product was purified by silica gel column chromatography with hexane / EtOAc (0%-40%), followed by reversed-phase rapid column chromatography (C18, NH4OAc (aq) 10 mM (pH 7) / ACN 60%-75%), and separated into an off-white solid.

[0489] Yield: 24 mg (29%).

[0490] LC-MS [M+H] + : 315.4, Rt = 11.76min (Method-C).

[0491] 1H NMR (400 MHz, DMSO-d6): δ 7.90 (s, 1H), 7.83 (dt, J = 8.3, 0.8 Hz, 1H), 7.74 (d, J = 3.6 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.06 (s, 4H), 7.03(d, J = 8.0 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.80 (dd, J = 3.5, 0.8 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 6.21 (s, 2H), 2.24 (s, 3H).

[0492] Example 11

[0493] 1-(6-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -Indole-4-amine

[0494]

[0495] Following the general method C, method 1, use N -(4-Chlorophenyl)-1-(6-nitropyridin-2-yl)-1 H Synthesis of 4-indole-2-amine (intermediate 25). PtO2 (0.2 eq) was used instead of Pd / C 10% (wet), and the reaction was stirred at RT for 2 h under H2 atmosphere. The crude product was purified by silica gel column chromatography with hexane / EtOAc (0%–50%), followed by reversed-phase rapid column chromatography (C18, NH4OAc (aq) 10 mM (pH 7) / ACN 60%–80%), and separated as a gray solid.

[0496] Yield: 17 mg (15%).

[0497] LC-MS [M+H] + : 335.1, Rt = 12.01min (Method-C).

[0498] 1 H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.95 (dt,J = 8.4, 0.8 Hz, 1H), 7.78 (d, J = 3.5 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.27 - 7.21 (m, 2H), 7.13- 7.06 (m, 3H), 6.93 (d, J = 7.7 Hz, 1H), 6.79 - 6.69 (m, 2H), 6.34 (dd, J =8.1, 0.6 Hz, 1H), 6.23 (s, 2H).

[0499] Example 12

[0500] 1-(5-aminopyridin-2-yl)- N -(4-methoxyphenyl)-3-methyl-1 H -Indole-5-amine

[0501]

[0502] Following the general method C, method 1, use N -(4-methoxyphenyl)-3-methyl-1-(5-nitropyridin-2-yl)-1 H Synthesis of 5-indole-5-amine (intermediate 26). The reaction was carried out under H2 atmosphere and stirred at RT for 3 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-70%) and separated into a light brown solid.

[0503] Yield: 30 mg (64%).

[0504] LC-MS [M+H] + : 345.4, Rt = 10.57min (Method-C).

[0505] 1 H NMR (400 MHz, DMSO-d6): δ 7.92 (d, J = 8.5 Hz, 1H), 7.86 (dd, J =2.9, 0.7 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 1.2 Hz, 1H), 7.30 (d, J = 8.4Hz, 1H), 7.14 - 7.09 (m, 2H), 7.01 - 6.96 (m, 2H), 6.90 (dd, J= 8.9, 2.2 Hz,1H), 6.86 - 6.79 (m, 2H), 5.25 (s, 2H), 3.69 (s, 3H), 2.22 (d, J = 1.2 Hz, 3H).

[0506] Example 13

[0507] 1-(5-aminopyridin-2-yl)- N -(4-methoxyphenyl)-2-methyl-1 H -Indole-5-amine

[0508]

[0509] Following the general method C, method 1, use N -(4-methoxyphenyl)-2-methyl-1-(5-nitropyridin-2-yl)-1 H Synthesis of 5-indole-5-amine (intermediate 27). The reaction was carried out under H2 atmosphere and stirred at RT for 3 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-60%) and separated into an off-white solid.

[0510] Yield: 54 mg (62%).

[0511] LC-MS [M+H] + : 345.5, Rt = 10.24min (Method-C).

[0512] 1 H NMR (400 MHz, DMSO-d6): δ 7.96 - 7.90 (m, 1H), 7.43 (s, 1H), 7.18 -7.10 (m, 2H), 7.07 (d, J = 2.1 Hz, 1H), 6.98 (dd, J = 8.7, 0.7 Hz, 1H), 6.96- 6.89 (m, 2H), 6.84 - 6.77 (m, 2H), 6.74 (dd, J = 8.7, 2.1 Hz, 1H), 6.19 (d, J = 0.8 Hz, 1H), 5.54 (s, 2H), 3.69 - 3.66 (m, 3H), 2.28 - 2.24 (m, 3H).

[0513] Example 14

[0514] 1-(6-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-5-amine

[0515]

[0516] Following the general method C, method 2, use N -(4-Methoxyphenyl)-1-(6-Nitropyridin-2-yl)-1 H Synthesis of 5-indole-5-amine (intermediate 28). The crude product was purified by silica gel column chromatography using DCM / MeOH (0%-20%) and separated into a pale brown solid.

[0517] Yield: 8.2 mg (8%).

[0518] 1 H NMR (400 MHz, MeOD): δ 8.08 - 8.03 (m, 1H), 7.65 (d, J = 3.4 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.22 - 7.19 (m, 1H), 7.04 - 6.98 (m, 2H), 6.95(dd, J = 8.9, 2.3 Hz, 1H), 6.84 - 6.80 (m, 2H), 6.75 (dd, J = 7.7, 0.6 Hz, 1H), 6.49 (dd, J = 3.5, 0.8 Hz, 1H), 6.40 (dd, J = 8.1, 0.6 Hz, 1H), 3.76 (s, 3H).

[0519] Example 15

[0520] 1-(6-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-4-amine

[0521]

[0522] Following the general method C, method 2, use N -(4-Methoxyphenyl)-1-(6-Nitropyridin-2-yl)-1 H Synthesis of 4-indole-indole (intermediate 29). The crude product was purified by silica gel column chromatography using DCM / MeOH (0%-20%) and separated into a yellow solid.

[0523] Yield: 23 mg (15%).

[0524] 1 H NMR (400 MHz, MeOD): δ 7.61 - 7.53 (m, 3H), 7.14 - 7.09 (m, 2H),7.04 (t, J = 8.0 Hz, 1H), 6.89 - 6.83 (m, 2H), 6.80 - 6.70 (m, 3H), 6.44 (dd, J = 8.1, 0.6 Hz, 1H), 3.78 (s, 3H).

[0525] Example 16

[0526] 1-(5-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-5-amine

[0527]

[0528] Following the general method C, method 2, use N -(4-methoxyphenyl)-1-(5-nitropyridin-2-yl)-1 H Synthesis of 5-indole-5-amine (intermediate 30). The crude product was purified by silica gel column chromatography using DCM / MeOH (0%-20%) and separated into a light brown solid.

[0529] Yield: 21 mg (18%).

[0530] 1 H NMR (400 MHz, MeOD): δ 7.95 (dd, J = 2.8, 0.8 Hz, 1H), 7.70 - 7.65(m, 1H), 7.50 (d, J = 3.3 Hz, 1H), 7.32 (dd, J = 8.6, 0.8 Hz, 1H), 7.27 (dd, J = 8.6, 2.8 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.02 - 6.97 (m, 2H), 6.93(dd, J= 8.8, 2.2 Hz, 1H), 6.84 - 6.77 (m, 2H), 6.48 (dd, J = 3.3, 0.8 Hz, 1H), 3.75 (s, 3H).

[0531] General Method D

[0532]

[0533] Use a suitable carbamate (e.g., intermediate 13: (6-(5-((4-chlorophenyl)amino)-1) H A solution of 1-(5-aminopyridin-2-yl)-indole-1-yl)pyridin-3-yl)tert-butyl carbamate in 4M HCl in dioxane (6 mL / mmol) was stirred at RT for 5 h. Crude volatiles were removed under reduced pressure. Then, saturated aqueous sodium bicarbonate solution and EtOAc were added, and the mixture was stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (x3). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, water, and brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography using hexane / EtOAc to obtain the desired indole product (e.g., Example 17: 1-(5-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -indole-5-amine).

[0534] Example 17

[0535] 1-(5-aminopyridin-2-yl)-N-(4-chlorophenyl)-1 H -Indole-5-amine

[0536]

[0537] Following general method D, (6-(5-((4-chlorophenyl)amino)-1 H The product was synthesized from tert-butyl carbamate (intermediate 13) 1-indol-1-yl)pyridin-3-yl)carbamate. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–100%) and separated into a brown solid.

[0538] Yield: 24 mg (48%).

[0539] LC-MS [M+H] + : 335.1 / 337.0, Rt = 11.19 min (Method-C).

[0540] 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.99 - 7.93 (m, 1H), 7.89(dd, J = 2.9, 0.7 Hz, 1H), 7.72 (d, J = 3.3 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.21 - 7.11 (m, 3H), 7.00 - 6.92 (m, 3H), 6.55 (dd, J = 3.3, 0.8 Hz, 1H), 5.36 (s, 2H).

[0541] Example 18

[0542] 1-(5-aminopyridin-2-yl)- N -(3-Chlorophenyl)-1 H -Indole-5-amine

[0543]

[0544] Following general method D, (6-(5-((3-chlorophenyl)amino)-1 H Synthesized from 1-indolyl)pyridinyl)tert-butyl carbamate (intermediate 14). The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–100%) and separated as a brown solid.

[0545] Yield: 13 mg (42%).

[0546] LC-MS [M+H] + : 335.1 / 337.0, Rt = 11.19min (Method-C).

[0547] 1 H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 2.9, 0.6 Hz, 1H), 7.74 (d, J = 3.3 Hz, 1H), 7.40 - 7.33 (m,2H), 7.18 - 7.12 (m, 2H), 7.00 (dd, J= 8.8, 2.2 Hz, 1H), 6.90 - 6.85 (m,2H), 6.70 - 6.65 (m, 1H), 6.58 (dd, J = 3.3, 0.8 Hz, 1H), 5.37 (s, 2H).

[0548] Example 19

[0549] 4-((1-(5-aminopyridin-2-yl)-1 H -indol-5-yl)amino)benzonitrile

[0550]

[0551] Following general method D, (6-(5-((4-cyanophenyl)amino)-1 H 1-Indol-1-yl)pyridin-3-yl)tert-butyl carbamate (intermediate 15) was synthesized. The crude product was purified by preparative HPLC (10 mM NH4HCO3 (pH 7, using HCOOH) / ACN, 40%-55%) and separated into a white solid.

[0552] Yield: 7 mg (23%).

[0553] LC-MS [M+H] + : 326.2, Rt = 3.67min (Method-A).

[0554] 1 H NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.77 (d, J = 3.3 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.44- 7.36 (m, 2H), 7.16 (dd, J = 8.6, 2.9 Hz, 1H), 7.04 (dd, J = 8.8, 2.2 Hz, 1H), 6.99 - 6.92 (m, 2H), 6.63 - 6.58 (m, 1H), 5.39 (s, 2H).

[0555] Example 20

[0556] 1-(5-aminopyridin-2-yl)-N-(p-tolyl)-1H -Indole-4-amine

[0557]

[0558] Following general method D, (6-(4-(p-tolylamino)-1 H The product was synthesized from tert-butyl carbamate (indol-1-yl)pyridin-3-yl)carbamate (intermediate 20). The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–100%) and separated into a brown solid.

[0559] Yield: 13 mg (45%).

[0560] LC-MS [M+H] + : 315.1, Rt = 11.13min (Method-C).

[0561] 1 H NMR (400 MHz, DMSO-d6): δ 7.91 - 7.87 (m, 2H), 7.60 (d, J = 3.4 Hz, 1H), 7.41 (dt, J = 8.2, 0.8 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.15 (dd, J =8.6, 2.9 Hz, 1H), 7.06 (s, 4H), 7.01 (t, J = 8.0 Hz, 1H), 6.82 (d, J = 7.2Hz, 1H), 6.76 (dd, J = 3.5, 0.8 Hz, 1H), 5.39 (s, 2H), 2.24 (s, 3H).

[0562] Example 21

[0563] 1-(5-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -Indole-4-amine

[0564]

[0565] Following general method D, (6-(4-((3-methoxyphenyl)amino)-1 HSynthesized from tert-butyl (-indol-1-yl)pyridin-3-yl)carbamate (intermediate 21). The reaction mixture was stirred at RT for 16 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%–20%) and separated as a brown solid.

[0566] Yield: 46 mg (50%).

[0567] LC-MS [M+H] + : 331.4, Rt = 10.35min (Method-C).

[0568] 1 H NMR (400 MHz, DMSO-d6): δ 8.06 (s, 1H), 7.90 (dd, J = 2.9, 0.7 Hz, 1H), 7.63 (d, J = 3.4 Hz, 1H), 7.49 (dt, J = 8.3, 0.8 Hz, 1H), 7.36 (d, J =8.6 Hz, 1H), 7.19 - 7.02 (m, 3H), 6.93 (d, J = 7.3 Hz, 1H), 6.76 - 6.66 (m,3H), 6.39 (ddd, J = 8.2, 2.5, 0.9 Hz, 1H), 5.40 (s, 2H), 3.70 (s, 3H).

[0569] Example 22

[0570] 1-(5-aminopyridin-2-yl)- N -(m-Tolyl)-1 H -Indole-4-amine

[0571]

[0572] Following general method D, (6-(4-(m-tolylamino)-1 H Synthesized from 1-indolyl)pyridinyl)tert-butyl carbamate (intermediate 22). The reaction mixture was stirred at RT for 16 h. The crude product was purified by silica gel column chromatography using hexane / EtOAc (0%-100%) and separated as a brown solid.

[0573] Yield: 50 mg (55%).

[0574] LC-MS [M+H] +: 315.4, Rt = 10.98min (Method-C).

[0575] 1 H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.91 (dt, J = 2.9, 0.6 Hz, 1H), 7.61 (d, J = 3.4 Hz, 1H), 7.46 (dt, J = 8.3, 0.8 Hz, 1H), 7.36 (dd, J =8.6, 0.7 Hz, 1H), 7.16 (ddd, J = 8.6, 2.9, 0.6 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.98 - 6.87 (m, 3H), 6.74 (dt, J = 3.4, 0.7Hz, 1H), 6.67 - 6.61 (m, 1H), 5.40 (s, 2H), 2.25 (s, 3H).

[0576] Example 23

[0577] 1-(5-aminopyridin-2-yl)- N -(3-Chlorophenyl)-1 H -Indole-4-amine

[0578]

[0579] Following general method D, (6-(4-((3-chlorophenyl)amino)-1 H Synthesized from tert-butyl (-indol-1-yl)pyridin-3-yl)carbamate (intermediate 23). The reaction mixture was stirred at RT for 16 h. The crude product was purified by silica gel column chromatography with hexane / EtOAc (0%-50%), followed by reversed-phase rapid column chromatography (C18, NH4OAc (aq) 10 mM (pH 7) / ACN 0%-100%), and separated as a brown solid.

[0580] Yield: 14 mg (17%).

[0581] LC-MS [M+H] +: 335.0 / 336.8, Rt = 11.27min (Method-C).

[0582] 1 H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1H), 7.91 (dd, J = 2.9, 0.7 Hz, 1H), 7.66 (d, J = 3.4 Hz, 1H), 7.58 (dt, J = 8.3, 0.9 Hz, 1H), 7.37 (d, J =8.6 Hz, 1H), 7.24 - 7.08 (m, 3H), 7.06 - 7.00 (m, 2H), 6.94 (d, J = 6.9 Hz, 1H), 6.78 (ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 6.65 (dd, J = 3.4, 0.8 Hz, 1H), 5.41 (s, 2H).

[0583] Bioassay

[0584] The ability of certain compounds disclosed herein to reduce the accumulation of GM1 gangliosides in p.R60H / p.R60H-β-Gal canine fibroblasts was evaluated in the following manner.

[0585] Cell culture, transfection and compound applications

[0586] WT β-Gal (ref. SV-2025-V04, STEMNOVATE) and p.R60H / p.R60H-β-Gal canine fibroblasts (ref. GM11473, Coriell) were cultured in DMEM medium (ref. 11574486, Gibco) containing 10% FCS (ref. 10500, Gibco) and 1% penicillin / streptomycin (P / S) (10,000 µg / mL) (ref. 15140122, Gibco) in 96-well plates (ref. 89626, IBIDI) at 37°C and 5% CO2. Forty-eight hours after inoculation, 0.1 mg / mL of exogenous GM1 bovine ganglioside (ref. G7641, Sigma Aldrich) was added. Two days later, the test compound (or DMSO as a control) was added to the culture at the specified concentration and cultured for four consecutive days. The culture was then fixed in PBS with 4% paraformaldehyde (ref. 15710, ElectronMicroscopy Sciences) at RT for 15 min.

[0587] Immunocytochemistry and Microscopic Imaging

[0588] Canine fibroblasts were permeabilized for 15 min at RT with PBS containing 0.3% Triton X-100 (ref. T8787, Sigma-Aldrich). Cytoplasmic labeling was performed for 15 min at RT using HCS CellMask (ThermoFisher Scientific) (Table S2). Subsequently, fibroblasts were blocked for 1 h at RT with PBS containing 0.5% bovine serum albumin (BSA, ref. A9647, Sigma-Aldrich) and 10% normal donkey serum (ref. S30, EMD Millipore). Antibody was diluted with PBS + 0.5% BSA and incubated overnight at 4°C with the primary antibody against ganglioside GM1 (Abcam). The cells were incubated for 1 h at RT using Alexa Fluor® 488 donkey anti-rabbit IgG (Invitrogen) as the secondary antibody. Nuclei were counterstained with DAPI (ThermoFisher Scientific) in PBS at RT for 10 min.

[0589] Cells were imaged using a LIPSI Nikon microscope equipped with a 40x objective lens (NA=1.15). Twenty-five images were acquired per channel per well, with a 10% overlap (5×5 squares) and a frame size of 2048×2048 pixels. Images were analyzed using NIS software. Cellular regions were delineated using Cell Mask staining, and nuclei were delineated using DAPI. The area of ​​green dots (GM1 gangliosides) within the cytoplasm (excluding the nucleus) was determined. The ratio of the GM1 ganglioside area to the total cell area was calculated to account for differences in cell size. Furthermore, only cells with nuclei were included in the analysis.

[0590] Some of the compounds disclosed herein can reduce the accumulation of GM1 gangliosides in p.R60H / p.R60H-β-Gal canine fibroblasts at concentrations of 1.56 µM and 0.05 µM, with the following effects:

[0591] A reduction of >90% compared to untreated samples is denoted as A;

[0592] Compared to untreated samples, the reduction is between 70% and 90%, denoted as B;

[0593] A reduction of less than 70% compared to untreated samples is denoted as C.

[0594] Table 2 below shows the percentage reduction of GM1 gangliosides in Examples 1-23 at 1.56 µM and 0.05 µM.

[0595] Table 2

[0596]

[0597] This disclosure also relates to the following specific implementation schemes, where [1] represents the first implementation scheme, [2] represents the second implementation scheme, and so on:

[0598] [1] Compound of formula (I):

[0599] (I)

[0600] Or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0601] A1, A2, and A3 are each independently N or CH, provided that one of A1, A2, and A3 is N, and two of A1, A2, and A3 are CH.

[0602] R1, R2, and R5 are each independently selected from hydrogen, halogens, -ORa, and -C. 1-4Alkyl, -C 3-6 cycloalkyl and -(5- to 10-membered)-C 3-7 Heterocyclic groups, wherein the -C 1-4 Alkyl, -C 3-6 cycloalkyl and -(5- to 10-membered)-C 3-7 The heterocyclic group is optionally substituted by one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-;

[0603] Ra is -C 1-4 Alkyl groups, which are optionally substituted with one, two or three halogen atoms;

[0604] R 3a It is -NR6R7, where

[0605] R6 is hydrogen or -C 1-4 Alkyl, and

[0606] R7 is selected from hydrogen, -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-;

[0607] R 3b Selected from hydrogen, halogens and C 1-4 alkyl;

[0608] R4 is -NR8R9, where

[0609] R8 is hydrogen or -C 1-4 Alkyl, and

[0610] R9 is selected from -C 6-10 Aryl and -(5- to 10-yuan)-C 1-9 Heteroaryl, wherein the -C 6-10 Aryl and -(5- to 10-yuan)-C 1-9The heteroaryl group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl; and

[0611] Rb and Rc are each independently selected from hydrogen and C, which are optionally substituted with 1, 2, or 3 halogen atoms. 1-4 alkyl;

[0612] R 3a R 3b R4 and R5 each replace a ring that would originally exist in equation (I), R 3a R 3b Hydrogen atoms at any position connected to R4 and R5.

[0613] [2] [1] compounds, wherein the compounds have the structure of formula (II):

[0614] (II)

[0615] Or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R 3a R 3b R4 and R5 are as defined in [1].

[0616] [3] [1] compounds, wherein the compounds have the structure of formula (III):

[0617] (III)

[0618] Or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R 3a R 3b R4 and R5 are as defined in [1].

[0619] [4] [1] compounds, wherein the compounds have the structure of formula (IV):

[0620] (IV)

[0621] Or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R 3a R 3b R4 and R5 are as defined in [1].

[0622] [5] The compound of any one of [1]-[4] and its pharmaceutically acceptable salt and solvate, wherein R4 is attached to the 4 position of the indole ring.

[0623] [6] The compound of any one of [1]-[4] and its pharmaceutically acceptable salt and solvate, wherein R4 is attached to the 5 position of the indole ring.

[0624] [7] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[6], wherein R1, R2 and R5 are each independently selected from hydrogen, halogen, -C 1-4 Alkoxy and -C 1-4 Alkyl, wherein the -C 1-4 The alkyl group is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

[0625] [8] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[7], wherein R1, R2 and R5 are each independently selected from hydrogen, halogen and -C 1-2 alkyl.

[0626] [9] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[8], wherein R6 is hydrogen and R 3a It is -NHR7, where R7 is as defined in [1].

[0627]

[10] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[9], wherein R6 and R7 are both hydrogen and R 3a It is -NH2.

[0628]

[11] A compound or a pharmaceutically acceptable salt or solvate thereof from any of [1]-[8], wherein R6 is -C 1-4 Alkyl and R 3a -N(C) 1-4 Alkyl)R7, wherein R7 is as defined in [1].

[0629]

[12] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[9] or

[11] , wherein R7 is selected from -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-.

[0630]

[13] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-[9],

[11] or

[12] , wherein R7 is -C 1-4 Alkyl group, optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from halogen, hydroxyl, -C 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

[0631]

[14] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-[9],

[11] or

[12] , wherein R7 is -C 3-10 Cycloalkyl group, optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, hydroxyl, -C 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

[0632]

[15] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-[9],

[11] or

[12] , wherein R7 is -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

[0633]

[16] A compound of any one of [1]-

[15] or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is hydrogen and R4 is -NHR9, wherein R9 is as defined in [1].

[0634]

[17] A compound or a pharmaceutically acceptable salt or solvate thereof from any of [1]-

[15] , wherein R8 is -C 1-4 Alkyl and R4 is -N(C) 1-4 Alkyl)R9, wherein R9 is as defined in [1].

[0635]

[18] A compound or a pharmaceutically acceptable salt or solvate thereof from any of [1]-

[17] , wherein R9 is -C 6-10 The aryl group, optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

[0636]

[19] A compound of any one of [1]-

[18] or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is an unsubstituted phenyl or a phenyl substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2 and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-2 alkyl.

[0637]

[20] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-

[19] , wherein R9 is a phenyl group substituted with one or two substituents, each substituent being independently selected from halogens, -CN, -OH, -O(C 1-2 )alkyl, unsubstituted -C 1-4 Alkyl groups and -C atoms substituted with 1, 2, or 3 halogen atoms1-4 alkyl.

[0638]

[21] A compound or a pharmaceutically acceptable salt or solvate thereof from any of [1]-

[17] , wherein R9 is -(5- to 10-benzene)-C 1-9 Heteroaryl, wherein the -(5- to 10-aryl)-C 1-9 The heteroaryl group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl group; and Rb and Rc are each independently selected from hydrogen and -C, optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

[0639]

[22] A compound or a pharmaceutically acceptable salt or solvate thereof from any of [1]-

[21] , wherein R 3b It is hydrogen.

[0640]

[23] [1] compounds, selected from:

[0641] 1-(5-(dimethylamino)pyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-5-amine;

[0642] 1-(5-aminopyridin-2-yl)-N-(p-tolyl)-1 H -Indole-5-amine;

[0643] 1-(5-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -Indole-5-amine;

[0644] 1-(5-aminopyridin-2-yl)- N -(m-Tolyl)-1 H -Indole-5-amine;

[0645] 1-(5-aminopyridin-2-yl)- N -(3-methoxyphenyl)-N-methyl-1 H -Indole-5-amine;

[0646] 1-(6-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -Indole-5-amine;

[0647] 1-(6-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -Indole-5-amine;

[0648] 1-(5-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-4-amine;

[0649] 1-(5-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -Indole-4-amine;

[0650] 1-(6-aminopyridin-2-yl)- N -(p-Tolyl)-1 H -Indole-4-amine;

[0651] 1-(6-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -Indole-4-amine;

[0652] 1-(5-aminopyridin-2-yl)- N -(4-methoxyphenyl)-3-methyl-1 H -Indole-5-amine;

[0653] 1-(5-aminopyridin-2-yl)- N -(4-methoxyphenyl)-2-methyl-1 H -Indole-5-amine;

[0654] 1-(6-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-5-amine;

[0655] 1-(6-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-4-amine;

[0656] 1-(5-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-5-amine;

[0657] 1-(5-aminopyridin-2-yl)-N-(4-chlorophenyl)-1 H -Indole-5-amine;

[0658] 1-(5-aminopyridin-2-yl)- N -(3-Chlorophenyl)-1 H-Indole-5-amine;

[0659] 4-((1-(5-aminopyridin-2-yl)-1 H -indol-5-yl)amino)benzonitrile;

[0660] 1-(5-aminopyridin-2-yl)-N-(p-tolyl)-1 H -Indole-4-amine;

[0661] 1-(5-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -Indole-4-amine;

[0662] 1-(5-aminopyridin-2-yl)- N -(m-Tolyl)-1 H -indole-4-amine; and

[0663] 1-(5-aminopyridin-2-yl)- N -(3-Chlorophenyl)-1 H -Indole-4-amine,

[0664] Or its pharmaceutically acceptable salts or solvates.

[0665]

[24] A pharmaceutical composition comprising a compound of any one of [1]-

[23] or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

[0666]

[25] A method of treating or preventing a patient’s condition associated with altered GLB1 activity, comprising administering to a patient in need an effective amount of any of the compounds of [1]-

[23] or a pharmaceutically acceptable salt or solvate thereof.

[0667]

[26] A method of treating or preventing GM1 ganglioside storage disease or Mochio syndrome type B, comprising administering to a patient in need an effective amount of any of the compounds of [1]-

[23] or a pharmaceutically acceptable salt or solvate thereof.

[0668]

[27]

[26] The method further includes administering an effective amount of enzyme for enzyme replacement therapy to the patient.

[0669]

[28]

[27] method, wherein the enzyme is β-galactosidase or an analogue thereof.

[0670] The method of any one of

[29]

[26] -

[28] further includes administering a small molecule molecular chaperone to the patient.

[0671]

[30]

[29] 's method, wherein the small molecule chaperone competitively binds to the enzyme.

[0672] The method of

[31] ,

[29] or

[30] , wherein the small molecule chaperone is selected from iminoglycosides, imino sugars, amino sugars, thiophene glycosides, glycosidases, sulfatases, glycosyltransferases, phosphoesterases and peptidase inhibitors.

[0673] The method of any one of

[32]

[26] -

[31] , wherein the small molecule chaperone is selected from 1-deoxygalactosinosin (DGJ), N-nonyldeoxygalactosin (NN-DNJ), N-butyldeoxygalactosinosin (NB-DGJ), galactose, fluoroiminotol and episifagmine.

[0674]

[33] A method for increasing the β-galactosidase activity of a patient in need, comprising administering to the patient an effective amount of a compound as defined in [1]-

[23] or a pharmaceutically acceptable salt or solvate thereof.

[0675]

[34] A compound of any one of [1]-

[23] or a pharmaceutically acceptable salt or solvate thereof, used as a medicine.

[0676]

[35] A compound of any one of [1]-

[23] or a pharmaceutically acceptable salt or solvate thereof, used for the prevention or treatment of conditions associated with altered GLB1 activity.

[0677]

[36]

[35] The use of compounds, wherein the condition associated with altered GLB1 activity is selected from GM1 ganglioside storage disease and Mochio syndrome type B.

[0678]

[37] Use of any compound of any one of [1]-

[23] or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the prevention or treatment of a condition associated with altered GLB1 activity.

[0679]

[38]

[37] uses of compounds, wherein the condition associated with altered GLB1 activity is selected from GM1 ganglioside storage disease and Mochio syndrome type B.

[0680]

[39] A pharmaceutical composition comprising a compound as defined in any one of [1]-

[23] or a pharmaceutically acceptable salt or solvate thereof, for the prevention or treatment of a condition associated with altered GLB1 activity.

[0681]

[40]

[39] The pharmaceutical composition for use in which the condition associated with altered GLB1 activity is selected from GM1 ganglioside storage disease and Mochio syndrome type B.

[0682]

[41] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[6] or [9]-

[22] , wherein R1, R2 and R5 are each independently selected from hydrogen, halogen, -ORa, -C 1-4 Alkyl and -C 3-6 cycloalkyl, wherein the -C 1-4 Alkyl and -C 3-6 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-, wherein Ra is a -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

[0683]

[42] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-

[22] or

[41] , wherein R5 is hydrogen and R1 and R2 are each independently selected from hydrogen, halogen and unsubstituted -C 1-2 alkyl.

[0684]

[43] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-

[22] ,

[41] or

[42] , wherein R1 and R5 are each hydrogen and R2 is an unsubstituted -C 1-2 alkyl.

[0685]

[44] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-

[22] or

[41] -

[43] , wherein R2 and R5 are each hydrogen and R1 is an unsubstituted -C 1-2 alkyl.

[0686]

[45] A compound of any one of [1]-

[22] or

[41] -

[44] or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2 and R5 are each hydrogen.

[0687]

[46] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[9],

[12] ,

[13] ,

[16] -

[22] or

[41] -

[45] , wherein R 3a It is -NHR7, where R7 is -C 1-4 alkyl.

[0688]

[47] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-[8],

[11] -

[13] ,

[16] -

[22] or

[41] -

[45] , wherein R 3a -N(C) 1-2 Alkyl)R7, wherein R7 is -C 1-4 alkyl.

[0689]

[48] ​​

[46] or

[47] of a compound or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is methyl or ethyl.

[0690]

[49] Compounds of [1]-[8],

[11] -

[22] or

[41] -

[45] or pharmaceutically acceptable salts or solvates thereof, wherein R6 is methyl.

[0691]

[50] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-[9],

[11] -

[13] ,

[16] -

[22] or

[41] -

[45] , wherein R7 is -C 1-4 Alkyl group, which is substituted with one or two substituents, each substituent being independently selected from halogen, hydroxyl, -C 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

[0692]

[51]

[50] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -C 1-2 Alkyl group, which is substituted with one or two substituents, each substituent being independently selected from halogen, hydroxyl, -C 1-2 Alkoxy, monohalogenated (C 1-2 )alkyl-, dihalogenated (C 1-2 )alkyl-, trihalogenated (C 1-2 )alkyl-, monohalogenated (C 1-2 )alkoxy-, dihalo (C 1-2 )alkoxy- and trihalo (C 1-2 )alkoxy-.

[0693]

[52] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[9],

[11] ,

[12] ,

[14] ,

[16] -

[22] or

[41] -

[45] , wherein R7 is an unsubstituted -C 3-10 Cycloalkyl.

[0694]

[53]

[52] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R7 is an unsubstituted -C 3-6 Cycloalkyl.

[0695]

[54] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[9],

[11] ,

[12] ,

[14] ,

[16] -

[22] or

[41] -

[45] , wherein R7 is -C 3-10 Cycloalkyl groups, which are substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

[0696]

[55]

[54] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -C 3-6 Cycloalkyl groups, which are substituted with one or two substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-2 Alkoxy, monohalogenated (C 1-2 )alkyl-, dihalogenated (C 1-2 )alkyl-, trihalogenated (C 1-2 )alkyl-, monohalogenated (C 1-2 )alkoxy-, dihalo (C 1-2 )alkoxy- and trihalo (C 1-2 )alkoxy-.

[0697]

[56] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[9],

[11] ,

[12] ,

[15] -

[22] or

[41] -

[45] , wherein R7 is an unsubstituted -C 1-2 Alkyl-C 3-6 Cycloalkyl.

[0698]

[57] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-[9],

[11] ,

[12] ,

[15] -

[22] or

[41] -

[45] , wherein R7 is -C 1-4 Alkyl-C 3-10 Cycloalkyl groups, which are substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

[0699]

[58]

[57] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -C 1-2 Alkyl-C 3-6 Cycloalkyl groups, which are substituted with one or two substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-2 Alkoxy, monohalogenated (C 1-2 )alkyl-, dihalogenated (C 1-2 )alkyl-, trihalogenated (C 1-2 )alkyl-, monohalogenated (C 1-2 )alkoxy-, dihalo (C 1-2 )alkoxy- and trihalo (C 1-2 )alkoxy-.

[0700]

[59] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-[8],

[11] -

[13] ,

[16] -

[22] or

[41] -

[45] , wherein R6 and R7 are each -C 1-4 Alkyl and R 3a -N(C) 1-4 Alkyl)2.

[0701]

[60]

[59] compounds or their pharmaceutically acceptable salts or solvates, wherein R 3a -N(C) 1-2 Alkyl)2.

[0702]

[61]

[59] or

[60] of a compound or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is -N(CH3)2.

[0703]

[62] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-

[13] ,

[16] -

[22] or

[41] -

[46] , wherein R 3a It can be -NH2, -NH(CH3) or -N(CH3)2.

[0704]

[63] A compound of any one of [1]-

[15] ,

[17] -

[22] or

[41] -

[62] or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is methyl or ethyl.

[0705]

[64]

[63] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R8 is methyl.

[0706]

[65] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-

[18] ,

[22] or

[41] -

[64] , wherein R9 is -C 6-10 Aryl group, which is substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

[0707]

[66] A compound of any one of [1]-

[19] ,

[22] or

[41] -

[65] , or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is a phenyl group substituted with one, two or three substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2 and -C which is optionally substituted with one, two or three halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-2 alkyl.

[0708]

[67] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-

[19] ,

[22] or

[41] -

[66] , wherein R9 is Where m is 1 or 2 and R 10 Selected from halogens, -CN, -OH, -C 1-4 Alkyl and -C 1-4 Alkyl group.

[0709]

[68] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-

[19] ,

[22] or

[41] -

[67] , wherein R9 is R 9a : or R 9b : , where R 10 Selected from halogens, -CN, -O(C) 1-2 )alkyl and -C 1-4 alkyl.

[0710]

[69] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-

[19] ,

[22] or

[41] -

[68] , wherein R9 is , , , , , or .

[0711]

[70] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-

[17] ,

[21] ,

[22] or

[41] -

[64] , wherein R9 is an unsubstituted -(5- to 10-benzene)-C 1-9 Mixed aromatic compounds.

[0712]

[71]

[70] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R9 is an unsubstituted 5- or 6-heteroaryl group having 1, 2 or 3 heteroatoms.

[0713]

[72] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-

[17] ,

[21] ,

[22] or

[41] -

[64] , wherein R9 is -(5- to 10-benzene)-C 1-9 A heteroaryl group, which is substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

[0714]

[73]

[72] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R9 is a 5- or -6-membered heteroaryl group having 1, 2 or 3 heteroatoms, wherein the 5- or -6-membered heteroaryl group is substituted by 1, 2 or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2 and -C which is optionally substituted by 1, 2 or 3 halogen atoms. 1-4 Alkyl group; and Rb and Rc are each independently selected from hydrogen and -C, optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

[0715]

[74] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1]-

[19] ,

[21] ,

[22] ,

[41] -

[46] ,

[72] or

[73] , wherein Rb and Rc are both hydrogen.

[0716]

[75] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1], [5]-[8],

[16] -

[22] ,

[41] -

[45] or

[63] -

[74] , wherein for , , , , or .

[0717]

[76] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1]-

[20] ,

[22] ,

[41] -

[68] or

[75] , wherein R4 is R 4a : or R 4b : Where m is 1 or 2 and R 10 Selected from halogens, -CN, -OH, -C 1-4 Alkyl and -C 1-4 Alkyl group.

[0718]

[77]

[76] compounds or their pharmaceutically acceptable salts or solvates, wherein R 4a and R 4b It is attached to the 4th or 5th position of the indole ring.

[0719]

[78] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1], [2], [5], [7]-

[22] ,

[41] or

[45] -

[76] , wherein R 3a R is attached to the 5-position of the 2-pyridyl ring. 3b R4 is hydrogen, attached to the 4-position of the indole ring, R5 is hydrogen, and R1 and R2 are each independently selected from hydrogen, halogen, and -C. 1-2 alkyl.

[0720]

[79]

[78] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 is hydrogen and R2 is methyl or ethyl.

[0721]

[80]

[78] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 is methyl or ethyl and R2 is hydrogen.

[0722]

[81]

[78] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 and R2 are hydrogen.

[0723] The compound of any one of

[82]

[78] -

[81] or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is -NH2 or -N(Me)2.

[0724]

[83] A compound or a pharmaceutically acceptable salt or solvate thereof from any one of [1], [2], [5], [7]-

[22] or

[41] -

[76] , wherein R 3a R is attached to the 6-position of the 2-pyridyl ring. 3b R4 is hydrogen, attached to the 4-position of the indole ring, R5 is hydrogen, and R1 and R2 are each independently selected from hydrogen, halogen, and -C. 1-2 alkyl.

[0725]

[84]

[83] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 is hydrogen and R2 is methyl or ethyl.

[0726]

[85]

[83] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 is methyl or ethyl and R2 is hydrogen.

[0727]

[86]

[83] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 and R2 are both hydrogen.

[0728]

[87]

[83] -

[86] any compound or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is -NH2 or -N(Me)2.

[0729]

[88] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1], [2], [6]-

[22] or

[41] -

[76] , wherein R 3a R is attached to the 5-position of the 2-pyridyl ring. 3b R4 is hydrogen, attached to the 5-position of the indole ring, R5 is hydrogen, and R1 and R2 are each independently selected from hydrogen, halogen, and -C. 1-2 alkyl.

[0730]

[89]

[88] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 is hydrogen and R2 is methyl or ethyl.

[0731]

[90]

[88] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 is methyl or ethyl and R2 is hydrogen.

[0732]

[91]

[88] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 and R2 are both hydrogen.

[0733] The compound of any one of

[92]

[88] -

[91] or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is -NH2 or -N(Me)2.

[0734]

[93] A compound or a pharmaceutically acceptable salt or solvate thereof of any one of [1], [2], [7]-

[22] or

[41] -

[76] , wherein R 3a R is attached to the 6-position of the 2-pyridyl ring. 3b R4 is hydrogen, attached to the 5-position of the indole ring, R5 is hydrogen, and R1 and R2 are each independently selected from hydrogen, halogen, and -C. 1-2 alkyl.

[0735]

[94]

[93] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 is hydrogen and R2 is methyl or ethyl.

[0736]

[95]

[93] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 is methyl or ethyl and R2 is hydrogen.

[0737]

[96]

[93] compounds or pharmaceutically acceptable salts or solvates thereof, wherein R1 and R2 are both hydrogen.

[0738]

[97]

[93] -96] any compound or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is -NH2 or -N(Me)2.

[0739]

[98]

[24] pharmaceutical compositions, wherein the compound is a salt or solvate of any one of

[41] -

[97] or thereof that is pharmaceutically acceptable.

[0740] The method of

[99]

[25] , wherein the compound is a salt or solvate of any one of

[41] -

[97] or thereof that is pharmaceutically acceptable.

[0741] The method of any one of

[100]

[26] -

[32] , wherein the compound is a salt or solvate of any one of

[41] -

[97] or thereof that is pharmaceutically acceptable.

[0742] The method of

[101]

[33] , wherein the compound is a salt or solvate of any one of

[41] -

[97] or thereof that is pharmaceutically acceptable.

[0743]

[102]

[34] compounds for use, wherein the compound is a salt or solvate of any one of

[41] -

[97] or thereof that is pharmaceutically acceptable.

[0744]

[103]

[35] or

[36] of the use of a compound, wherein the compound is a salt or solvate of any one of

[41] -

[97] or thereof that is pharmaceutically acceptable.

[0745]

[104]

[37] or

[38] compounds, wherein the compound is a salt or solvate of any one of

[41] -

[97] or a pharmaceutically acceptable salt thereof.

[0746]

[105]

[39] or

[40] pharmaceutical compositions wherein the compound is a salt or solvate of any one of

[41] -

[97] or thereof that is pharmaceutically acceptable.

[0747]

[106] A compound of any one of [1]-

[23] or

[41] -

[97] , wherein the method of using it to increase the β-galactosidase activity of a patient in need.

[0748] Use of any of the compounds in [1]-

[23] or

[41] -

[97] for the manufacture of a medicament for increasing the β-galactosidase activity of patients in need.

[0749] All publications referenced in this specification are incorporated herein by reference. While the invention has been described with reference to specific embodiments, it should be understood that modifications may be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. Compound of formula (I): (I) Or a pharmaceutically acceptable salt or solvate thereof, wherein: A1, A2, and A3 are each independently N or CH, provided that one of A1, A2, and A3 is N, and two of A1, A2, and A3 are CH. R1, R2, and R5 are each independently selected from hydrogen, halogens, -ORa, and -C. 1-4 Alkyl, -C 3-6 cycloalkyl and -(5- to 10-membered)-C 3-7 Heterocyclic groups, wherein the -C 1-4 Alkyl, -C 3-6 cycloalkyl and -(5- to 10-membered)-C 3-7 The heterocyclic group is optionally substituted by one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-; Ra is -C 1-4 Alkyl groups, which are optionally substituted with one, two or three halogen atoms; R 3a It is -NR6R7, where R6 is hydrogen or -C 1-4 Alkyl, and R7 is selected from hydrogen, -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-; R 3b Selected from hydrogen, halogens and C 1-4 alkyl; R4 is -NR8R9, where R8 is hydrogen or -C 1-4 Alkyl, and R9 is selected from -C 6-10 Aryl and -(5- to 10-yuan)-C 1-9 Heteroaryl, wherein the -C 6-10 Aryl and -(5- to 10-yuan)-C 1-9 The heteroaryl group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl; and Rb and Rc are each independently selected from hydrogen and C, which are optionally substituted with 1, 2, or 3 halogen atoms. 1-4 alkyl; R 3a R 3b R4 and R5 each replace a ring that would originally exist in equation (I), R 3a R 3b Hydrogen atoms at any position connected to R4 and R5.

2. The compound according to claim 1, wherein the compound has the structure of formula (II): (II) Or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R 3a R 3b R4 and R5 are as defined in claim 1.

3. The compound according to claim 1, wherein the compound has the structure of formula (III): (III) Or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R 3a R 3b R4 and R5 are as defined in claim 1.

4. The compound according to claim 1, wherein the compound has the structure of formula (IV): (IV) Or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R 3a R 3b R4 and R5 are as defined in claim 1.

5. The compound according to any one of claims 1-4, and its pharmaceutically acceptable salt and solvate, wherein R4 is attached at the 4-position of the indole ring.

6. The compound according to any one of claims 1-4, and its pharmaceutically acceptable salt and solvate, wherein R4 is attached at the 5-position of the indole ring.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, and R5 are each independently selected from hydrogen, halogen, -C 1-4 Alkoxy and -C 1-4 Alkyl, wherein the -C 1-4 The alkyl group is either unsubstituted or substituted with one or two substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, and R5 are each independently selected from hydrogen, halogen, and -C. 1-2 alkyl.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen and R 3a It is -NHR7, where R7 is as defined in claim 1.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 and R7 are both hydrogen and R 3a It is -NH2.

11. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is -C 1-4 Alkyl and R 3a -N(C) 1-4 (alkyl)R7, wherein R7 is as defined in claim 1.

12. The compound according to any one of claims 1-9 or 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C 1-4 Alkyl, -C 3-10 cycloalkyl and -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, halogenated (C 1-4 )alkyl- and halogenated (C 1-4 )alkoxy-.

13. The compound according to any one of claims 1-9, 11 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -C 1-4 Alkyl group, optionally substituted with 1, 2 or 3 substituents, each substituent independently selected from halogen, hydroxyl, -C 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

14. The compound according to any one of claims 1-9, 11 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -C 3-10 Cycloalkyl group, optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, hydroxyl, -C 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

15. The compound according to any one of claims 1-9, 11 or 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -C 1-4 Alkyl-C 3-10 cycloalkyl, wherein the -C 1-4 Alkyl-C 3-10 The cycloalkyl group is optionally substituted with one, two, or three substituents, each substituent being independently selected from halogens, hydroxyl groups, and -C groups. 1-4 Alkoxy, monohalogenated (C 1-4 )alkyl-, dihalogenated (C 1-4 )alkyl-, trihalogenated (C 1-4 )alkyl-, monohalogenated (C 1-4 )alkoxy-, dihalo (C 1-4 )alkoxy- and trihalo (C 1-4 )alkoxy-.

16. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is hydrogen and R4 is -NHR9, wherein R9 is as defined in claim 1.

17. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is -C 1-4 Alkyl and R4 is -N(C) 1-4 (alkyl)R9, wherein R9 is as defined in claim 1.

18. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is -C 6-10 The aryl group, optionally substituted with 1, 2, or 3 substituents, each substituent independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is an unsubstituted phenyl or a phenyl substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl groups, wherein Rb and Rc are each independently selected from hydrogen and -C optionally substituted with 1, 2 or 3 halogen atoms. 1-2 alkyl.

20. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is a phenyl group substituted with one or two substituents, each substituent being independently selected from halogens, -CN, -OH, -O(C) 1-2) Alkyl, unsubstituted -C 1-4 Alkyl groups and -C atoms substituted with 1, 2, or 3 halogen atoms 1-4 alkyl.

21. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is -(5- to 10-benzene)-C 1-9 Heteroaryl, wherein the -(5- to 10-aryl)-C 1-9 The heteroaryl group is optionally substituted with 1, 2, or 3 substituents, each substituent being independently selected from halogens, -C(=O)N(Rb)2, -NHC(=O)Rb, -S(=O)2N(Rb)2, -NHS(=O)2Rb, -CN, -ORc, -N(Rc)2, and -C which is optionally substituted with 1, 2, or 3 halogen atoms. 1-4 Alkyl group; and Rb and Rc are each independently selected from hydrogen and -C, optionally substituted with 1, 2 or 3 halogen atoms. 1-4 alkyl.

22. The compound according to any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b It is hydrogen.

23. The compound according to claim 1, wherein the compound is selected from: 1-(5-(dimethylamino)pyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-5-amine; 1-(5-aminopyridin-2-yl)-N-(p-tolyl)-1 H -Indole-5-amine; 1-(5-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -Indole-5-amine; 1-(5-aminopyridin-2-yl)- N -(m-Tolyl)-1 H -Indole-5-amine; 1-(5-aminopyridin-2-yl)- N -(3-methoxyphenyl)-N-methyl-1 H -Indole-5-amine; 1-(6-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -Indole-5-amine; 1-(6-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -Indole-5-amine; 1-(5-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-4-amine; 1-(5-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -Indole-4-amine; 1-(6-aminopyridin-2-yl)- N -(p-Tolyl)-1 H -Indole-4-amine; 1-(6-aminopyridin-2-yl)- N -(4-Chlorophenyl)-1 H -Indole-4-amine; 1-(5-aminopyridin-2-yl)- N -(4-methoxyphenyl)-3-methyl-1 H -Indole-5-amine; 1-(5-aminopyridin-2-yl)- N -(4-methoxyphenyl)-2-methyl-1 H -Indole-5-amine; 1-(6-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-5-amine; 1-(6-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-4-amine; 1-(5-aminopyridin-2-yl)- N -(4-Methoxyphenyl)-1 H -Indole-5-amine; 1-(5-aminopyridin-2-yl)-N-(4-chlorophenyl)-1 H -Indole-5-amine; 1-(5-aminopyridin-2-yl)- N -(3-Chlorophenyl)-1 H -Indole-5-amine; 4-((1-(5-aminopyridin-2-yl)-1 H -indol-5-yl)amino)benzonitrile; 1-(5-aminopyridin-2-yl)-N-(p-tolyl)-1 H -Indole-4-amine; 1-(5-aminopyridin-2-yl)- N -(3-Methoxyphenyl)-1 H -Indole-4-amine; 1-(5-aminopyridin-2-yl)- N -(m-Tolyl)-1 H -Indole-4-amine; and 1-(5-aminopyridin-2-yl)- N -(3-Chlorophenyl)-1 H -Indole-4-amine, Or its pharmaceutically acceptable salts or solvates.

24. A pharmaceutical composition comprising a compound according to any one of claims 1-23 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

25. A method of treating or preventing a patient’s condition related to altered GLB1 activity, comprising administering to a patient in need an effective amount of a compound as defined in any one of claims 1-23 or a pharmaceutically acceptable salt or solvate thereof.

26. A method for treating or preventing GM1 ganglioside storage disease or Mochio syndrome type B in a patient, comprising administering to a patient in need an effective amount of a compound as defined in any one of claims 1-23 or a pharmaceutically acceptable salt or solvate thereof.

27. The method of claim 26, further comprising administering to the patient an effective amount of the enzyme for enzyme replacement therapy.

28. The method of claim 27, wherein the enzyme is β-galactosidase or an analogue thereof.

29. The method according to any one of claims 26-28, further comprising administering a small molecule molecular chaperone to the patient.

30. The method of claim 29, wherein the small molecule chaperone competitively binds to the enzyme.

31. The method according to claim 29 or 30, wherein the small molecule chaperone is selected from iminoglycosides, imino sugars, amino sugars, thiophene glycosides, glycosidases, sulfatases, glycosyltransferases, phosphoesterases, and peptidase inhibitors.

32. The method according to any one of claims 26-31, wherein the small molecule chaperone is selected from 1-deoxygalactosinosin (DGJ), N-nonyldeoxygalactosinosin (NN-DNJ), N-butyldeoxygalactosinosin (NB-DGJ), galactose, fluoroiminotol, and episifagmine.

33. A method for increasing the β-galactosidase activity of a patient in need, comprising administering to the patient an effective amount of a compound as defined in any one of claims 1-23 or a pharmaceutically acceptable salt or solvate thereof.

34. The compound according to any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, used as a medicine.

35. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, for the prevention or treatment of conditions associated with altered GLB1 activity.

36. The compound for use according to claim 35, wherein the condition associated with altered GLB1 activity is selected from GM1 ganglioside storage disease and Mochio syndrome type B.

37. Use of the compound of any one of claims 1-23 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the prevention or treatment of conditions associated with altered GLB1 activity.

38. Use of the compound according to claim 37, wherein the condition associated with altered GLB1 activity is selected from GM1 ganglioside storage disease and Mochio syndrome type B.

39. A pharmaceutical composition comprising a compound as defined in any one of claims 1-23 or a pharmaceutically acceptable salt or solvate thereof, for the prevention or treatment of conditions associated with altered GLB1 activity.

40. The pharmaceutical composition for use according to claim 39, wherein the condition associated with altered GLB1 activity is selected from GM1 ganglioside storage disease and Mochio syndrome type B.

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