(Aza)spiroheptane derivatives for the treatment of neurodegenerative disorders

Abstract

The present application relates to compounds of formula (B1A), (B1B), (B1C) JPEG2025527459000149.jpg87170 or a salt, solvate, hydrate, polymorph, tautomer, racemate or stereoisomer thereof, pharmaceutical compositions containing such compounds and compounds for use as a medicament, particularly for use in the treatment of neurodegenerative disorders such as Alzheimer's disease.

Description

[Technical Field]

[0001] The present invention relates to (aza)spiroheptane derivatives useful in the treatment of certain neurodegenerative disorders, such as those characterized by cytotoxic tau misfolding and / or aggregation and / or aggregation of amyloid-β. [Background technology]

[0002] Tau is a protein that can bind to, and thereby stabilize and regulate, microtubule structure and function in neurons. Binding of tau to microtubules is regulated by tau phosphorylation. Several tau phosphorylation sites and their corresponding kinases have been identified, which regulate the phosphorylation state of tau and, consequently, the affinity of tau binding to microtubules.

[0003] Tauopathies are characterized by insoluble aggregates or polymers of hyperphosphorylated tau formed by the self-polymerization of tau monomers.

[0004] A key aspect of tau aggregation is its associated cytotoxicity, which compromises neuronal integrity and functionality and ultimately leads to disease symptoms. A direct role for tau in disease development has been clearly established by the elucidation of familial mutations in tau, which appear to be responsible for very early and sometimes aggressive forms of tauopathy. Such mutations involve changes in the amino acid sequence of tau that directly or indirectly promote neurotoxic aggregation.

[0005] Alzheimer's disease, the best known of these, involves the deposition of tau protein in neurons in the form of neurofibrillary tangles (NFTs), and was first described by its namesake, Alois Alzheimer, in one of his own patients with the disorder.

[0006] The term "Alzheimer's disease," as used herein, refers to a chronic, progressive neurological disorder characterized by neurodegeneration with memory decline as its most significant (early) symptom. As the disease progresses, symptoms include confusion, irritability and aggression, mood swings, speech impairment, and long-term memory decline, and affected individuals may become generally withdrawn due to their sensory decline. Tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, leading to the aggregation of an insoluble form of tau. (These aggregates of hyperphosphorylated tau protein are also called PHFs, or "paired helical filaments.") The exact mechanism of tangle formation is not fully understood, and whether it is the primary causative factor in the disease or plays a more peripheral role remains controversial. AD is also classified as an amyloidosis due to the presence of senile plaques.

[0007] Other conditions in which neurofibrillary tangles are commonly found include progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia linked to chromosome 17 with parkinsonism, Ritiko-Bodig disease (Guam Parkinsonism-Dementia Complex), tangle-predominant dementia with NFTs that resemble AD but lack senile plaques, gangliogliomas and gangliocytomas, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis complex, Hallervorden-Spatz disease, and lipofuscinosis.

[0008] Tauopathies other than Alzheimer's disease are sometimes grouped together as the "Pick complex." In Pick's disease and corticobasal degeneration, tau protein is deposited in the form of inclusions within enlarged or "ballooned" neurons. Another type of dementia, argyrophilic grain disease (AGD), is characterized by the presence of large numbers of argyrophilic granules and coiled bodies on microscopic examination of brain tissue.

[0009] Currently used treatments for tauopathies, including Alzheimer's disease, only provide symptomatic benefit without affecting the underlying neurodegeneration. No treatments are currently available that aim to inhibit cytotoxic tau misfolding and / or aggregation to slow or halt disease progression. Summary of the Invention [Problem to be solved by the invention]

[0010] Therefore, there is a need for novel therapies that target the molecular mechanisms underlying toxic tau misfolding and / or aggregation to reduce neuronal cell death and / or degeneration in patients suffering from tauopathies such as Alzheimer's disease (AD). [Means for solving the problem]

[0011] To at least partially overcome the above-mentioned problems, the present invention provides novel compounds as defined herein.

[0012] The object of the present invention are compounds of formula (B1A), formula (B1B), formula (B1C), their use for the treatment of diseases related to dysfunctional biological function of tau protein, including Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with parkinsonism (linked to chromosome 17, FTDP-17), their preparation and medicaments based on the compounds according to the invention in the management or prevention of the disease.

[0013] In a first aspect, the present invention provides compounds of formula (B1A), formula (B1B), formula (B1C) [ka] (In the formula, A 1a is C 6~10 Aryl, C 3~6cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; each of said groups is unsubstituted or selected from the group consisting of one or more R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; X 1a -CO-, -SO2-, -C(R 3a ) 2- or 5-membered heteroarylene; Y 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Z 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Each R 3a are independently hydrogen, halo or C 1~6 alkyl; Each R 5a are independently hydrogen or C 1~6 alkyl; X 2ais a single bond or -CO-; Y 2a is a single bond or -C(R 4a )2- and Z 2a is a single bond or -(C(R 4a )2) n - or -CO-; n is an integer selected from 1 or 2; Each R 4a are independently hydrogen, halo, or C 1~6 alkyl; or two R 4a together with the atoms to which they are attached, C 3~6 can form a cycloalkyl; A 2a is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl, C 3~6 Cycloalkyl and C 1~6 alkyl; each of said groups is unsubstituted or contains one or more R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl); [ka] (In the formula, A 1b is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; each of said groups is unsubstituted or selected from the group consisting of one or more R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3b is hydrogen or C 1~6 alkyl; Y 1b -CO-, -C(R 5b ) 2- or 5-membered heteroarylene; Z 1b is -C(R 5b )2- and; R 4b is hydrogen, C 1~6 Alkyl or C 1~6 alkoxycarbonyl; Each R 5b are independently hydrogen, halo or C 1~6 alkyl; Each R 6b are independently hydrogen or C 1~6 alkyl; Y 2b is -C(R 5b ) 2- or single bond; Z 2b is a single bond or -(C(R 5b )2) m - or -CO-; m is an integer selected from 1 or 2; A 2b is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl, C 3~6 Cycloalkyl and C 1~6 alkyl; each of said groups is unsubstituted or contains one or more R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl); [ka] (In the formula, A 1c is C 6~10 Aryl, C 3~6cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; each of said groups is unsubstituted or selected from the group consisting of one or more R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3c is hydrogen or C 1~6 alkyl; Y 1c is a single bond or -C(R 4c )2-, -NR 6c -, -O-, or 5-membered heteroarylene; Z 1c is a single bond or -C(R 4c )2- or -O-; Each R 4c are independently hydrogen, halo or C 1~6 alkyl; Each R 6c are independently hydrogen or C 1~6 alkyl; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- and Z 2c is a single bond or -(C(R 5c )2) p - or -CO-; p is an integer selected from 1 or 2; Each R 5c are independently hydrogen, halo, or C 1~6 alkyl; or two R 5c together with the atoms to which they are attached, C 3~6 can form a cycloalkyl; A 2c is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S, C 3~6 Cycloalkyl, hydrogen, -N(R 6c )2 and C 1~6 alkyl; each of said groups is unsubstituted or contains one or more R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl) or a salt, solvate, hydrate, polymorph, tautomer, racemate or stereoisomer thereof, or a prodrug thereof.

[0014] Preferably, the present invention provides compounds of formula (B1A), formula (B1B), formula (B1C) [ka] (In the formula, A 1a is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; each of said groups is unsubstituted or selected from the group consisting of one or more R 1a and each R 1a are independently halo, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; X 1a -CO-, -SO2-, -C(R 3a ) 2- or 5-membered heteroarylene; Y 1a is -C(R 3a )2-, -NR 5a - or -O-; or Y 1a is a single bond; Z 1a is a single bond or -C(R 3a )2-, -NR 5a- or -O-; Each R 3a are independently hydrogen, halo or C 1~6 alkyl; Each R 5a are independently hydrogen or C 1~6 alkyl; X 2a is a single bond or -CO-; Y 2a is -C(R 4a )2- or Y 2a is a single bond, Z 2a is a single bond or -(C(R 4a )2) n - or -CO-; n is an integer selected from 1 or 2; Each R 4a are independently hydrogen, halo, or C 1~6 alkyl; or two R 4a together with the atoms to which they are attached, C 3~6 can form a cycloalkyl; A 2a is C 6~10 Aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl and C 3~6 cycloalkyl; each of said groups is unsubstituted or contains one or more R 2a each R 2a are independently halo, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; However, A 1a teeth, [ka] (In the formula, R 1a1 and R 1a2 are each independently, C 1~2 alkyl, or R 1a1 and R 1a2 together with the carbon atoms to which they are attached, C3~6 Forming a cycloalkyl, R 1a has the same meaning as defined herein, and s is an integer selected from 0, 1, or 2. rather than; A 2a teeth, [ka] (In the formula, R 2a has the same meaning as defined herein, and s is an integer selected from 0, 1, or 2. shall not be; However, the compound is 2-benzyl-6-(toluene-4-sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(1,3-benzodioxol-5-ylmethyl)-6-[(4-methylphenyl)sulfonyl-2,6-diazaspiro[3.3]heptane; 2-(1,3-benzodioxol-5-ylmethyl)-6-(phenylmethyl)-2,6-diazaspiro[3.3]heptane; 2-benzyl-6-(tosyl)-2,6-diazaspiro[3.3]heptane; 6-Benzyl-2,6-diazaspiro[3.3]heptan-2-yl)(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methanone; (5-cyclohexyl-1H-pyrazol-3-yl)(6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-isopropyl-1H-imidazol-4-yl)methanone; (5-Isopropyl-1H-pyrazol-3-yl)(6-(1-methylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (5-Isopropyl-1H-pyrazol-3-yl)(6-(thiophene-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; [2-(4-Fluoro-1-methyl-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone shall not be); [ka] (In the formula, A 1b is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; each of said groups is unsubstituted or selected from the group consisting of one or more R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3b is hydrogen or C 1~6 alkyl; Y 1b -CO-, -C(R 5b ) 2- or 5-membered heteroarylene; Z 1b is -C(R 5b )2- and; R 4b is hydrogen, C 1~6 Alkyl or C 1~6 alkoxycarbonyl; Each R 5b are independently hydrogen, halo or C 1~6 alkyl; Each R 6b are independently hydrogen or C 1~6 alkyl; Y 2b is -C(R 5b ) 2- or single bond; Z 2b is a single bond or -(C(R 5b )2) m - or -CO-; m is an integer selected from 1 or 2; A 2b is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl, C 3~6 Cycloalkyl and C 1~6 alkyl; each of said groups is unsubstituted or contains one or more R 2b and each R 2b are independently hydrogen, halo, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl); [ka] (In the formula, A 1c is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; each of said groups is unsubstituted or selected from the group consisting of one or more R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1c together with the atoms to which they are attached, C 6~10can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3c is hydrogen or C 1~6 alkyl; Y 1c is a single bond or -C(R 4c )2-, -NR 6c -, -O-, or 5-membered heteroarylene; Z 1c is a single bond or -C(R 4c )2- or -O-; Each R 4c are independently hydrogen, halo or C 1~6 alkyl; Each R 6c are independently hydrogen or C 1~6 alkyl; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- and Z 2c is a single bond or -(C(R 5c )2) p - or -CO-; p is an integer selected from 1 or 2; Each R 5c are independently hydrogen, halo, or C 1~6 alkyl; or two R 5c together with the atoms to which they are attached, C 3~6 can form a cycloalkyl; A 2c is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S, C 3~6 Cycloalkyl and -N(R 6c )2; each of said groups is unsubstituted or contains one or more R 2c each R2c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl, However, A 1c teeth, [ka] Instead, A 2c teeth, [ka] It is not However, the compound is N-benzyl-2-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-amine; N-(2-(2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)-6,7-dimethoxy-2,3-dihydro-1H-cyclopenta[b]quinolin-9-amine; 6-((2-((benzyloxy)carbonyl)-2-azaspiro[3.3]heptan-6-yl)amino)-2-chloropyrimidine-4-carboxylic acid; Benzyl 6-((2-chloro-6-(methoxycarbonyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (This is not or a salt, solvate, hydrate, polymorph, tautomer, racemate or stereoisomer thereof, or a prodrug thereof.

[0015] In a second aspect, the present invention also relates to a pharmaceutical composition comprising a compound according to the first aspect of the invention and at least one pharmaceutically acceptable carrier.

[0016] The present invention also relates to a compound according to the first aspect of the invention or a pharmaceutical composition according to the second aspect of the invention for use as a medicament.

[0017] The compounds and compositions are useful in the treatment of certain neurodegenerative disorders, such as those characterized by inhibiting cytotoxic tau misfolding and / or aggregation, to slow or halt the progression of such diseases. Preferably, the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, Alzheimer's disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, Pick's disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy, and Creutzfeldt-Jakob disease, and preferably, the neurodegenerative disorder is Alzheimer's disease.

[0018] These and other characteristics, features and advantages of the present invention will become apparent from the following detailed description, which illustrates, by way of example, the principles of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0019] When describing the present invention, the terms used should be construed in accordance with the following definitions, unless the context dictates otherwise.

[0020] Unless otherwise defined, all terms used in disclosing the present invention, including scientific and technical terms, have the meanings commonly understood by those skilled in the art to which this invention belongs. Definitions of terms used herein are included as a further guide to better understand the teachings of the present invention. When describing the compounds, processes, articles and uses of the present invention, the terms used should be construed in accordance with the following definitions, unless the context dictates otherwise.

[0021] As used herein, the singular forms "a," "an," and "the" include both singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

[0022] The terms "comprising," "including," and "composed of," as used herein, are synonymous with "including," "comprises," or "containing," and are inclusive or open-ended and do not exclude additional, unrecited members, elements, or method steps. The terms "comprising," "including," and "composed of" also encompass the term "consisting of."

[0023] The recitation of numerical ranges by endpoints includes all integers and, where appropriate, decimals subsumed within the range (e.g., 1 to 5, e.g., when referring to the number of elements, can include 1, 2, 3, and 4; e.g., when referring to measurements, can also include 1.5, 2, 2.75, and 3.80). The recitation of endpoints also includes the endpoints themselves (e.g., 1.0 to 5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all subranges subsumed therein.

[0024] The term "and / or," as used herein, should be construed as a specific disclosure of each of the two specified features or components, with or without the other. Thus, when used herein in phrases such as "A and / or B," the term "and / or" is intended to include "A and B," "A or B," "A" (alone) and "B" (alone). Similarly, when used in phrases such as "A, B and / or C," the term "and / or" is intended to encompass each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0025] Throughout this specification, the reference to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment, although they may. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as would be apparent to one of ordinary skill in the art from this disclosure. Furthermore, as would be understood by one of ordinary skill in the art, while some embodiments described herein include some features, but not others, included in other embodiments, combinations of features from different embodiments are intended to form different embodiments within the scope of the present invention. For example, in the following claims and description, any of the embodiments may be used in any combination.

[0026] The term "leaving group" or "LG," as used herein, means a chemical group that is susceptible to displacement by a nucleophile or that is cleaved and removed or hydrolyzed under basic or acidic conditions. In particular embodiments, the leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate, tosylate, triflate).

[0027] The term "protecting group" or "PG" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The partial chemical structures of protecting groups vary widely. One function of a protecting group is to serve as an intermediate in the synthesis of a parent drug substance. Chemical protecting groups and protection / deprotection strategies are well known in the art. See "Protective Groups in Organic Chemistry," Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). Protecting groups are often utilized to mask the reactivity of certain functional groups, for example, to create and break chemical bonds in an orderly, planned manner to aid in the efficiency of a desired chemical reaction. Protecting a functional group of a compound alters other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0028] Whenever the term "substituted" is used herein, it is intended to indicate that one or more hydrogen atoms on the atom designated with "substituted" have been replaced with a selection from the designated group, provided that the normal valence of the designated atom is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently robust to survive isolation from a reaction mixture.

[0029] The term "halo" or "halogen" as a group or part of a group is generic to fluoro, chloro, bromo, and iodo.

[0030] The term "cyano," as used herein, refers to the group --CN.

[0031] The terms "hydroxyl" or "hydroxy" as used herein refer to the group --OH.

[0032] The term "oxo" as used herein refers to the group =O.

[0033] The term “alkyl” as a group or part of a group refers to an alkyl group of formula C, with no unsaturated sites. n H 2n+1 where n is a number equal to or greater than 1. The alkyl groups may be straight or branched and may be substituted as indicated herein. Generally, alkyl groups of the present invention contain 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that may be included in the named group. For example, the term "C" as a group or part of a group 1~6 "Alkyl" is a group of formula C n H 2n+1 (wherein n is a number ranging from 1 to 6). Thus, for example, "C 1~6 "Alkyl" includes all straight or branched alkyl groups having 1 to 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl, and t-butyl); pentyl and its isomers, hexyl and its isomers, etc. For example, C 1~4 Alkyl includes all straight or branched alkyl groups having 1 to 4 carbon atoms and thus includes, for example, methyl, ethyl, n-propyl, i-propyl, 2-methyl-ethyl, butyl and its isomers (e.g., n-butyl, i-butyl and t-butyl), etc. In particular embodiments, the term alkyl includes C as further defined herein. 1~12 Alkyl (C 1~12 hydrocarbons), and more specifically C 1~9 Alkyl (C 1~9 hydrocarbons), and more particularly, C 1~6 Alkyl (C 1~6Non-limiting examples of alkyl include methyl, ethyl, 1-propyl (n-propyl), 2-propyl (iPr), 1-butyl, 2-methyl-1-propyl (i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2- Examples include methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-icosyl.

[0034] When the suffix "ene" is used in conjunction with an alkyl group (i.e., "alkylene"), it is intended to mean an alkyl group, as defined herein, having two single bonds as points of attachment to other groups. As used herein, the term "alkylene," alone or as part of another substituent, also referred to as "alkanediyl," refers to a divalent alkyl group, i.e., an alkyl group having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane, i.e., having two single bonds for attachment to two other groups. Alkylene groups can be straight or branched and can be substituted as indicated herein. Non-limiting examples of alkylene groups include methylene (-CH-), ethylene (-CH-CH-), methylmethylene (-CH(CH)-), 1-methyl-ethylene (-CH(CH)-CH-), n-propylene (-CH-CH-CH-), 2-methylpropylene (-CH-CH(CH)-CH-), 3-methylpropylene (-CH-CH-CH(CH)-), n-butylene (-CH-CH-CH-CH-), 2-methylbutylene (-CH-CH(CH)-CH-CH-), 4-methylbutylene (-CH-CH-CH-CH(CH)-), pentylene and its chain isomers, and hexylene and its chain isomers.

[0035] The term "hydrocarbyl" group is used herein according to the definition provided by IUPAC as follows: a monovalent group formed by removing a hydrogen atom from a hydrocarbon (i.e., a group containing only carbon and hydrogen).

[0036] The term "alkenyl" as a group or part of a group includes one or more groups having at least one (usually 1 to 3, preferably 1) site of unsaturation which may be linear or branched, i.e., at least one sp 2 Carbon-sp 2"C" refers to an unsaturated hydrocarbyl group containing a carbon-carbon double bond. Generally, the alkenyl groups of the present invention contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms. When a subscript is used in this specification after a carbon atom, the subscript refers to the number of carbon atoms that may be contained in the named group. 2~6 Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, etc. The double bond may be in the cis or trans configuration.

[0037] When the suffix "ene" is used in conjunction with an alkenyl group (i.e., "alkenylene"), it is intended to mean an alkenyl group, as defined herein, having two single bonds as points of attachment to other groups. As used herein, the term "alkenylene," alone or as part of another substituent, refers to a divalent alkenyl group, i.e., an alkenyl group having two monovalent centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkene, i.e., having two single bonds for attachment to two other groups. Alkenylene groups can be linear or branched and can be substituted as indicated herein. Non-limiting examples of alkenylene groups include -CH=CH-, -C(CH3)=CH-, -C(CH3)=C(CH3)-, -CH=CH-CH2-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-, -CH2-CH2-CH=CH-, and the like.

[0038] The term "alkynyl" as a group or part of a group refers to an alkynyl group containing at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., sp 1 Carbon-sp 1 It refers to a branched or straight chain hydrocarbon containing a carbon-carbon triple bond. In a particular embodiment, the term alkynyl refers to a group having at least one (usually 1 to 3, preferably 1) site of unsaturation, i.e., at least one sp 1 Carbon-sp 1C as further defined herein above, in which there is a carbon triple bond 2~12 Alkynyl (C 2~12 hydrocarbons), preferably C 2~9 Alkynyl (C 2~9 hydrocarbons), and even more preferably C 2~6 Alkynyl (C 2~6 Examples of alkynyl include, but are not limited to: ethynyl (-C°CH), 3-ethyl-cyclohept-1-ynylene, and 1-propynyl (propargyl, -CHC°CH).

[0039] When the suffix "ene" is used in conjunction with an alkynyl group (i.e., "alkynylene"), it is intended to mean an alkynyl group, as defined herein, having two single bonds as points of attachment to other groups. As used herein, the term "alkynylene," by itself or as part of another substituent, refers to a divalent alkynyl group, i.e., an alkynyl group having two single bonds for attachment to two other groups. Alkynylene groups can be straight or branched and can be substituted as indicated herein. Non-limiting examples of alkynylene groups include -C°C-, -CH-C°C-, -C°C-CH-, -CH-CH-C°C-, and the like.

[0040] The term "cycloalkyl" as a group or part of a group refers to a monovalent saturated hydrocarbyl group having one or more cyclic structures, and a cyclic alkyl group containing from 3 to 20 carbon atoms, more preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms; more preferably from 3 to 6 carbon atoms. Cycloalkyl includes all saturated hydrocarbon groups containing one or more rings, including monocyclic, bicyclic, or tricyclic groups. For example, cycloalkyl includes C 1, C 2, C 3, C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, C 12, C 13, C 14, C 15, C 16, C 17, C 18, C 19, C 20, C 21, C 22, C 23, C 24, C 25, C 26, C 27, C 28, C 29, C 30, C 31, C 32, C 33, C 34, C 35, C 36, C 37, C 38, C 39, C 40, C 41, C 42, C 43, C 44, C 45, C 46, C 47, C 48, C 49, C 50, C 51, C 52, C 53, C 54, C 55, C 56, C 57, C 58, C 59 ... 3~10 Monocyclic or C 7~18Polycyclic saturated hydrocarbons are included. The additional rings of polycyclic cycloalkyls may be either fused, bridged, and / or linked through one or more spiro atoms. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that may be included in the named group. For example, the term "C 3~10 "Cycloalkyl" refers to a cyclic alkyl group containing 3 to 10 carbon atoms. For example, the term "C 3~8 "Cycloalkyl" refers to a cyclic alkyl group containing from 3 to 8 carbon atoms. For example, the term "C 3~6 "Cycloalkyl" refers to a cyclic alkyl group containing from 3 to 6 carbon atoms. For the avoidance of doubt, systems in which a cycloalkyl ring is fused to a heterocyclic ring will be considered heterocyclic, regardless of the ring attached to the core structure. Systems in which a cycloalkyl ring is fused to an aryl ring will be considered aryl, regardless of the ring attached to the core structure. Systems in which a cycloalkyl ring is fused to a heteroaryl ring will be considered heteroaryl, regardless of the ring attached to the core structure.

[0041] The term "alkoxy" or "alkyloxy" as a group or part of a group refers to an alkyl group of the formula -OR b where R b is alkyl as defined herein. 1~6 Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0042] The term "aryl" as a group or part of a group refers to a polyunsaturated aromatic hydrocarbyl group, typically containing 6 to 20 atoms; preferably 6 to 10 atoms, having either a single ring (i.e., phenyl) or multiple aromatic rings fused together or covalently linked (e.g., naphthyl), in which at least one ring is aromatic. Typical aryl groups include, but are not limited to, one ring or two or three rings fused together, derived from benzene, naphthalene, anthracene, biphenyl, etc. The aromatic ring may optionally contain one or two additional rings. Systems in which an aryl ring is fused to a cycloalkyl ring, cycloalkenyl ring, or cycloalkynyl ring are considered aryl, regardless of the ring attached to the core structure. Systems in which an aryl ring is fused to a heterocycle are considered heterocycles, regardless of the ring attached to the core structure. Systems in which an aryl ring is fused to a heteroaryl are considered heteroaryl, regardless of the ring attached to the core structure. Examples of suitable aryls include C 6~20 Aryl, preferably C 6~10 Aryl, more preferably C 6~9 Examples of aryl include phenyl, biphenylyl, biphenylene, or 1- or 2-naphthanyl; 1-, 2-, 3-, 4-, 5-, or 6-tetralinyl (also known as 1,2,3,4-tetrahydronaphthalene); 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 4-, 5-, 6-, or 7-indenyl; 4- or 5-indanyl; 5-, 6-, 7-, or 8-tetrahydronaphthyl; 1,2,3,4-tetrahydronaphthyl; and 1,4-dihydronaphthyl; 1-, 2-, 3-, 4-, or 5-pyrenyl. Preferred aryl is phenyl.

[0043] When the suffix "ene" is used in conjunction with an aryl group (i.e., "arylene"), it is intended to mean an aryl group, as defined herein, having two single bonds as points of attachment to other groups. As used herein, the term "arylene," alone or as part of another substituent, refers to a divalent aryl group, i.e., an aryl group having two monovalent centers, i.e., two single bonds for attachment to two other groups, obtained by removing two hydrogen atoms from the same or two different carbon atoms of a parent aryl. Arylene groups can be substituted as indicated herein.

[0044] The term "arylalkyl" as a group or part of a group refers to alkyl, as defined herein, in which at least one hydrogen atom is replaced by at least one aryl, as defined herein. Non-limiting examples of arylalkyl groups include benzyl, phenethyl, dibenzylmethyl, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethyl, and the like. The term "C 6~10 Aryl C 1~6 "Alkyl" means that the alkyl portion of the arylalkyl group can contain 1 to 6 carbon atoms and the aryl portion is 6 to 10 carbon atoms.

[0045] The term "aryloxy" as a group or part of a group refers to an aryl group of the formula -OR f where R f refers to aryl as defined herein.

[0046] The term "haloalkyl" as a group or part of a group refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are each replaced by a halogen, as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.

[0047] The term "haloalkoxy" as a group or part of a group refers to a group of the formula -OR e where R e is haloalkyl as defined herein. Non-limiting examples of suitable haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy, 2-bromoethoxy, pentafluoroethyl, 3,3,3-trichloropropoxy, and 4,4,4-trichlorobutoxy.

[0048] The term "heterocyclyl," as used herein, refers to a non-aromatic, fully saturated or partially unsaturated ring system containing 3 to 18 atoms, preferably 3 to 14 atoms (3-14 membered heterocyclyl), including at least one N, O, S, or P (e.g., a 3- to 7-membered monocyclic, a 7- to 14-membered bicyclic, preferably containing a total of 3 to 10 ring atoms (3- to 10-membered heterocyclyl), more preferably 4 to 10 atoms (4- to 10-membered heterocyclyl), and even more preferably 5 to 10 atoms (5- to 10-membered heterocyclyl). Each ring of the heterocycle or heterocyclyl may have 1, 2, 3, or 4 heteroatoms selected from N, O, P, and / or S, and the N and S heteroatoms may optionally be oxidized, and and N heteroatoms may be optionally quaternized; at least one carbon atom of a heterocyclyl may be oxidized to form at least one C=O. A heterocyclyl may be attached to any heteroatom or carbon atom of a ring or ring system, if valence allows. The rings of a polycyclic heterocyclyl or heterocycle may be fused, bridged, and / or linked through one or more spiro atoms. A system in which a heterocycle or heterocyclyl is fused to an aryl ring is considered a heterocycle or heterocyclyl, regardless of the ring attached to the core structure. A system in which a heterocycle or heterocyclyl is fused to a heteroaryl ring is considered a heteroaryl, regardless of the ring attached to the core structure.

[0049] Non-limiting exemplary heterocycles or heterocyclic groups include piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl (tetrahydro-2H-thiopyranyl), tetrahydrofuranyl, pyrrolidinyl, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, imidazolinyl, pyrazolidinyl. Imidazolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, indolinyl, isoindolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl), 2H-pyrrolyl, pyrrolinyl (1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, etc.), 4H-quinolizinyl, 2-oxopiperazinyl, pyrazolinyl (2-pyrazolinyl, 3-pyrazolinyl, etc.), -pyrazolinyl, etc.), tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl-1-oxide, tetrahydro-2H-thiopyranyl-1,1-dioxide, 2H-pyranyl, 4H-pyranyl, dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothio Phenyl, N-formyl-piperazinyl, thiomorpholinyl, dihydrofuranyl, dihydrothienyl, tetrahydrothienyl, dihydropyrazolyl, dihydroimidazolyl, isothiazolinyl, thiazolinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, Dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl, tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl, dihydro-benzoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, tetrahydro-benzoxazolyl, dihydro-benzoxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, tetrahydro-benzoxazinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxanyl, dihydro-purinyl, tetra Hydro-purinyl, dihydro-quinolinyl, 1,2,3,4-tetrahydroquinolinyl, dihydro-isoquinolinyl, 3,4-dihydroisoquinolin-(1H)-yl, tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, dihydro-quinazolinyl, tetrahydro-quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-imidazolyl, hexahydropyrrolo[3,4-b][1,4] Oxazin-(2H)-yl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-1H-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, (octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, 3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazinyl, 2,3,4,9-tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3-dihydro-1H-pyrrolo[1,2-a]indolyl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptenyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.0]hexanyl , 5-azaspiro[2.4]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 3,6-diazabicyclo[3.2.1]octyl, 1,4-dihydroindeno[1,2-c]pyrazolyl, dihydropyranyl, dihydropyridinyl, dihydroquinolinyl, 8H-indeno[1,2-d]thiazolyl, tetrahydroimidazo[1,Examples of suitable aryl groups include 2-a]pyridinyl, pyridin-2(1H)-one, and 8-azabicyclo[3.2.1]oct-2-enyl. The term "aziridinyl" as used herein includes aziridin-1-yl and aziridin-2-yl. The term "oxiranyl" as used herein includes oxiranyl-2-yl. The term "thiiranyl" as used herein includes thiiran-2-yl. The term "azetidinyl" as used herein includes azetidin-1-yl, azetidin-2-yl, and azetidin-3-yl. The term "oxetanyl" as used herein includes oxetan-2-yl and oxetan-3-yl. The term "thietanyl" as used herein includes thietan-2-yl and thietan-3-yl. The term "pyrrolidinyl" as used herein includes pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl. The term "tetrahydrofuranyl" as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. The term "tetrahydrothiophenyl" as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. The term "succinimidyl" as used herein includes succinimide-1-yl and succinimide-3-yl. The term "dihydropyrrolyl" as used herein includes 2,3-dihydropyrrol-1-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydropyrrol-1-yl, 2,5-dihydro-1H-pyrrol-3-yl, and 2,5-dihydropyrrol-5-yl. The term "2H-pyrrolyl" as used herein includes 2H-pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl, and 2H-pyrrol-5-yl. The term "3H-pyrrolyl" as used herein includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl, and 3H-pyrrol-5-yl. The term "dihydrofuranyl" as used herein includes 2,3-dihydrofuran-2-yl, 2,Examples of dihydrothiophenyl include 3-dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5-dihydrofuran-4-yl, and 2,5-dihydrofuran-5-yl. The term "dihydrothiophenyl," as used herein, includes 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3-dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5-dihydrothiophen-4-yl, and 2,5-dihydrothiophen-5-yl. The term "imidazolidinyl" as used herein includes imidazolidin-1-yl, imidazolidin-2-yl, and imidazolidin-4-yl. The term "pyrazolidinyl" as used herein includes pyrazolidin-1-yl, pyrazolidin-3-yl, and pyrazolidin-4-yl. The term "imidazolinyl" as used herein includes imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl, and imidazolin-5-yl. The term "pyrazolinyl," as used herein, includes 1-pyrazolin-3-yl, 1-pyrazolin-4-yl, 2-pyrazolin-1-yl, 2-pyrazolin-3-yl, 2-pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3-pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-4-yl, and 3-pyrazolin-5-yl. The term "dioxolanyl," also known as "1,3-dioxolanyl," as used herein, includes dioxolan-2-yl, dioxolan-4-yl, and dioxolan-5-yl. The term "dioxolyl," also known as "1,The term "3-dioxolyl" as used herein includes dioxol-2-yl, dioxol-4-yl, and dioxol-5-yl. The term "oxazolidinyl" as used herein includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, and oxazolidin-5-yl. The term "isoxazolidinyl" as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, and isoxazolidin-5-yl. The term "oxazolinyl," as used herein, includes 2-oxazolinyl-2-yl, 2-oxazolinyl-4-yl, 2-oxazolinyl-5-yl, 3-oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4-oxazolinyl-2-yl, 4-oxazolinyl-3-yl, 4-oxazolinyl-4-yl and 4-oxazolinyl-5-yl. The term "isoxazolinyl" as used herein includes 2-isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl-3-yl, 3-isoxazolinyl-4-yl, 3-isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl-4-yl, and 4-isoxazolinyl-5-yl. The term "thiazolidinyl" as used herein includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, and thiazolidin-5-yl. The term "isothiazolidinyl" as used herein includes isothiazolin-2-yl, isothiazolin-3-yl, isothiazolin-4-yl, The term "thiazolinyl," as used herein, includes 2-thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3-thiazolinyl-2-yl, 3-thiazolinyl-4-yl, 3-thiazolinyl-5-yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4-thiazolinyl-4-yl, and 4-thiazolinyl-5-yl. The term "isothiazolinyl" as used herein includes 2-isothiazolinyl-3-yl, 2-isothiazolinyl-4-yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl-4-yl, 3-isothiazolinyl-5-yl, 4-isothiazolinyl-2-yl, 4-isothiazolinyl-3-yl, 4-isothiazolinyl-4-yl, and 4-isothiazolinyl-5-yl. The term "piperidyl," also known as "piperidinyl," as used herein includes piperid-1-yl, piperid-2-yl, piperid-3-yl, and piperid-4-yl. The term "dihydropyridinyl," as used herein, includes 1,2-dihydropyridin-1-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 1,4-dihydropyridin-1-yl, 1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin-3-yl, yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-4-yl, 3,4-dihydropyridin-5-yl and 3,4-dihydropyridin-6-yl.The term "tetrahydropyridinyl" as used herein includes 1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-2-yl, 1,2,3,4-tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6-tetrahydropyridin- The term "tetrahydropyranyl," also known as "oxanyl" or "tetrahydro-2H-pyranyl," as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl, and tetrahydropyran-4-yl. The term "tetrahydrothiopyranyl," also known as "thianil" or "tetrahydro-2H-thiopyranyl," as used herein includes tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, and tetrahydrothiopyran-4-yl. The term "2H-pyranyl," as used herein, includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl, and 2H-pyran-6-yl. The term "4H-pyranyl," as used herein, includes 4H-pyran-2-yl, 4H-pyran-3-yl, and 4H-pyran-4-yl.The term "3,4-dihydro-2H-pyranyl" as used herein includes 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl, and 3,4-dihydro-2H-pyran-6-yl. The term "3,6-dihydro-2H-pyranyl" as used herein includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl, and 3,6-dihydro-2H-pyran-6-yl. The term "tetrahydrothiophenyl" as used herein includes tetrahydrothiophen-2-yl, tetrahydrothiophenyl-3-yl, and tetrahydrothiophenyl-4-yl. The term "2H-thiopyranyl" as used herein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, and 2H-thiopyran-6-yl. The term "4H-thiopyranyl" as used herein includes 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, and 4H-thiopyran-4-yl. The term "3,4-dihydro-2H-thiopyranyl" as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3-yl, 3,4-dihydro-2H-thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl, and 3,4-dihydro-2H-thiopyran-6-yl. The term "3,6-dihydro-2H-thiopyranyl" as used herein includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6-dihydro-2H-thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl, and 3,6-dihydro-2H-thiopyran-6-yl. The term "piperazinyl," also known as "piperazidinyl," as used herein includes piperazin-1-yl and piperazin-2-yl.The term "morpholinyl" as used herein includes morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl. The term "thiomorpholinyl" as used herein includes thiomorpholin-2-yl, thiomorpholin-3-yl, and thiomorpholin-4-yl. The term "dioxanyl" as used herein includes 1,2-dioxan-3-yl, 1,2-dioxan-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl, and 1,4-dioxan-2-yl. The term "dithianyl" as used herein includes 1,2-dithian-3-yl, 1,2-dithian-4-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl, 1,3-dithian-5-yl, and 1,4-dithian-2-yl. The term "oxathianyl" as used herein includes oxathian-2-yl and oxathian-3-yl. The term "trioxanyl" as used herein includes 1,2,3-trioxan-4-yl, 1,2,3-trioxan-5-yl, 1,2,4-trioxan-3-yl, 1,2,4-trioxan-5-yl, 1,2,4-trioxan-6-yl, and 1,3,4-trioxan-2-yl. The term "azepanyl" as used herein includes azepan-1-yl, azepan-2-yl, azepan-3-yl, and azepan-4-yl. The term "homopiperazinyl" as used herein includes homopiperazin-1-yl, homopiperazin-2-yl, homopiperazin-3-yl, and homopiperazin-4-yl. The term "indolinyl" as used herein includes indolin-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl. The term "quinolizinyl" as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl.The term "isoindolinyl" as used herein includes isoindolin-1-yl, isoindolin-2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl. The term "3H-indolyl" as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6-yl, and 3H-indol-7-yl. The term "quinolizinyl" as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl. The term "quinolizinyl" as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl, and quinolizidin-4-yl. The term "tetrahydroquinolinyl" as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin-2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl, and tetrahydroquinolin-8-yl. The term "tetrahydroisoquinolinyl" as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl, and tetrahydroisoquinolin-8-yl. The term "chromanyl" as used herein includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl, and chroman-8-yl. The term "1H-pyrrolidine" as used herein includes 1H-pyrrolidin-1-yl, 1H-pyrrolidin-2-yl, 1H-pyrrolidin-3-yl, 1H-pyrrolidin-5-yl, 1H-pyrrolidin-6-yl and 1H-pyrrolidin-7-yl.The term "3H-pyrrolidine" as used herein includes 3H-pyrrolidin-1-yl, 3H-pyrrolidin-2-yl, 3H-pyrrolidin-3-yl, 3H-pyrrolidin-5-yl, 3H-pyrrolidin-6-yl and 3H-pyrrolidin-7-yl.

[0050] When the suffix "ene" is used in conjunction with a heterocyclyl group (i.e., "heterocyclylene"), it is intended to mean a heterocyclyl group, as defined herein, having two single bonds as points of attachment to other groups. As used herein, the term "heterocyclylene," alone or as part of another substituent, refers to a divalent heterocyclyl group, i.e., a heterocyclyl group having two monovalent centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of a parent heterocyclyl, i.e., having two single bonds for attachment to two other groups. Heterocyclylene groups can be substituted as indicated herein.

[0051] The term "heteroaryl" refers to an aromatic ring system containing 5 to 18 atoms, preferably 5 to 14 atoms (5-14-membered heteroaryl), and even more preferably 5 to 10 atoms (5-10-membered heteroaryl), including at least one N, O, S, or P, containing one or two rings that may be fused together or covalently linked, each ring typically containing 5 to 6 atoms; at least one of the rings is aromatic, the N and S heteroatoms may be optionally oxidized, the N heteroatom may be optionally quaternized, and at least one carbon atom of the heteroaryl may be oxidized to form at least one C=O. Systems in which a heteroaryl ring is fused to a cycloalkyl ring, cycloalkenyl ring, or cycloalkynyl ring are considered heteroaryl, regardless of the ring attached to the core structure. Systems in which a heteroaryl ring is fused to a heterocyclic ring are considered heteroaryl, regardless of the ring attached to the core structure. Systems in which a heteroaryl ring is fused to an aryl ring are considered heteroaryl, regardless of the ring attached to the core structure. Non-limiting examples of such heteroaryls include pyridinyl, pyrrolyl, thiophenyl (also known as thienyl), furanyl, thiazolyl, isothiazolyl, thiadiazolyl, triazol-2-yl, 1H-pyrazol-5-yl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, pyranyl, thiopyranyl, imidazo[2,1-b][1,3]thiazolyl, Thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-Benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, benzo[c][1,2,5]oxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, thienopyridinyl, purinyl, 9H-purinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, imidazo[5,1-a]isoquinolinyl, imidazo[1,5-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl , quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl; acridinyl, phthalazinyl, 1,4-dihydroindeno[1,2-c]-1H-pyrazolyl, 2,3-dihydro-1H-inden-1-one, 2,3-dihydro-1H-indenyl, 3,4-dihydroquinolin-2(1H)-one, 5,6-dihydroimidazo[5,1-a]isoquinolinyl, 8H-indeno[1,2-d]thiazolyl, benzo[d]oxazol-2(3H)-one, quinolin-2(1H)-one, quinazolin-4(1H)-one, quinazolin-2,4(1H,3H)-dione, benzo-[d]oxazolyl and pyrazolo[1,5-a]pyridinyl.

[0052] In some preferred embodiments, the term "5- or 6-membered heteroaryl" refers to an aromatic ring system containing one or more heteroatoms selected from N, S, or O, and in some embodiments, heteroaryl can be selected from the group including, for example, pyridinyl, thiadiazolyl, thiazolyl, imidazolyl, isoxazolyl, pyrimidinyl, thienyl, or furanyl.

[0053] The term "pyrrolyl" (also known as azolyl), as used herein, includes pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl. The term "furanyl" (also known as "furyl"), as used herein, includes furan-2-yl and furan-3-yl (also known as furan-2-yl and furan-3-yl). The term "thiophenyl" (also known as "thienyl"), as used herein, includes thiophen-2-yl and thiophen-3-yl (also known as thien-2-yl and thien-3-yl). The term "pyrazolyl" (also known as 1H-pyrazolyl and 1,2-diazolyl), as used herein, includes pyrazol-1-yl, pyrazol-3-yl, or 1H-pyrazol-5-yl, pyrazol-4-yl, and pyrazol-5-yl. The term "imidazolyl," as used herein, includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, and imidazol-5-yl. The term "oxazolyl" (also known as 1,3-oxazolyl), as used herein, includes oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl. The term "isoxazolyl" (also known as 1,2-oxazolyl), as used herein, includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. The term "thiazolyl" (also known as 1,3-thiazolyl), as used herein, includes thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl (also known as 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl). The term "isothiazolyl" (also known as 1,2-thiazolyl), as used herein, includes isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl.The term "triazolyl" as used herein includes triazol-2-yl, 1H-triazolyl, and 4H-1,2,4-triazolyl, and "1H-triazolyl" includes 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, and 1H-1,2,4-triazol-5-yl. "4H-1,2,4-triazolyl" includes 4H-1,2,4-triazol-4-yl and 4H-1,2,4-triazol-3-yl. The term "oxadiazolyl" as used herein includes 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, and 1,3,4-oxadiazol-2-yl. The term "thiadiazolyl" as used herein includes 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl (also known as furazan-3-yl), and 1,3,4-thiadiazol-2-yl. The term "tetrazolyl" as used herein includes 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term "oxatriazolyl" as used herein includes 1,2,3,4-oxatriazol-5-yl and 1,2,3,5-oxatriazol-4-yl. The term "thiatriazolyl" as used herein includes 1,2,3,4-thiatriazol-5-yl and 1,2,3,5-thiatriazol-4-yl. The term "pyridinyl" (also known as "pyridyl") as used herein includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl (also known as 2-pyridyl, 3-pyridyl, and 4-pyridyl).The term "pyrimidyl," as used herein, includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl, and pyrimid-6-yl. The term "pyrazinyl," as used herein, includes pyrazin-2-yl and pyrazin-3-yl. The term "pyridazinyl," as used herein, includes pyridazin-3-yl and pyridazin-4-yl. The term "oxazinyl" (also known as "1,4-oxazinyl"), as used herein, includes 1,4-oxazin-4-yl and 1,4-oxazin-5-yl. The term "dioxinyl" (also known as "1,4-dioxinyl"), as used herein, includes 1,4-dioxin-2-yl and 1,4-dioxin-3-yl. The term "thiazinyl" (also known as "1,4-thiazinyl") as used herein includes 1,4-thiazin-2-yl, 1,4-thiazin-3-yl, 1,4-thiazin-4-yl, 1,4-thiazin-5-yl, and 1,4-thiazin-6-yl. The term "triazinyl" as used herein includes 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, and 1,2,3-triazin-5-yl. The term "imidazo[2,1-b][1,3]thiazolyl" as used herein includes imidazo[2,1-b][1,3]thiazol-2-yl, imidazo[2,1-b][1,3]thiazol-3-yl, imidazo[2,1-b][1,3]thiazol-5-yl, and imidazo[2,1-b][1,3]thiazol-6-yl. The term "thieno[3,2-b]furanyl" as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan-5-yl. The term "thieno[3,2-b]thiophenyl" as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl, and thieno[3,2-b]thien-6-yl.The term "thieno[2,3-d][1,3]thiazolyl" as used herein includes thieno[2,3-d][1,3]thiazol-2-yl, thieno[2,3-d][1,3]thiazol-5-yl, and thieno[2,3-d][1,3]thiazol-6-yl. The term "thieno[2,3-d]imidazolyl" as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl, and thieno[2,3-d]imidazol-5-yl. The term "tetrazolo[1,5-a]pyridinyl" as used herein includes tetrazolo[1,5-a]pyridin-5-yl, tetrazolo[1,5-a]pyridin-6-yl, tetrazolo[1,5-a]pyridin-7-yl, and tetrazolo[1,5-a]pyridin-8-yl. The term "indolyl" as used herein includes indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, and indol-7-yl. The term "indolizinyl" as used herein includes indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term "isoindolyl," as used herein, includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl, and isoindol-7-yl. The term "benzofuranyl" (also known as benzo[b]furanyl), as used herein, includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, and benzofuran-7-yl. The term "isobenzofuranyl" (also known as benzo[c]furanyl), as used herein, includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, and isobenzofuran-7-yl.The term "benzothiophenyl" (also known as benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, and -7-benzo[b]thiophenyl (also known as benzothien-2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl, and benzothien-7-yl). The term "isobenzothiophenyl" (also known as benzo[c]thienyl) as used herein includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien-6-yl, and isobenzothien-7-yl. The term "indazolyl" (also known as 1H-indazolyl or 2-azaindolyl), as used herein, includes 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl and 2H-indazol-7-yl. The term "benzimidazolyl" as used herein includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, and benzimidazol-7-yl. The term "1,3-benzoxazolyl" as used herein includes 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, and 1,3-benzoxazol-7-yl. The term "1,2-benzisoxazolyl" as used herein includes 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl and 1,2-benzisoxazol-7-yl.The term "2,1-benzisoxazolyl" as used herein includes 2,1-benzisoxazol-3-yl, 2,1-benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6-yl, and 2,1-benzisoxazol-7-yl. The term "1,3-benzothiazolyl" as used herein includes 1,3-benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, and 1,3-benzothiazol-7-yl. The term "1,2-benzisothiazolyl" as used herein includes 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl, and 1,2-benzisothiazol-7-yl. The term "2,1-benzisothiazolyl" as used herein includes 2,1-benzisothiazol-3-yl. Examples of benzotriazolyl include 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl, and 2,1-benzisothiazol-7-yl. The term "benzotriazolyl," as used herein, includes benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, and benzotriazol-7-yl. The term "1,2,3-benzoxadiazolyl," as used herein, includes 1,2,3-benzoxadiazol-4-yl, 1,2,3-benzoxadiazol-5-yl, 1,2,3-benzoxadiazol-6-yl, and 1,2,3-benzoxadiazol-7-yl. The term "2,1,3-benzoxadiazolyl" as used herein includes 2,1,3-benzoxadiazol-4-yl, 2,1,3-benzoxadiazol-5-yl, 2,1,3-benzoxadiazol-6-yl, and 2,1,3-benzoxadiazol-7-yl. The term "1,2,3-benzothiadiazolyl" as used herein includes 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 1,2,3-benzothiadiazol-6-yl, and 1,2,3-benzothiadiazol-7-yl. The term "2,1,3-benzothiadiazolyl" as used herein includes 2,1,3-benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-6-yl, and 2,1,3-benzothiadiazol-7-yl. The term "thienopyridinyl" as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, and thieno[3,2-b]pyridinyl. The term "purinyl" as used herein includes purin-2-yl, purin-6-yl, purin-7-yl, and purin-8-yl.The term "imidazo[1,2-a]pyridinyl" as used herein includes imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, and imidazo[1,2-a]pyridin-7-yl. The term "1,3-benzodioxolyl" as used herein includes 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 1,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl. The term "quinolinyl" as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, and quinolin-8-yl. The term "isoquinolinyl" as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, and isoquinolin-8-yl. The term "cinnolinyl" as used herein includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl, and cinnolin-8-yl. The term "quinazolinyl" as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, and quinazolin-8-yl. The term "quinoxalinyl" as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.

[0054] When the suffix "ene" is used in conjunction with a heteroaryl group (i.e., "heteroarylene"), it is intended to mean a heteroaryl group, as defined herein, having two single bonds as points of attachment to other groups. As used herein, the term "heteroarylene," alone or as part of another substituent, refers to a divalent heteroaryl group, i.e., a heteroaryl group having two monovalent centers, i.e., two single bonds for attachment to two other groups, obtained by removing two hydrogen atoms from the same or two different carbon atoms of a parent heteroaryl. Heteroarylene groups can be substituted as indicated herein.

[0055] Heteroaryl and heterocycle or heterocyclyl as used herein include, by way of example and without limitation, groups described in Paquette, Leo A. "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), especially Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. "Comprehensive Heterocyclic Chemistry" (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.

[0056] The term "carbonyl" as a group or part of a group refers to the group -C(=O)-, alternatively -CO-.

[0057] The term "carboxy", "carboxyl" or "hydroxycarbonyl" as a group or part of a group refers to the group -C(=O)-OH.

[0058] The term "alkoxycarbonyl" or "alkyloxycarbonyl" as a group or part of a group refers to a group of the formula -C(=O)-OR b where R b refers to alkyl as defined herein.

[0059] The term "amino" as a group or part of a group refers to the group -NH2.

[0060] The term “mono- or di-alkylamino” as a group or part of a group refers to a group of the formula —N(R l )(R b ) group (wherein R l is hydrogen or alkyl, and R b is alkyl as defined herein. Thus, the term includes monoalkylamino groups (e.g., monoalkylamino groups such as methylamino and ethylamino) and dialkylamino groups (e.g., dialkylamino groups such as dimethylamino and diethylamino). Non-limiting examples of suitable mono- or di-alkylamino groups include n-propylamino, isopropylamino, n-butylamino, i-butylamino, sec-butylamino, t-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di-i-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-i-propylamino, n-butylmethylamino, i-butylmethylamino, t-butylmethylamino, ethyl-n-propylamino, ethyl-i-propylamino, n-butylethylamino, i-butylethylamino, t-butylethylamino, di-n-butylamino, di-i-butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.

[0061] The term “alkylcarbonylamino” as a group or part of a group refers to a group of the formula —N(R l )-C(=O)-R b where R l is hydrogen or alkyl, and R brefers to alkyl as defined herein.

[0062] The term "single bond," as used herein with respect to a linking group, i.e., when used in a manner that selects certain linking groups in formulas herein from a single bond, etc., refers to a molecule in which the linking group is absent, and thus refers to a compound in which there is a direct single bond connection between the two moieties connected by the linking group.

[0063] The nomenclature of any substituent occurring at more than one site in a compound of the invention shall be considered to be independently selected.

[0064] Substituents are optionally named with or without bonds. Regardless of the reference to a bond, if a substituent is multivalent, any and all possible orientations of the substituent (relative to its position in the referenced structure) are intended.

[0065] Any reference to "a compound according to the invention" or "a compound of formula (I)" also includes, unless expressly indicated otherwise, any isomers, such as stereoisomers and tautomers, salts, such as pharmaceutically and / or physiologically acceptable salts, hydrates, solvates and polymorphs of such compounds.

[0066] As used herein and unless otherwise specified, the term "solvate" includes any combination that may be formed by a derivative of the present invention with a suitable inorganic solvent (e.g., hydrate) or organic solvent such as, but not limited to, alcohols, ketones, esters, ethers, nitriles, etc.

[0067] Preferred statements (features) and embodiments of the methods, compositions, and uses of the present invention are set forth below. Each statement and embodiment of the present invention so defined may be combined with any other statement and / or embodiment, unless expressly indicated otherwise. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or statement indicated as being preferred or advantageous. The present invention is particularly encompassed herein by any one or any combination of one or more of the below-numbered statements and embodiments, and any other aspects and / or embodiments.

[0068] 1. Compounds of formula (B1A), formula (B1B) or formula (B1C) [ka] (In the formula, A 1a is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1a is C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl containing at least one N, O and / or S, and 5- to 9-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1a is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1a is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; X 1a -CO-, -SO2-, -C(R 3a ) 2- or 5-membered heteroarylene; Y 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Z 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Each R 3a are independently hydrogen, halo or C 1~6 alkyl; Each R 5a are independently hydrogen or C 1~6 alkyl; X 2a is a single bond or -CO-; Y 2a is a single bond or -C(R 4a )2- and Z 2ais a single bond or -(C(R 4a )2) n - or -CO-; n is an integer selected from 1 or 2; Each R 4a are independently hydrogen, halo, or C 1~6 alkyl; or two R 4a together with the atoms to which they are attached, C 3~6 can form a cycloalkyl; A 2a is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl, C 3~6 Cycloalkyl and C 1~6 alkyl; preferably, A 2a is C 6~10 aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, C 3~6 Cycloalkyl and C 1~4 alkyl; preferably, A 2a is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2a is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl); [ka] (In the formula, A 1b is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 3~6 cycloalkyl, 5-9 membered heteroaryl containing at least one N, O and / or S, and 5-9 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; preferably, A 1b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3b is hydrogen or C 1~6 alkyl; Y 1b -CO-, -C(R 5b ) 2- or 5-membered heteroarylene; Z 1b is -C(R 5b )2- and; R 4b is hydrogen, C 1~6 Alkyl or C 1~6 alkoxycarbonyl; Each R 5b are independently hydrogen, halo or C 1~6 alkyl; Each R 6b are independently hydrogen or C 1~6 alkyl; Y 2b is -C(R 5b ) 2- or single bond; Z 2b is a single bond or -(C(R 5b )2) m - or -CO-; m is an integer selected from 1 or 2; A 2b is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl, C 3~6 Cycloalkyl and C 1~6alkyl; preferably, A 2b is C 6~10 aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, C 3~6 Cycloalkyl and C 1~4 alkyl; preferably, A 2b is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2b is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 cycloalkyl; preferably, A 2b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl); [ka] (In the formula, A 1c is C 6~10 Aryl, C 3~6cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl containing at least one N, O and / or S, and 5- to 9-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3c is hydrogen or C 1~6alkyl; Y 1c is a single bond or -C(R 4c )2-, -NR 6c -, -O-, or 5-membered heteroarylene; Z 1c is a single bond or -C(R 4c )2- or -O-; Each R 4c are independently hydrogen, halo or C 1~6 alkyl; Each R 6c are independently hydrogen or C 1~6 alkyl; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- and Z 2c is a single bond or -(C(R 5c )2) p - or -CO-; p is an integer selected from 1 or 2; Each R 5c are independently hydrogen, halo, or C 1~6 alkyl; or two R 5c together with the atoms to which they are attached, C 3~6 can form a cycloalkyl; A 2c is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S, C 3~6 Cycloalkyl, hydrogen, -N(R 6c )2 and C 1~6 alkyl; preferably, A 2c is C 6~10 aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, C 3~6 Cycloalkyl and C 1~4alkyl; preferably, A 2c is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2c is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl) or a salt, solvate, hydrate, polymorph, tautomer, racemate or stereoisomer thereof, or a prodrug thereof.

[0069] 2. Compounds of formula (B1A), formula (B1B) or formula (B1C) [ka] (In the formula, A 1a is C 6~10 Aryl, C 3~6cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; each of said groups is unsubstituted or selected from the group consisting of one or more R 1a and each R 1a are independently halo, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; X 1a -CO-, -SO2-, -C(R 3a ) 2- or 5-membered heteroarylene; Y 1a is -C(R 3a )2-, -NR 5a - or -O-; or Y 1a is a single bond; Z 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Each R 3a are independently hydrogen, halo or C 1~6 alkyl; Each R 5a are independently hydrogen or C 1~6 alkyl; X2a is a single bond or -CO-; Y 2a is -C(R 4a )2- or Y 2a is a single bond, Z 2a is a single bond or -(C(R 4a )2) n - or -CO-; n is an integer selected from 1 or 2; Each R 4a are independently hydrogen, halo, or C 1~6 alkyl; or two R 4a together with the atoms to which they are attached, C 3~6 can form a cycloalkyl; A 2a is C 6~10 Aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl and C 3~6 cycloalkyl; each of said groups is unsubstituted or contains one or more R 2a each R 2a are independently halo, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; However, A 1a teeth, [ka] (In the formula, R 1a1 and R 1a2 are each independently, C 1~2 alkyl, or R 1a1 and R 1a2 together with the carbon atoms to which they are attached, C3~6 Forming a cycloalkyl, R 1a has the same meaning as defined herein, and s is an integer selected from 0, 1, or 2. rather than; A 2a teeth, [ka] (In the formula, R 2a has the same meaning as defined herein, and s is an integer selected from 0, 1, or 2. shall not be; However, the compound is 2-benzyl-6-(toluene-4-sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(1,3-benzodioxol-5-ylmethyl)-6-[(4-methylphenyl)sulfonyl-2,6-diazaspiro[3.3]heptane; 2-(1,3-benzodioxol-5-ylmethyl)-6-(phenylmethyl)-2,6-diazaspiro[3.3]heptane; 2-benzyl-6-(tosyl)-2,6-diazaspiro[3.3]heptane; 6-Benzyl-2,6-diazaspiro[3.3]heptan-2-yl)(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methanone; (5-cyclohexyl-1H-pyrazol-3-yl)(6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-isopropyl-1H-imidazol-4-yl)methanone; (5-Isopropyl-1H-pyrazol-3-yl)(6-(1-methylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; (5-Isopropyl-1H-pyrazol-3-yl)(6-(thiophene-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone; [2-(4-Fluoro-1-methyl-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone shall not be); [ka] (In the formula, A 1b is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; each of said groups is unsubstituted or selected from the group consisting of one or more R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1b together with the atoms to which they are attached, C 6~10can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3b is hydrogen or C 1~6 alkyl; Y 1b -CO-, -C(R 5b ) 2- or 5-membered heteroarylene; Z 1b is -C(R 5b )2- and; R 4b is hydrogen, C 1~6 Alkyl or C 1~6 alkoxycarbonyl; Each R 5b are independently hydrogen, halo or C 1~6 alkyl; Each R 6b are independently hydrogen or C 1~6 alkyl; Y 2b is -C(R 5b ) 2- or single bond; Z 2b is a single bond or -(C(R 5b )2) m - or -CO-; m is an integer selected from 1 or 2; A 2b is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl, C 3~6 Cycloalkyl and C 1~6 alkyl; each of said groups is unsubstituted or contains one or more R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl); [ka] (In the formula, A 1c is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; each of said groups is unsubstituted or selected from the group consisting of one or more R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3c is hydrogen or C 1~6 alkyl; Y 1c is a single bond or -C(R 4c )2-, -NR6c -, -O-, or 5-membered heteroarylene; Z 1c is a single bond or -C(R 4c )2- or -O-; Each R 4c are independently hydrogen, halo or C 1~6 alkyl; Each R 6c are independently hydrogen or C 1~6 alkyl; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- and Z 2c is a single bond or -(C(R 5c )2) p - or -CO-; p is an integer selected from 1 or 2; Each R 5c are independently hydrogen, halo, or C 1~6 alkyl; or two R 5c together with the atoms to which they are attached, C 3~6 can form a cycloalkyl; A 2c is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S, C 3~6 Cycloalkyl and -N(R 6c )2; each of said groups is unsubstituted or contains one or more R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl, However, A 1c teeth, [ka] Instead, A 2c teeth, [ka] It is not However, the compound is N-benzyl-2-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-amine; N-(2-(2-fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)-6,7-dimethoxy-2,3-dihydro-1H-cyclopenta[b]quinolin-9-amine; 6-((2-((benzyloxy)carbonyl)-2-azaspiro[3.3]heptan-6-yl)amino)-2-chloropyrimidine-4-carboxylic acid; Benzyl 6-((2-chloro-6-(methoxycarbonyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (This is not or a salt, solvate, hydrate, polymorph, tautomer, racemate or stereoisomer thereof, or a prodrug thereof.

[0070] 3. A compound according to statement 1 or 2, A 1a is C 6~10Aryl, C 4~6 cycloalkyl, 5-9 membered heteroaryl containing at least one N, O and / or S, and 5-9 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1a is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1a is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., 1, 2, 3 or 4 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl and C 3~6 cycloalkyl; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., one or two R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; X 1a -CO-, -SO2-, -C(R 3a ) 2- or 5-membered heteroarylene; preferably, X 1a -CO-, -SO2-, -C(R 3a ) 2- or 1,2,4-thiadiazolyl; preferably, X 1a is -CO-, -SO2- or -C(R 3a )2-selected; Y 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Z 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Each R 3a are independently hydrogen, halo or C 1~6 alkyl; preferably, each R 3a is hydrogen, halo or C 1~4 alkyl; preferably, each R 3a is hydrogen, halo or C 1~2 is alkyl; Each R 5a are independently hydrogen or C 1~6alkyl; preferably, each R 5a is hydrogen or C 1~4 alkyl; preferably, each R 5a is hydrogen or C 1~2 is alkyl; X 2a is a single bond or -CO-; Y 2a is a single bond or -C(R 4a )2- and Z 2a is a single bond or -(C(R 4a )2) n - or -CO-; n is an integer selected from 1 or 2; Each R 4a are independently hydrogen, halo, or C 1~6 alkyl; or two R 4a together with the atoms to which they are attached, C 3~6 cycloalkyl; preferably, each R 4a are independently hydrogen, halo or C 1~4 alkyl; or two R 4a together with the atoms to which they are attached, C 3~5 cycloalkyl; preferably, each R 4a are independently hydrogen, halo or C 1~2 alkyl; or two R 4a together with the atoms to which they are attached, C 3~4 can form a cycloalkyl; A 2a is C 6~10 Aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, and C 3~6 cycloalkyl; preferably, A 2a is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2ais phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2a , e.g., 1, 2, 3 or 4 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2a , e.g., 1, 2 or 3 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1b is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl containing at least one N, O and / or S, and 5- to 9-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; preferably, A 1b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., 1, 2, 3 or 4 R 1b and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., 1, 2 or 3 R 1b and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl and C 3~6 cycloalkyl; and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., 1, 2 or 3 R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R are selected from the group consisting of alkoxy, cyano, and hydroxy; 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., one or two R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1btogether with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; R 3b is hydrogen or C 1~6 alkyl; preferably, each R 3b is hydrogen or C 1~4 alkyl; preferably, each R 3b is hydrogen or C 1~2 is alkyl; Y 1b -CO-, -C(R 5b ) 2- or 5-membered heteroarylene; preferably, Y 1b -CO-, -C(R 5b ) 2- or 1,2,4-thiadiazolyl; Z 1b is -C(R 5b )2- and; R 4b is hydrogen, C 1~6 Alkyl or C 1~6 alkoxycarbonyl; preferably, R 4b is hydrogen, C 1~4 Alkyl or C 1~4 alkoxycarbonyl; preferably, R 4b is hydrogen, C 1~2 Alkyl or C 1~2 alkoxycarbonyl; Each R 5b are independently hydrogen, halo or C 1~6 alkyl; preferably, each R 5b are independently hydrogen, halo or C 1~4 alkyl; preferably, each R 5b are independently hydrogen, halo or C 1~2 alkyl; preferably, each R 5b are independently hydrogen or C 1~2 alkyl; Each R 6b are independently hydrogen or C 1~6alkyl; preferably, each R 6b are independently hydrogen or C 1~4 alkyl; preferably, each R 6b are independently hydrogen or C 1~2 alkyl; Y 2b is -C(R 5b ) 2- or single bond; Z 2b is a single bond or -(C(R 5b )2) m - or -CO-; m is an integer selected from 1 or 2; A 2b is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl, C 3~6 Cycloalkyl and C 1~6 alkyl; preferably, A 2b is C 6~10 aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, C 3~6 Cycloalkyl and C 1~4 alkyl; preferably, A 2b is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2b is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 cycloalkyl; preferably, A 2b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., 1, 2, 3 or 4 R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., 1, 2 or 3 R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b)2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., one or two R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1c is C 6~10 Aryl, C 3~6 cycloalkyl, 5-10 membered heteroaryl containing at least one N, O and / or S, and 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl containing at least one N, O and / or S, and 5- to 9-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 4~6cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., 1, 2, 3 or 4 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1ctogether with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., 1, 2 or 3 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl and C 3~6 cycloalkyl; and / or two R 1c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., one or two R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3c is hydrogen or C 1~6 alkyl; preferably, each R 3c is hydrogen or C 1~4 alkyl; preferably, each R 3c is hydrogen or C 1~2 is alkyl; Y 1c is a single bond or -C(R 4c )2-, -NR 6c-, -O-, or 5-membered heteroarylene; preferably, Y 1c is a single bond or -C(R 4c )2-, -NR 6c -, -O-, or 1,2,4-thiadiazolyl; Z 1c is a single bond or -C(R 4c )2- or -O-; Each R 4c are independently hydrogen, halo or C 1~6 alkyl; preferably, each R 4c is hydrogen, halo or C 1~4 alkyl; preferably, each R 4c is hydrogen, halo or C 1~2 is alkyl; Each R 6c are independently hydrogen or C 1~6 alkyl; preferably, each R 6c is hydrogen or C 1~4 alkyl; preferably, each R 6c is hydrogen or C 1~2 is alkyl; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- and Z 2c is a single bond or -(C(R 5c )2) p - or -CO-; p is an integer selected from 1 or 2; Each R 5c are independently hydrogen, halo, or C 1~6 alkyl; or two R 5c together with the atoms to which they are attached, C 3~6 cycloalkyl; preferably, each R 5c are independently hydrogen, halo or C 1~4 alkyl; or two R 5c together with the atoms to which they are attached, C 3~5cycloalkyl; preferably, each R 5c are independently hydrogen, halo or C 1~2 alkyl; or two R 5c together with the atoms to which they are attached, C 3~4 can form a cycloalkyl; A 2c is C 6~10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S, C 3~6 Cycloalkyl and -N(R 6c )2; preferably, A 2c is C 6~10 Aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, and C 3~6 cycloalkyl; preferably, A 2c is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2c is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c and C 1~6alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2c , e.g., 1, 2, 3 or 4 R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2c , e.g., 1, 2 or 3 R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 Compounds that can form aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl.

[0071] 4. A compound according to any one of statements 1 to 3, A 1a is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1a is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1a , e.g., 1, 2, 3 or 4 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C1~6 Alkoxycarbonyl and C 3~6 cycloalkyl; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R are selected from the group consisting of alkoxy, cyano, and hydroxy; 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., one or two R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; X 1a -CO-, -SO2-, -C(R 3a ) 2- or 1,2,4-thiadiazolyl; preferably, X 1a is -CO-, -SO2- or -C(R 3a )2-selected; Y1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Z 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Each R 3a is hydrogen, halo or C 1~4 alkyl; preferably, each R 3a is hydrogen, halo or C 1~2 is alkyl; Each R 5a is hydrogen or C 1~4 alkyl; preferably, each R 5a is hydrogen or C 1~2 is alkyl; X 2a is a single bond or -CO-; Y 2a is a single bond or -C(R 4a )2- and Z 2a is a single bond or -(C(R 4a )2) n - or -CO-; n is an integer selected from 1 or 2; Each R 4a are independently hydrogen, halo or C 1~4 alkyl; or two R 4a together with the atoms to which they are attached, C 3~5 cycloalkyl; preferably, each R 4a are independently hydrogen, halo or C 1~2 alkyl; or two R 4a together with the atoms to which they are attached, C 3~4 can form a cycloalkyl; A 2a is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2ais phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2a , e.g., 1, 2, 3 or 4 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2a , e.g., 1, 2 or 3 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1bis C 6~10 Aryl, C 3~6 cycloalkyl, 5-9 membered heteroaryl containing at least one N, O and / or S, and 5-9 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; preferably, A 1b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 1b , e.g., 1, 2, 3 or 4 R 1b and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., 1, 2 or 3 R 1b and each R 1a are independently hydrogen, halo, C1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl and C 3~6 cycloalkyl; and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., 1, 2 or 3 R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., one or two R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; Each R 3b is hydrogen or C 1~4alkyl; preferably, each R 3b is hydrogen or C 1~2 is alkyl; Y 1b -CO-, -C(R 5b ) 2- or 1,2,4-thiadiazolyl; Z 1b is -C(R 5b )2- and; R 4b is hydrogen, C 1~4 Alkyl or C 1~4 alkoxycarbonyl; preferably, R 4b is hydrogen, C 1~2 Alkyl or C 1~2 alkoxycarbonyl; Each R 5b are independently hydrogen, halo or C 1~4 alkyl; preferably, each R 5b are independently hydrogen, halo or C 1~2 alkyl; preferably, each R 5b are independently hydrogen or C 1~2 alkyl; Each R 6b are independently hydrogen or C 1~4 alkyl; preferably, each R 6b are independently hydrogen or C 1~2 alkyl; Y 2b is -C(R 5b ) 2- or single bond; Z 2b is a single bond or -(C(R 5b )2) m - or -CO-; m is an integer selected from 1 or 2; A 2b is C 6~10 aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, C 3~6 Cycloalkyl and C 1~4 alkyl; preferably, A 2b is C 6~10Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2b is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 cycloalkyl; preferably, A 2b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 2b , e.g., 1, 2, 3 or 4 R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., 1, 2 or 3 R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., one or two R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1c is C 6~10 Aryl, C 3~6 cycloalkyl, 5-9 membered heteroaryl containing at least one N, O and / or S, and 5-9 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R1c , e.g., 1, 2, 3 or 4 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., 1, 2 or 3 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl and C 3~6 cycloalkyl; and / or two R 1c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., one or two R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1c together with the atoms to which they are attached, C 6~10can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; Each R 3c is hydrogen or C 1~4 alkyl; preferably, each R 3c is hydrogen or C 1~2 is alkyl; Y 1c is a single bond or -C(R 4c )2-, -NR 6c -, -O-, or 1,2,4-thiadiazolyl; Z 1c is a single bond or -C(R 4c )2- or -O-; Each R 4c is hydrogen, halo or C 1~4 alkyl; preferably, each R 4c is hydrogen, halo or C 1~2 is alkyl; Each R 6c is hydrogen or C 1~4 alkyl; preferably, each R 6c is hydrogen or C 1~2 is alkyl; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- and Z 2c is a single bond or -(C(R 5c )2) p - or -CO-; p is an integer selected from 1 or 2; Each R 5c are independently hydrogen, halo or C 1~4 alkyl; or two R 5c together with the atoms to which they are attached, C 3~5 cycloalkyl; preferably, each R 5c are independently hydrogen, halo or C 1~2 alkyl; or two R 5ctogether with the atoms to which they are attached, C 3~4 can form a cycloalkyl; A 2c is C 6~10 Aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, and C 3~6 cycloalkyl; preferably, A 2c is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2c is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2c , e.g., 1, 2, 3 or 4 R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2c , e.g., 1, 2 or 3 R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 Compounds that can form aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl.

[0072] 5. A compound according to any one of statements 1 to 4, A 1a is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1a is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1a , e.g., 1, 2, 3 or 4 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl and C 3~6 cycloalkyl; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R are selected from the group consisting of alkoxy, cyano, and hydroxy; 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., one or two R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1atogether with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; A 2a is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2a is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2a , e.g., 1, 2, 3 or 4 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2a , e.g., 1, 2 or 3 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1b is C 6~10 Aryl, C 3~6 cycloalkyl, 5-9 membered heteroaryl containing at least one N, O and / or S, and 5-9 membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; preferably, A 1b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 1b , e.g., 1, 2, 3 or 4 R 1b and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl, (R 5a )2N-carbonyl and C 1~6alkylcarbonylamino; and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., 1, 2 or 3 R 1b and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl and C 3~6 cycloalkyl; and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., 1, 2 or 3 R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R are selected from the group consisting of alkoxy, cyano, and hydroxy; 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., one or two R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; A 2b is C 6~10 aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, C 3~6 Cycloalkyl and C 1~4 alkyl; preferably, A 2b is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2b is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 cycloalkyl; preferably, A 2b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 2b , e.g., 1, 2, 3 or 4 R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., 1, 2 or 3 R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., one or two R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1c is C 6~10 Aryl, C 3~6cycloalkyl, 5- to 9-membered heteroaryl containing at least one N, O and / or S, and 5- to 9-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1c , e.g., 1, 2, 3 or 4 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., 1, 2 or 3 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl and C3~6 cycloalkyl; and / or two R 1c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., one or two R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 2c is C 6~10 Aryl, 5-9 membered heteroaryl containing at least one N, O and / or S, and C 3~6 cycloalkyl; preferably, A 2c is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2c is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2c , e.g., 1, 2, 3 or 4 R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2c , e.g., 1, 2 or 3 R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 Compounds that can form aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl.

[0073] 6. A compound according to any one of statements 1 to 5, X 1a -CO-, -SO2-, -C(R 3a ) 2- or 1,2,4-thiadiazolyl; Y 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Z 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Each R 3ais hydrogen, halo or C 1~2 is alkyl; Each R 5a is hydrogen or C 1~2 is alkyl; X 2a is a single bond or -CO-; Y 2a is a single bond or -C(R 4a )2- and Z 2a is a single bond or -(C(R 4a )2) n - or -CO-; n is an integer selected from 1 or 2; Each R 4a are independently hydrogen, halo or C 1~2 alkyl; or two R 4a together with the atoms to which they are attached, C 3~4 A compound capable of forming a cycloalkyl.

[0074] 7. A compound according to any one of statements 1 to 5, Each R 3b is hydrogen or C 1~2 is alkyl; Y 1b -CO-, -C(R 5b ) 2- or 1,2,4-thiadiazolyl; Z 1b is -C(R 5b )2- and; R 4b is hydrogen, C 1~2 Alkyl or C 1~2 alkoxycarbonyl; Each R 5b are independently hydrogen, halo or C 1~2 alkyl; preferably, each R 5b are independently hydrogen or C 1~2 alkyl; Each R 6b are independently hydrogen or C 1~2 alkyl; Y 2b is -C(R5b ) 2- or single bond; Z 2b is a single bond or -(C(R 5b )2) m - or -CO-; and m is an integer selected from 1 or 2.

[0075] 8. A compound according to any one of statements 1 to 5, Each R 3c is hydrogen or C 1~2 is alkyl; Y 1c is a single bond or -C(R 4c )2-, -NR 6c -, -O-, or 1,2,4-thiadiazolyl; Z 1c is a single bond or -C(R 4c )2- or -O-; Each R 4c is hydrogen, halo or C 1~2 is alkyl; Each R 6c is hydrogen or C 1~2 is alkyl; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- and Z 2c is a single bond or -(C(R 5c )2) p - or -CO-; p is an integer selected from 1 or 2; Each R 5c are independently hydrogen, halo or C 1~2 alkyl; or two R 5c together with the atoms to which they are attached, C 3~4 A compound capable of forming a cycloalkyl.

[0076] 9. A compound according to any one of statements 1 to 6, X1a is -CO-, -SO2- or -C(R 3a )2-selected; Y 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Z 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Each R 3a is hydrogen; each R 5a is hydrogen; X 2a is a single bond or -CO-; Y 2a is a single bond or -C(R 4a )2- and Z 2a is a single bond or -(C(R 4a )2) n - or -CO-; n is an integer selected from 1 or 2; Each R 4a are independently selected from hydrogen.

[0077] 10. A compound according to any one of statements 1 to 5 and 7, Each R 3b is hydrogen; Y 1b -CO-, -C(R 5b )2-selected; Z 1b is -C(R 5b )2- and; R 4b is selected from hydrogen; Each R 5b is hydrogen; Each R 6b is hydrogen; Y 2b is -C(R 5b ) 2- or single bond; Z 2b is a single bond or -(C(R 5b )2)m - or -CO-; and m is an integer selected from 1 or 2.

[0078] 11. A compound according to any one of statements 1 to 5 and 8, Each R 3c is hydrogen; Y 1c is a single bond or -C(R 4c )2-, -NR 6c - or -O-; Z 1c is a single bond or -C(R 4c )2- or -O-; Each R 4c is hydrogen; Each R 6c is hydrogen; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- and Z 2c is a single bond or -(C(R 5c )2) p - or -CO-; p is an integer selected from 1 or 2; Each R 5c is hydrogen, compound.

[0079] 12.Structural formula (B1A1), (B1A2), (B1A3), (B1A4), (B1A5), (B1A6), (B1B1), (B1B2), [ka] (In the formula, A 1a , Y 1a , Z 1a , R 2a , R 3a , R 4a , Y 2a , Z 2a , A 2a , A 1b , Y 1b , Z 1b , R2b , R 3b , R 4b , Y 2b , Z 2b , A 2b , A 1c , Y 1c , Z 1c , R 2c , R 3c , R 4c , X 2c , Y 2c , Z 2c and A 2c has the same meaning as defined in any one of statements 1-11, and na is an integer selected from 1, 2, 3, or 4; nb is an integer selected from 1, 2, 3, or 4; and each nc and mc is an integer selected from 1, 2, 3, or 4). 12. The compound according to any one of statements 1 to 11, having the following structure:

[0080] 13. A compound according to any one of statements 1 to 12, A 1a is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl and C 3~6 cycloalkyl; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R are selected from the group consisting of alkoxy, cyano, and hydroxy; 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., one or two R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; A 2a is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2a , e.g., 1, 2 or 3 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1b is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; preferably, A 1b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 1b , e.g., 1, 2 or 3 R 1b and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl and C 3~6 cycloalkyl; and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b, e.g., 1, 2 or 3 R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., one or two R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; A 2b is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2b is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 cycloalkyl; preferably, A 2b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 2b , e.g., 1, 2 or 3 R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., one or two R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1c is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 5~6cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1c , e.g., 1, 2 or 3 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl and C 3~6 cycloalkyl; and / or two R 1c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., one or two R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 2c is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2c is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2c , e.g., 1, 2 or 3 R2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 A compound that can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl.

[0081] 14. Structural formula (B1A8), (B1A9), (B1A10), (B1A11), (B1A12), (B1A13), [ka] (In the formula, A 1a , Y 1a , Z 1a and A 2a has the same meaning as defined in any one of Statements 1 to 13) 14. The compound according to any one of statements 1 to 13, having the following structure:

[0082] 15.Structural formula (B1A14), (B1A15), (B1A16), (B1A17), (B1A18), (B1A19), (B1A20), (B1A21), (B1A22), (B1A23), (B1A24), [ka] (In the formula, A 1a and A 2a has the same meaning as defined in any one of Statements 1 to 14) 15. The compound according to any one of statements 1 to 14, having the following structure:

[0083] 16. A compound according to any one of statements 1 to 15, A 1a is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl and C 3~6 cycloalkyl; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R are selected from the group consisting of alkoxy, cyano, and hydroxy; 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., one or two R 1a and each R 1a are independently hydrogen, halo, C1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; A 2a is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2a , e.g., 1, 2 or 3 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1b is C 6~10 Aryl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1b is C 6~10 Aryl, C 5~6cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; preferably, A 1b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 1b , e.g., 1, 2 or 3 R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R are selected from the group consisting of alkoxy, cyano, and hydroxy; 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., one or two R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; A 2b is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2b is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 cycloalkyl; preferably, A 2b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 2b , e.g., 1, 2 or 3 R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., one or two R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1c is C 6~10 Aryl, C 4~6cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1c , e.g., 1, 2 or 3 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl and C 3~6 cycloalkyl; and / or two R 1c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., one or two R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 2c is C 6~10 Aryl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A2c is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2c , e.g., 1, 2 or 3 R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 Compounds that can form aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl.

[0084] 17. A compound according to any one of statements 1 to 16, A 1a is phenyl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N; Each of the above groups may be unsubstituted or may contain one or more R 1a , e.g., 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1a , e.g., one or two R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; A 2a is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2a , e.g., 1, 2 or 3 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1b is phenyl, C 5~6cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; preferably, A 1b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 1b , e.g., 1, 2 or 3 R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclyl; preferably each of the foregoing groups is unsubstituted or contains one or more R 1b , e.g., one or two R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1b together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclyl; A 2b is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 cycloalkyl; preferably, A 2b is phenyl; Each of the above groups may be unsubstituted or may contain one or more R 2b , e.g., 1, 2 or 3 R 2b and each R 2b are independently hydrogen, halo, C1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 2b , e.g., one or two R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 1c is phenyl, C 4~6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and 5- to 6-membered saturated or partially saturated heterocyclyl containing at least one N, O and / or S; preferably, A 1c is C 6~10 Aryl, C 5~6cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups may be unsubstituted or may contain one or more R 1c , e.g., 1, 2 or 3 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl and C 3~6 cycloalkyl; and / or two R 1c together with the atoms to which they are attached, C 6~10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl; preferably, each of the above groups is unsubstituted or contains one or more R 1c , e.g., one or two R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 and / or two R 1c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; A 2c is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 4~6 cycloalkyl; preferably, A 2c is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups may be unsubstituted or may contain one or more R 2c , e.g., 1, 2 or 3 R 2c each R2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 Compounds that can form aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclyl.

[0085] 18.Structural formula (B1A25), (B1A26) [ka] (In the formula, R 1a , Y 1a , Z 1a , X 2a , X 1a , Y 2a , Z 2a and A 2a has the same meaning as defined in any one of statements 1 to 17, and ma is an integer selected from 1, 2, 3, or 4, pa is an integer selected from 0 or 1, qa is an integer selected from 0 or 1, and D 1a is selected from CH2, O or NH, and E 1a is selected from CH, N, O or S 18. The compound according to any one of statements 1 to 17, having the following structure:

[0086] 19. Structural formula (B1A27), (B1A28), [ka] (In the formula, R 1a , Y 1a , Z 1a , X 1a , Y 2a, Z 2a and A 2a has the same meaning as defined in any one of statements 1 to 18, and ma is an integer selected from 1, 2, 3, or 4, pa is an integer selected from 0 or 1, qa is an integer selected from 0 or 1, and D 1a is selected from CH2, O or NH, and E 1a is selected from CH, N, O or S 19. The compound according to any one of statements 1 to 18, having the following structure:

[0087] 20. Structural formula (B1A29), (B1A30), (B1A31), (B1A32), [ka] (In the formula, R 1a , Y 1a , Z 1a , X 1a , Y 2a , Z 2a and A 2a has the same meaning as defined in any one of statements 1 to 19, and ma is an integer selected from 1, 2, 3, or 4, pa is an integer selected from 0 or 1, qa is an integer selected from 0 or 1, and D 1a is selected from CH2, O or NH, and E 1a is selected from CH, N, O or S 20. The compound according to any one of statements 1 to 19, having the following structure:

[0088] 21. Structural formula (B1A33), (B1A34), (B1A35), (B1A36), (B1A37), (B1A38), (B1A39), (B1A40), (B1A41), (B1A42), (B1A43), [ka] (In the formula, R 1a and A 2ahas the same meaning as defined in any one of statements 1 to 20, and ma is an integer selected from 1, 2, 3, or 4, pa is an integer selected from 0 or 1, and D 1a is selected from CH2, O or NH 21. The compound according to any one of statements 1 to 20, having the following structure:

[0089] 22. Structural formula (B1A44), (B1A45), (B1A46), (B1A47), (B1A48), (B1A49), (B1A50), (B1A51), (B1A52), (B1A53), (B1A54), [ka] (In the formula, R 1a and A 2a has the same meaning as defined in any one of statements 1 to 21, and ma is an integer selected from 1, 2, 3, or 4, qa is an integer selected from 0 or 1, and E 1a is selected from CH, O or N 22. The compound according to any one of statements 1 to 21, having the following structure:

[0090] 23.Structural formula (B1A55), (B1A56), (B1A57), (B1A58), (B1A59), (B1A60), (B1A61), (B1A62), (B1A63), (B1A64), (B1A65), [ka] (In the formula, R 1a and A 2a has the same meaning as defined in any one of statements 1 to 22, and ma is an integer selected from 1, 2, 3, or 4. 23. The compound according to any one of statements 1 to 22, having the following structure:

[0091] 24.Structural formula (B1A66), (B1A67), (B1A68), (B1A69), (B1A70), (B1A71), (B1A72), (B1A73), (B1A74), (B1A75), (B1A76), [ka] (In the formula, R 1a and A 2a has the same meaning as defined in any one of statements 1 to 23, and ma is an integer selected from 1, 2, 3, or 4. 24. The compound according to any one of statements 1 to 23, having the following structure:

[0092] 25. Structural formula (B1A77), (B1A78), [ka] (In the formula, R 1a and A 2a has the same meaning as defined in any one of statements 1 to 24, and ma is an integer selected from 1, 2, 3, or 4. 25. The compound of any one of statements 1 to 24, having the formula:

[0093] 26. Structural formula (B1A79), (B1A80), [ka] (In the formula, R 1a , R 2a and A 2a has the same meaning as defined in any one of statements 1 to 25, and ma is an integer selected from 1, 2, 3, or 4, na is an integer selected from 1, 2, 3, or 4, and E 1a is selected from CH, O or N 26. The compound of any one of statements 1 to 25, having the formula:

[0094] 27. The compound according to any one of statements 1 to 26, selected from the group comprising the compounds listed in Table 1B.

[0095] 28. A pharmaceutical composition comprising a compound according to any one of statements 1 to 27 and at least one pharmaceutically acceptable carrier.

[0096] 29. A compound according to any one of statements 1 to 27 or a pharmaceutical composition according to statement 28 for use as a medicament or pharmaceutical product.

[0097] 30. A compound according to any one of statements 1 to 27 for use as a therapeutically active substance.

[0098] 31. A compound according to any one of statements 1 to 27 or a pharmaceutical composition according to statement 28 for use in the prevention and / or treatment of neurodegenerative disorders, such as neurodegenerative disorders characterised by cytotoxic tau misfolding and / or aggregation, for slowing or halting the progression of such diseases.

[0099] 32. The compound or pharmaceutical composition for use according to statement 31, wherein said disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down's syndrome, Pick's disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt-Jakob disease, preferably wherein said neurodegenerative disorder is Alzheimer's disease.

[0100] 33. A compound according to any one of statements 1 to 27 or a pharmaceutical composition according to statement 28 for the prevention and / or treatment of a disease selected from the group consisting of Parkinson's disease, Alzheimer's disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down's syndrome, Pick's disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt-Jakob disease, preferably wherein the neurodegenerative disorder is Alzheimer's disease.

[0101] 34. A method for the prevention and / or treatment of neurodegenerative disorders, such as neurodegenerative disorders characterized by cytotoxic tau misfolding and / or aggregation, for slowing or halting the progression of such disease, comprising administering to a subject in need thereof an effective amount of a compound according to any one of statements 1-27.

[0102] 35. The method according to statement 34, wherein the disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down's syndrome, Pick's disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy and Creutzfeldt-Jakob disease, preferably wherein said neurodegenerative disorder is Alzheimer's disease.

[0103] The present invention provides novel compounds of formula (B1A), formula (B1B) or formula (B1C) as defined herein, including all embodiments thereof as described herein.

[0104] In some embodiments of the compounds of formula (B1A) as defined herein (including all embodiments thereof as described herein): A 1a is phenyl, C 5~6cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups is unsubstituted or contains 1, 2 or 3 R 1a and each R 1a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 3~6 cycloalkyl; and / or two R 1a together with the atoms to which they are attached, C 6~10 Aryl, C 3~6 It can form a cycloalkyl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; X 1a -CO-, -SO2-, -C(R 3a ) 2- or 1,2,4-thiadiazolyl; Y 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Z 1a is a single bond or -C(R 3a )2-, -NR 5a - or -O-; Each R 3a is hydrogen; Each R 5a is hydrogen; X 2a is a single bond or -CO-; Y 2a is a single bond or -C(R 4a )2- and Z 2a is a single bond or -(C(R 4a )2) n - or -CO-; n is an integer selected from 1 or 2; Each R 4a is hydrogen; A2a is phenyl or 5-6 membered heteroaryl containing at least one N, O and / or S and C 5~6 selected from the group including cycloalkyl; Each of the above groups is unsubstituted or contains 1, 2 or 3 R 2a each R 2a are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3~6 Cycloalkyl and C 1~6 alkylcarbonylamino; and / or two R 2a together with the atoms to which they are attached, C 6~10 It can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl.

[0105] In some embodiments of the compounds of formula (B1B) as defined herein (including all embodiments thereof as described herein): A 1b is phenyl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; preferably, 1b is phenyl; Each of the above groups is unsubstituted or contains 1, 2 or 3 R 1b and each R 1b are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b)2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1b together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3b is hydrogen; Y 1b -CO-, -C(R 5b ) 2- or 1,2,4-thiadiazolyl; Z 1b is -C(R 5b )2- and; R 4b is hydrogen; each R 5b is hydrogen; each R 6b is hydrogen; Y 2b is -C(R 5b ) 2- or single bond; Z 2b is a single bond or -(C(R 5b )2) m - or -CO-; m is an integer selected from 1 or 2; A 2b is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 cycloalkyl; preferably, 2b is phenyl; Each of the above groups is unsubstituted or contains 1, 2 or 3 R 2b and each R 2b are independently hydrogen, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6b)2N-carbonyl, -SO2-R 6b and C 1~6 alkylcarbonylamino; and / or two R 2b together with the atoms to which they are attached, C 6~10 It can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl.

[0106] In some embodiments of the compounds of formula (B1C) as defined herein (including all embodiments thereof as described herein): A 1c is phenyl, C 5~6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S; Each of the above groups is unsubstituted or contains 1, 2 or 3 R 1c and each R 1c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl and C 1~6 alkylcarbonylamino; and / or two R 1c together with the atoms to which they are attached, C 6~10 can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl; R 3c is hydrogen; Y 1c is a single bond or -C(R 4c )2-, -NR 6c -, -O-, or 1,2,4-thiadiazolyl; Z 1c is a single bond or -C(R 4c )2- or -O-; Each R 4c is hydrogen; each R 6c is hydrogen; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- and Z 2c is a single bond or -(C(R 5c )2) p - or -CO-; p is an integer selected from 1 or 2; Each R 5c is hydrogen; A 2c is phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5~6 selected from the group including cycloalkyl; Each of the above groups is unsubstituted or contains 1, 2 or 3 R 2c each R 2c are independently hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkoxy, cyano, hydroxy, carboxyl, C 1~6 Alkoxycarbonyl, C 3~6 Cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c and C 1~6 alkylcarbonylamino; and / or two R 2c together with the atoms to which they are attached, C 6~10 It can form an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclyl.

[0107] In a preferred embodiment of the invention, the compound is selected from the group of compounds listed in Table 1B below or a salt, solvate, hydrate, polymorph, tautomer, racemate, stereoisomer or prodrug thereof.

[0108] Any reference to a compound of Formula (B1A), Formula (B1B) or Formula (B1C), as defined herein (including all embodiments thereof as described herein), also includes, unless expressly indicated otherwise, isomers, such as stereoisomers and tautomers, salts, such as pharmaceutically and / or physiologically acceptable salts, hydrates, solvates, polymorphs and prodrugs of such compounds.

[0109] The term "isomer," as used herein, refers to all possible isomeric forms that a compound of the formulae herein may take, including tautomeric and stereochemical forms, but not including positional isomers. Typically, the structures shown herein illustrate one tautomeric or resonance form of a compound, but the corresponding alternative configurations are also contemplated.

[0110] Depending on their substitution patterns, compounds of the present invention as defined herein (including all embodiments thereof as described herein) may or may not have one or more optical stereocenters and may exist as different enantiomers or diastereomers. Any such enantiomers, diastereomers, or other optical isomers are encompassed within the scope of the present invention. Unless otherwise specified, the chemical designation of a compound refers to a mixture of all possible stereochemically isomeric forms, including all diastereomers and enantiomers of its basic molecular structure (since compounds of the formulae herein may have at least one chiral center) as well as stereochemically pure or enriched compounds. More specifically, stereogenic centers can have either the R or S configuration, and multiple bonds can have either the cis or trans configuration. The terms R or S configuration are used herein in accordance with Chemical Abstracts nomenclature. The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and include reference to the position of substituents on ring moieties. The absolute stereochemical configuration of compounds of the formulae described herein can be readily determined by one skilled in the art using well-known methods such as, for example, X-ray diffraction.

[0111] The term "pharmaceutically acceptable salt" relates to any salt according to the present invention which the compounds may form and which are suitable for administration to a subject, particularly a human subject. Thus, the compounds of the present invention may optionally be salts of the compounds herein, particularly pharmaceutically acceptable non-toxic salts such as NaCl, NaCl, NaHCOOH ... + , Li + , K. + , Ca 2+ and Mg 2+ These salts include those derived by combining suitable cations, such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions, with an acid anion moiety, typically a carboxylic acid. The compounds of the present invention may have multiple positive or negative charges. The net charge of the compounds of the present invention may be either positive or negative. Any associated counterion typically depends on the synthesis and / or isolation method by which the compound is obtained. Typical counterions include, but are not limited to, ammonium, sodium, potassium, lithium, halides, acetates, trifluoroacetates, and the like, and mixtures thereof. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, particularly isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, and the like. It will be understood that the identity of any associated counterion is not a critical feature of the present invention, and the present invention encompasses compounds associated with any type of counterion. Furthermore, because compounds can exist in a variety of different forms, the present invention is intended to encompass not only compounds in a form associated with a counterion (e.g., a dry salt), but also those in a form not associated with a counterion (e.g., an aqueous or organic solution). Metal salts are typically prepared by reacting a metal hydroxide with a compound of the present invention. Examples of metal salts prepared in this manner include Li + , Na + and K. +These salts contain: (I) a metal salt with a low solubility, which can be precipitated from a solution of a more soluble salt by adding a suitable metal compound. Additionally, salts can be formed from the acid addition of certain organic and inorganic acids to a basic center, typically an amine or an acidic group. Examples of suitable acids include inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acids, sulfuric acid, nitric acid, and phosphoric acid; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid (i.e., 2-hydroxybenzoic acid), and p-aminosalicylic acid. Furthermore, the term also includes solvates, such as hydrates, alcoholates, etc., which the compounds of the formulae herein and salts thereof are able to form. Finally, it should be understood that the compositions herein include the compounds of the invention in their non-ionized form as well as in their zwitterionic form and in combination with a stoichiometric amount of water, such as in hydrates.

[0112] Also included within the scope of the present invention are salts of the parent compounds with one or more amino acids, particularly the naturally occurring amino acids found as components of proteins. The amino acids are typically those having a side chain with a basic or acidic group, e.g., lysine, arginine, or glutamic acid, or a neutral group, such as glycine, serine, threonine, alanine, isoleucine, or leucine.

[0113] The compounds of the invention as defined herein (including all embodiments thereof as described herein) also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts of the compounds of the invention include alkali metal (e.g., sodium), alkaline earth (e.g., magnesium), ammonium, and NX4 salts. +(wherein X is C1-C4 alkyl). Physiologically acceptable salts of hydrogen atoms or amino groups include salts of organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid. Physiologically acceptable salts of compounds containing a hydroxy group include salts of Na + and NX4 + (wherein X is typically independently selected from H or a C1-C4 alkyl group). However, salts of acids or bases that are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether derived from a physiologically acceptable acid or base, are within the scope of the present invention.

[0114] Non-limiting examples of suitable such salts include, but are not limited to, salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethoxybenzoic acid, ... and the like. Examples of suitable acid addition salts include those formed with organic acids such as benzenesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Other salts include 2,2-dichloroacetate, adipate, alginate, ascorbate, aspartate, 2-acetamidobenzoate, caproate, caprate, camphorate, cyclamate, lauryl sulfate, edisylate, esylate, isethionate, formate, galactarate, gentisate, gluceptate, glucuronate, oxoglutarate, hippurate, lactobionate, napadisylate, xinafoate, nicotinate, oleate, orotate, oxalate, palmitate, embonate, piroate, and p-aminobenzoate. Salicylate, sebacate, tannate, rhodanide, undecylenate, etc.; or salts formed when an acidic proton present in the parent compound is replaced by ammonia, arginine, benethamine, benzathine, calcium, choline, deanol, diethanolamine, diethylamine, ethanolamine, ethylenediamine, meglumine, glycine, hydrabamine, imidazole, lysine, magnesium, hydroxyethylmorpholine, piperazine, potassium, epolamine, sodium, trolamine, tromethamine, or zinc, etc.

[0115] The present invention includes within its scope the solvates of the compounds as defined herein (including all embodiments thereof as described herein).The term "solvate" refers to the crystal formed by an active compound and a second component (solvent) that is liquid at room temperature in isolated form.Such solvates can be formed with common organic solvents, for example, hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ether solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.Alternatively, the solvates of the compounds herein can be formed with water, in which case they will be hydrates.

[0116] Another embodiment of the present invention relates to various precursor or "prodrug" forms of the compounds of the present invention. It may be desirable to formulate the compounds of the present invention in the form of a chemical species that does not have significant biological activity itself, but that, when delivered to an animal, mammal, or human, undergoes a chemical reaction catalyzed by enzymes present in the normal functioning of the body, particularly in the stomach or serum, of the fish, and that has the effect of releasing a compound as defined herein. Generally, such prodrugs will be functional derivatives of the compounds described herein that are readily convertible in vivo, for example, by endogenous enzymes in the intestine or blood, into the required GPR17-modulating compound described herein. The term "prodrug" therefore refers to a species that is converted in vivo into a pharmaceutically active ingredient.

[0117] Prodrugs of the compounds of the present invention as defined herein (including all embodiments thereof as described herein) can have any form suitable for the formulator; for example, esters are a non-limiting and commonly used prodrug form. However, in the present context, prodrugs may necessarily exist in a form in which the covalent bond is cleaved by the action of an enzyme present at the target locus. For example, a covalent C—C bond may be selectively cleaved by one or more enzymes present at the target locus, and therefore prodrug forms other than readily hydrolyzable precursors, such as esters, amides, among others, may be used. The counterpart of the pharmaceutically active ingredient in a prodrug may have a variety of different structures, such as amino acid or peptide structures, alkyl chains, sugar moieties, etc., as known in the art.

[0118] For purposes of this invention, the term "therapeutically suitable prodrug" may be defined herein as a compound that has been modified so that it is converted in vivo, by single or multiple bioconversion processes, into a therapeutically active form that achieves the intended therapeutic result without undue toxicity, irritation, or allergic response upon contact with the tissues of an animal, mammal, or human to which the prodrug is administered.

[0119] More specifically, the term "prodrug," as used herein, refers to an inactive or significantly less active derivative of a compound, such as those represented by the structural formulas described herein, that undergoes spontaneous or enzymatic conversion in the body to release the pharmacologically active form of the compound. For a comprehensive review, see Rautio J. et al. ("Prodrugs: design and clinical applications" Nature Reviews Drug Discovery, 2008, doi:10.1038 / nrd2468).

[0120] The compounds of the present invention as defined herein (including all embodiments thereof as described herein) may also exist in various crystalline forms, i.e. polymorphs, and mixtures thereof, all of which are encompassed by the present invention.

[0121] The term "polymorph" refers to a specific crystalline form of a chemical compound that can crystallize into various crystalline forms that differ in the arrangement and / or structure of the molecules in the crystal lattice. Different crystalline forms typically differ in X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystalline appearance, optical and electrical properties, stability, and solubility. While polymorphs can have the same chemical composition, polymorphs may differ in composition due to the presence or absence of co-crystallized water or other molecules that may be weakly or strongly bound in the lattice. Polymorphs may differ in chemical, physical, and biological properties, such as crystalline appearance, density, hardness, color, chemical stability, melting point, hygroscopicity, suspendability, dissolution rate, and biological availability. Those skilled in the art will appreciate that a polymorph of a compound described herein may exhibit beneficial effects (e.g., suitability for the preparation of useful formulations, improved biological performance) compared to other polymorphs or polymorphic mixtures of the same compound. The preparation and isolation of specific polymorphs of a compound can be achieved by methods known to those skilled in the art, including, for example, crystallization using selected solvents and temperatures. One crystalline form may predominate due to the recrystallization solvent, crystallization rate, storage temperature, and other factors. Various polymorphs of a compound can be prepared by crystallization under different conditions. For a comprehensive discussion of polymorphism, see Rolf Hilfiker, Ed., Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006.

[0122] The present invention also includes pharmaceutical compositions comprising at least one compound according to the invention as defined herein (including all embodiments thereof as described herein) and at least one pharmaceutically acceptable carrier.

[0123] The term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier or other ingredient with which a compound of the invention is administered and that a person of ordinary skill in the art would understand to be pharmaceutically acceptable.

[0124] Tablets will contain excipients, glidants, fillers, binders, etc. Aqueous formulations will be prepared in sterile form and, when intended for delivery by other than oral administration, will generally be isotonic. Formulations optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986), including ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.

[0125] Subsequently, the term "pharmaceutically acceptable carrier," as used herein, means any material or substance with which an active ingredient is formulated, which facilitates its application or dissemination to the locus to be treated, for example, by dissolving, dispersing, or diffusing the composition, and / or facilitates its storage, transport, or handling without compromising its efficacy. A pharmaceutically acceptable carrier can be a solid or liquid or a gas that has been compressed into a liquid; for example, the compositions of the present invention may be suitable for use as a liquid concentrate, emulsion, solution, granule, powder, spray, aerosol, suspension, ointment, cream, tablet, pellet, or powder.

[0126] Pharmaceutical carriers suitable for use in the pharmaceutical compositions and their formulations are well known to those skilled in the art, and their selection is not particularly limited within the scope of the present invention. Pharmaceutical carriers may also include additives, such as wetting agents, dispersing agents, adhesives, adhesives, emulsifiers, solvents, coatings, antibacterial and antifungal agents (e.g., phenol, sorbic acid, chlorobutanol), isotonic agents (sugars or sodium chloride, etc.), etc., provided that such additives are consistent with pharmaceutical practice, e.g., carriers and additives that do not cause permanent damage to mammals. The pharmaceutical compositions of the present invention can be prepared by any known method, for example, by uniformly mixing, coating, and / or grinding the active ingredient with the selected carrier material and, if necessary, other additives such as surfactants, in a single-step or multi-step procedure. For example, they can also be prepared by micronization, with the aim of obtaining it in the form of microspheres, typically about 1 to 10 μm in diameter, i.e., for the production of microcapsules for controlled or sustained release of the active ingredient.

[0127] Suitable surfactants, also known as emulsifiers or emulsifiers, for use in the pharmaceutical compositions of the present invention are nonionic, cationic and / or anionic substances with good emulsifying, dispersing and / or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surfactants. Suitable soaps include alkali metal or alkaline earth metal salts, higher fatty acids (C 10 ~C 22Examples of suitable surfactants include unsubstituted or substituted ammonium salts of fatty acids such as oleic acid, stearic acid, or the sodium or potassium salts of natural fatty acid mixtures obtainable from palm oil or tallow. Synthetic surfactants include sodium or calcium salts of polyacrylic acid; fatty sulfonates and sulfates; sulfonated benzimidazole derivatives and alkylarylsulfonates. The fatty sulfonates or sulfates are usually in the form of alkali metal or alkaline earth metal salts, unsubstituted ammonium salts, or ammonium salts substituted with alkyl or acyl groups having 8 to 22 carbon atoms, such as the sodium or calcium salts of lignosulfonic acid or dodecylsulfonic acid, or mixtures of fatty alcohol sulfates obtained from natural fatty acids, alkali metal or alkaline earth metal salts of sulfates or sulfonate esters (e.g., sodium lauryl sulfate), and sulfonic acid / ethylene oxide adducts of fatty alcohols. Suitable sulfonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulfonates are sodium, calcium, or alcoholamine salts of dodecylbenzenesulfonic acid or dibutylnaphthalenesulfonic acid, or naphthalenesulfonic acid / formaldehyde condensation products. Corresponding phosphates, such as salts of phosphoric acid esters and p-nonylphenol ethylene and / or propylene oxide adducts, or phospholipids are also suitable. Suitable phospholipids for this purpose are natural (animal or plant cell-derived) or synthetic phospholipids of the cephalin or lecithin type, such as phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerin, lysolecithin, cardiolipin, dioctanylphosphatidylcholine, dipalmitoylphosphatidylcholine, and mixtures thereof.

[0128] Suitable nonionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, fatty amines, or amides containing at least 12 carbon atoms in the molecule; alkyl arenesulfonates and dialkyl sulfosuccinates; and polyglycol ether derivatives of aliphatic and alicyclic alcohols, saturated and unsaturated fatty acids, and alkylphenols, preferably containing 3 to 10 glycol ether groups, 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety, and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable nonionic surfactants are polypropylene glycols containing 1 to 10 carbon atoms in the alkyl chain, and water-soluble adducts of polyethylene oxide with ethylenediaminopolypropylene glycol, containing 20 to 250 ethylene glycol ether groups and / or 10 to 100 propylene glycol ether groups. Such compounds typically contain 1 to 5 ethylene glycol units per propylene glycol unit. Representative examples of nonionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycol ethers, polypropylene / polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol, and octylphenoxypolyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose, and pentaerythritol are also suitable nonionic surfactants.

[0129] Suitable cationic surfactants include quaternary ammonium salts, especially halides, having four hydrocarbon groups optionally substituted by halogen, phenyl, substituted phenyl, or hydroxy; e.g., at least one C as an N-substituent; 8~22 Quaternary ammonium salts containing alkyl (e.g., cetyl, lauryl, palmityl, myristyl, oleyl, etc.) and containing as further substituents unsubstituted or halogenated lower alkyl, benzyl and / or hydroxy lower alkyl.

[0130] For further detailed descriptions of surfactants suitable for this purpose, reference may be made, for example, to "McCutcheon's Detergents and Emulsifiers Annual" (MC Publishing Company, Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw", 2nd ed. (Hanser Verlag, Vienna, 1981), and "Encyclopaedia of Surfactants", (Chemical Publishing Company, New York, 1981).

[0131] The compounds of the present invention as defined herein (including all embodiments thereof as described herein) and pharmaceutically acceptable salts thereof (hereinafter collectively referred to as the active ingredients) can be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ophthalmic, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). The preferred route of administration can vary depending, for example, on the condition of the recipient.

[0132] While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention, both for veterinary and human use, comprise at least one active ingredient, as described above, together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic ingredients. The carrier(s) is optimally "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0133] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0134] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed with an optional binder, lubricant, inert diluent, preservative, surfactant, or dispersant in a suitable machine. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient contained therein. When formulated as an ointment, the active ingredient may be utilized with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, a polyhydric alcohol, e.g., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0135] The oil phase of the emulsion of the present invention can be composed of known ingredients in a known manner. This phase can simply contain an emulsifier (also known as an emulgent), but preferably it contains a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. In summary, one or more emulsifiers, with or without one or more stabilizers, make up the so-called emulsifying wax, which, together with the oil and fat, makes up the so-called emulsifying ointment base, which forms the oily dispersed phase of a cream formulation.

[0136] Because the solubility of active compounds in most oils likely to be used in pharmaceutical emulsion formulations is very low, the selection of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus, creams should optionally be non-greasy, non-transferring, and washable products with a consistency suitable for preventing leakage from tubes or other containers. Linear or branched monobasic or dibasic alkyl esters can be used, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, the latter three being preferred esters. These can be used alone or in combination, depending on the desired properties. Alternatively, high-melting lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0137] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0138] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Formulations suitable for nasal administration, where the carrier is a solid, include a coarse powder having a particle size of, for example, 20 to 500 μm (including increments of 5 μm, such as 30 μm, 35 μm, etc.), which may be administered by rapid inhalation through the nasal passage from a container of the powder held close to the nose, in the manner in which snuff is taken. Where the carrier is a liquid, suitable formulations for administration, for example, as a nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared by conventional means and may be delivered with other therapeutic agents.

[0139] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0140] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the recipient's blood; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. Such preparations may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the types described above.

[0141] Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.

[0142] It should be understood that the formulations of the present invention, in addition to the ingredients particularly listed above, may include other agents conventional in the art having regard to the type of formulation in question, e.g., those suitable for oral administration may include flavoring agents.

[0143] The compounds of the invention as defined herein (including all embodiments thereof as described herein) can be used to provide controlled release pharmaceutical formulations ("controlled release formulations") containing one or more compounds of the invention as the active ingredient, in which the release of the active ingredient can be controlled and regulated, thereby allowing for less frequent administration or an improved pharmacokinetic or toxicity profile of a given compound of the invention. Controlled release formulations suitable for oral administration, in which discrete units contain one or more compounds of the invention, can be prepared by conventional methods.

[0144] Additional components may be included to control the duration of action of the active ingredient in the composition. Controlled-release compositions can be achieved by selecting appropriate polymeric carriers, such as polyesters, polyamino acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, and protamine sulfate. Drug release rate and duration of action can also be controlled by incorporating the active ingredient into particles, e.g., microcapsules, of polymeric materials, such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethylmethacrylate, and other polymers mentioned above. Such methods include colloid drug delivery systems, such as liposomes, microspheres, microemulsions, nanoparticles, and nanocapsules. Depending on the route of administration, a protective coating may be required for the pharmaceutical composition. Suitable pharmaceutical forms for use as injectable solutions include sterile aqueous solutions or dispersions and sterile powders for their extemporaneous preparation. Typical carriers for this purpose include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, and mixtures thereof.

[0145] In view of the fact that when several active ingredients are used in combination, they do not necessarily exert their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition can also be in the form of a medical kit or package in which the two ingredients are contained in separate but adjacent containers or compartments. In connection with the latter, each active ingredient can therefore be formulated in a manner suitable for a different administration route than the other ingredients, for example, one of them can be in the form of an oral or parenteral preparation, while the other is in the form of an ampoule or aerosol for intravenous injection.

[0146] The compounds of the invention as defined herein (including all embodiments thereof as described herein) are useful in the prevention and / or treatment of neurodegenerative diseases or disorders, such as, but not limited to, neurodegenerative diseases or disorders characterised by cytotoxic tau misfolding and / or aggregation and / or aggregation of amyloid beta, as described herein, for slowing or halting the progression of such diseases or disorders in a subject such as an animal, particularly a human.

[0147] The terms "prevent" or "prevention," as used herein, refer to a reduction in the risk of acquiring a disease or disorder (i.e., the failure to develop at least one clinical symptom of the disease in a subject, particularly a human subject, who may be exposed to or predisposed to the disease but who does not yet show or exhibit symptoms of the disease).

[0148] The term "treating" or "treatment" of any disease or disorder, in one embodiment, includes ameliorating the disease or disorder (i.e., halting or reducing the onset of the disease or reducing at least one clinical symptom of the disease). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may or may not be discernible in a subject, particularly a human subject, based on or associated with the disease or disorder being treated. In yet another embodiment, "treating" or "treatment" refers to modulating or alleviating the disease or disorder in either a physical (e.g., stabilization of discernible or unrecognizable symptoms), a physiological (e.g., stabilization of physiological parameters), or both. In yet another embodiment, "treating" or "treatment" refers to slowing the onset or progression of the disease or disorder. Thus, "treating" or "treatment" includes any causal treatment of the underlying disease or disorder (i.e., disease-modifying), as well as any treatment of the signs and symptoms of the disease or disorder (with or without disease modification), and any reduction or amelioration of the disease or disorder or its signs and symptoms. The terms "disease(s)" and "disorder(s)" are generally used interchangeably herein.

[0149] The terms "diagnosis," "diagnoses," or "diagnosing" a disease or disorder, as used herein, in one embodiment, includes the identification and measurement of signs and symptoms associated with the disease.

[0150] The term "subject" refers to an animal, preferably a mammalian patient, in need of such treatment, such as a human. The term also refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The terms "human," "patient," and "human subject" are typically used interchangeably herein, unless clearly indicated otherwise.

[0151] The present invention also relates to a method of treating an animal disease or disorder, particularly a human disease or disorder, as described in more detail herein, which method comprises the administration of a therapeutically effective amount of a compound of the invention, as defined herein (including all embodiments thereof, as described herein).

[0152] The term "therapeutically effective amount," as used herein, means an amount of an active compound or pharmaceutical agent that, when administered to a subject, elicits in a tissue system or subject the biological or beneficial response sought by a researcher, veterinarian, physician, or other clinician, including alleviation or partial alleviation of the symptoms of the disease or disorder being treated. The therapeutically effective amount may vary depending on the compound, the disease and its severity, and the condition, age, weight, sex, etc., of the subject being treated, particularly a human subject.

[0153] The compounds of the invention as defined herein (including all embodiments thereof as described herein) are useful for the treatment or prevention of neurodegenerative disorders.

[0154] The term "neurodegenerative disorder," as used herein, unless otherwise specified, refers to a disease, disorder, or condition characterized by the degeneration (e.g., including loss of function and eventual cell death) of neurons in either the brain and / or nervous system of an individual. Progressive damage to nerve cells and nervous system connections can have a significant impact on motor skills, coordination, muscle strength, sensation, and / or cognition.

[0155] In particular embodiments, the neurodegenerative disorder may include or be characterized by the development of cognitive impairment in the subject.

[0156] In particular embodiments, the neurodegenerative disorder may include or be characterized by dementia or symptoms of dementia. Dementia may be diagnosed by any method known in the art, such as by cognitive and neuropsychological testing (e.g., memory, language ability). Neurodegenerative dementia is progressive and irreversible due to the damage to nerve cells and their interconnections. Neurodegenerative dementia includes, but is not limited to, Alzheimer's disease dementia, Lewy body dementia, vascular dementia, and frontotemporal dementia. Thus, the neurodegenerative disorder may be, include, or be characterized by Alzheimer's disease dementia, Lewy body dementia, vascular dementia, and / or frontotemporal dementia (FTD).

[0157] In particular embodiments, the neurodegenerative disorder, such as a neurodegenerative disorder comprising or characterized by dementia, may comprise or be characterized by protein aggregation as one of its primary symptoms. In particular embodiments, the neurodegenerative disorder may comprise or be characterized by tau or amyloid beta (Aβ) aggregation. In further particular embodiments, the neurodegenerative disorder may comprise or be characterized by tau aggregation and / or β-amyloid aggregation (i.e., β-amyloid plaque formation). In other words, in particular embodiments, the neurodegenerative disorder may be an amyloid beta (Aβ)-driven and / or tau-driven neurodegenerative disorder. In further particular embodiments, the neurodegenerative disorder may comprise or be characterized by tau-driven and / or Aβ-driven neurotoxicity. In further particular embodiments, the neurodegenerative disorder may be a tauopathy (e.g., Alzheimer's disease, Pick's disease, frontotemporal lobar degeneration (FTLD)) or a β-amyloidopathy (e.g., Alzheimer's disease, Down's syndrome).

[0158] In particular embodiments, the neurodegenerative disorder may be a tauopathy and / or an alpha-synucleinopathy, and thus includes, but is not limited to, Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis (ALS), Niemann-Pick disease, Hallervorden-Spatz syndrome, Down's syndrome, neuroaxonal dystrophy, and multiple system atrophy.

[0159] In further particular embodiments, the neurodegenerative disorder may be a tauopathy, a β-amyloidopathy and / or an α-synucleinopathy.

[0160] The term "tauopathy," as used herein, unless otherwise specified, refers to a disease characterized by dysfunction of tau protein, e.g., manifested as insoluble aggregates or polymers of the protein. The exact molecular mechanisms involved in tau aggregation are not precisely understood, but may involve partial denaturation or misfolding of tau, in that it has a strong conformational tendency to self-assemble into other higher-order structures. Misfolding and aggregation can be initiated by hyperphosphorylation of tau, although at this time it cannot be excluded that such abnormal phosphorylation is a consequence of aggregation rather than a cause of aggregation.

[0161] The compounds of the present invention (including all embodiments thereof as described herein) are particularly useful in the treatment of certain neurodegenerative disorders involving or characterized by cytotoxic tau misfolding and / or aggregation, to slow or halt the progression of such diseases, which can be grouped under the term tauopathies, as described elsewhere herein.

[0162] Tau is a protein that can bind to, thereby stabilizing and defining, microtubule structure and function in neurons. Binding of tau to microtubules is regulated by tau phosphorylation. Several tau phosphorylation sites and their corresponding kinases have been identified, which regulate the phosphorylation state of tau and, consequently, the affinity of tau binding to microtubules.

[0163] A key aspect of tau aggregation is its associated cytotoxicity, which compromises neuronal integrity and functionality and ultimately leads to disease symptoms. A direct role for tau in disease development has been clearly established by the elucidation of familial mutations in tau, which appear to be responsible for very early and sometimes aggressive forms of tauopathy. Such mutations involve changes in the amino acid sequence of tau that directly or indirectly promote neurotoxic aggregation.

[0164] Alzheimer's disease is the best-known of these, in which tau protein is deposited within neurons in the form of neurofibrillary tangles (NFTs). Alzheimer's disease was first described by its namesake, Alois Alzheimer, in one of his own patients with the disorder. The term "Alzheimer's disease," as used herein, refers to a chronic, progressive neurological disorder characterized by neurodegeneration with memory decline as its most significant (early) symptom. As the disease progresses, symptoms include confusion, irritability and aggression, mood swings, speech disorganization, and long-term memory decline, and sufferers may become generally withdrawn due to their sensory decline.

[0165] Tangles form through hyperphosphorylation of a microtubule-associated protein known as tau, which leads to the aggregation of tau in an insoluble form. (These aggregates of hyperphosphorylated tau protein are also called PHFs, or "paired helical filaments.") The exact mechanism of tangle formation is not fully understood, and it remains controversial whether it is the primary causative factor in the disease or plays a more peripheral role. AD is also classified as an amyloidosis due to the presence of senile plaques.

[0166] Other conditions in which neurofibrillary tangles are commonly found include progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia linked to chromosome 17 with parkinsonism, Ritiko-Bodig disease (Guam Parkinsonism-Dementia Complex), tangle-predominant dementia with NFTs that resemble AD but lack senile plaques, gangliogliomas and gangliocytomas, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis complex, Hallervorden-Spatz disease, and lipofuscinosis.

[0167] Non-Alzheimer's tauopathies are sometimes grouped together as the "Pick complex." In Pick's disease and corticobasal degeneration, tau protein is deposited in the form of inclusions within enlarged or "ballooned" neurons. Another type of dementia, argyrophilic grain disease (AGD), is characterized by the presence of large numbers of argyrophilic granules and coiled bodies on microscopic examination of brain tissue.

[0168] The compounds of the present invention (including all embodiments thereof as described herein) are particularly useful for the prevention and / or treatment of diseases associated with dysfunctional biological function of tau protein, which may include Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism (linked to chromosome 17, FTDP-17). A preferred indication is Alzheimer's disease.

[0169] The present invention also encompasses the compounds of the present invention (including all embodiments thereof as described herein) for use in the prevention and / or treatment of diseases associated with dysfunctional biological function of tau protein, which may include Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with parkinsonism (linked to chromosome 17, FTDP-17), a method of prevention and / or treatment comprising administering a therapeutically effective amount of a compound of the invention to a patient in need thereof.

[0170] The present invention also encompasses the prevention and / or treatment of diseases associated with dysfunctional biological function of tau protein, which may include Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with parkinsonism (linked to chromosome 17, FTDP-17), and methods of prevention and / or treatment, which comprise administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention (including all embodiments thereof as described herein).

[0171] The term "amyloidosis," as used herein, unless otherwise specified, refers to both systemic and focal amyloid-related diseases and prion-associated encephalopathies, and thus includes, but is not limited to, diabetes mellitus type II, Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Dow's syndrome, and others. These include: leukemia, leukemia, leukemia-associated ...

[0172] The term "alpha-synucleinopathies," as used herein, unless otherwise specified, refers to diseases characterized by the presence of pathological intracellular and / or extracellular deposits of insoluble alpha-synuclein polymers or aggregates, including, but not limited to, Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy.

[0173] The present invention further includes the compounds of the present invention for use in the prevention and / or treatment of brain diseases or disorders.

[0174] In particular embodiments, the brain disease or disorder may include or be characterized by dementia, such as, but not limited to, due to Alzheimer's disease-related dementia, vascular dementia, Lewy body dementia, frontotemporal dementia, alcohol-related dementia, Down's syndrome-related dementia, HIV-associated dementia, and chronic traumatic encephalopathy (CTE) dementia.

[0175] In particular embodiments, the brain disease or disorder may involve or be characterized by protein aggregation, such as, but not limited to, aggregation of tau and / or amyloid beta (Aβ).

[0176] In particular embodiments, the brain disease or disorder can be a neurodegenerative and / or vascular condition (e.g., a neurovascular condition). For example, the brain disease or disorder can be a neurovascular condition involving or characterized by aggregation of amyloid beta (Aβ), such as cerebral amyloid angiopathy.

[0177] In particular embodiments, the brain disease or disorder can be a tauopathy. For example, the brain disease or disorder can be primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), vacuolar tauopathy, Ritiko-Bodig disease (Guam Parkinsonism-Dementia Complex), ganglioglioma and gangliocytoma, meningioangiomatosis, or postencephalitic parkinsonism.

[0178] In particular embodiments, the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, vascular dementia, frontotemporal dementia with parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis (ALS), Niemann-Pick disease, Hallervorden-Spatz syndrome, Down's syndrome, neuroaxonal dystrophy, multiple system atrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), cystic fibrosis, and Creutzfeldt-Jakob disease.

[0179] In further detailed embodiments, the neurodegenerative disorder is selected from Parkinson's disease, Alzheimer's disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down's syndrome, Pick's disease, progressive supranuclear palsy, vascular dementia, neuroaxonal dystrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy, and Creutzfeldt-Jakob disease.

[0180] In a particular embodiment, the neurodegenerative disorder is Ca 2+ It is characterized by homeostatic dysfunction.

[0181] In particular embodiments, the neurodegenerative disorder is Alzheimer's disease.

[0182] The compounds of the present invention as described herein (including all embodiments thereof as described herein) can be prepared using a series of chemical reactions well known to those skilled in the art, which are further illustrated, which, taken together, constitute methods for preparing said compounds. The methods further described are intended as examples only and are not intended to limit the scope of the invention in any way.

[0183] Abbreviations used in the description herein, particularly in the schemes and examples, are as follows: Boc - ter-butoxycarbonyl, CDI - carbonyldiimidazole, DCC - N,N-dicyclohexylcarbodiimide, CHCl3 - chloroform, DCE - dichloroethane, DCM - dichloromethane, DIPEA - diisopropylethylamine, DMAc - dimethylacetamide, DMF - N,N-dimethylformamide, DMSO - dimethylsulfoxide, DPPA - diphenylphosphoryl azide, Et3N - triethylamine, EtOAc - ethyl acetate, EtOH - ethanol, Eq. - equivalent, Fmoc - fluorenylmethyloxycarbonyl chloride, h - hour, HATU - O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, HPLC - high performance liquid chromatography, KOtBu - caprylic / capric trioxide. Lithium tert-butoxide, LCMS - liquid chromatography mass spectrometry, LiHDMS - lithium bis(trimethylsilyl)amide, MeCN(CHCN)-ACN - acetonitrile, MeOH - methanol, min. - minute, mL - milliliter, MPLC - medium pressure liquid chromatography, NaBH - sodium borohydride, Na2CO3 - sodium carbonate, Na2SO4 - sodium sulfate, NHCl - ammonium chloride, NH3 - ammonia, NMP - 1-methyl-2-pyrrolidinone, NMR - nuclear magnetic resonance, 4-NPC - 4-nitrophenyl chloroformate, PyBOP - benzotriazol-1-yl)oxytripyrrolidinophosphonium hexafluorophosphate, RP - reverse phase, RT - room temperature, sat. - saturated, STAB - sodium triacetoxyborohydride, TEA - triethylamine, TFA - trifluoroacetic acid, THF - tetrahydrofuran.

[0184] The preparation of the compounds of the invention as defined herein (including all embodiments thereof as described herein) may be carried out in sequential or convergent synthetic routes.

[0185] Embodiments of the synthesis of compounds of the invention as defined herein (including all embodiments thereof as described herein) are shown in the following schemes.

[0186] The skills required to carry out these reactions and purification of the resulting products are known to those skilled in the art. The substituents and subscripts used in the description of the following processes have the meanings previously given herein unless otherwise indicated.

[0187] More specifically, compounds as defined herein (including all embodiments thereof as described herein) can be prepared by the methods shown below, by the methods shown in the present examples, or by similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. The reaction order is not limited to that presented in these schemes; however, the order of reaction steps can be freely changed depending on the starting materials and their respective reactivities. Starting materials are either commercially available or can be prepared by methods similar to those shown below, by methods described in the references cited in this description or in the examples, or by methods known in the art.

[0188] In some embodiments, compounds of formula B1A can be prepared according to the general procedures outlined in Scheme A.

[0189] [ka] Scheme A: wherein A 1a , Z 1a , Y 1a , X 1a , R 3ab , R 4a , X 2a , Y 2a , Z 2a and A 2a is as described herein Commercially available amine derivative 3 * Derivative * 2. Instead of Boc, other suitable protecting groups such as Ts can be used. After removal of the protecting group under standard conditions, intermediate 4 can be coupled to * 4* can be subjected to alkylation or reductive amination to provide compound B1A, where LG is a suitable leaving group such as, for example, an aldehyde or halogen.

[0190] In some embodiments, compounds of formula B1B can be prepared according to the general procedure outlined in Scheme B.

[0191] [ka] Scheme B: wherein A 1b , Z 1b , R 3b , R 4b , Y 4b , Z 2b and A 2b is as described herein Commercially available amine derivative 6 * Derivative 9 * Instead of Boc, other suitable protecting groups such as Ts can be used. After removal of the Boc protecting group under standard conditions, intermediate 7 can be obtained. * 7 * The appropriate aryl aldehyde 8 * In some embodiments, derivative 6 * R 4b is H, and if applicable, further reaction of B1B with a suitable reagent can result in a group R different from H. 4b can be introduced.

[0192] In some embodiments, compounds of Formula B1A1, Formula B1A2, Formula B1A3, Formula B1A4, Formula B1A5 can be prepared according to the general procedures outlined in Scheme A1.

[0193] [ka] Scheme A1: wherein A 1a , Y 1a , Z 1a , Z2a and A 2a is as described herein The commercially available compound 3 can be obtained by reductive amination in the presence of a suitable reducing reagent (e.g., STAB, NaBH4, Pd / CH2, etc.) in a suitable solvent or solvent mixture (e.g., DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.) at a temperature ranging from room temperature to 60°C. * Aldehyde 10 * (commercially available or synthesized by procedures known to those skilled in the art) to give the compound of formula 11 * Instead of Boc, other suitable protecting groups such as Fmoc, Ts, etc. can be used. After removal of the Boc protecting group under standard conditions, intermediate 12 can be obtained. * For example, intermediate 12 can be obtained by reacting intermediate 12 in the presence of a suitable base (e.g., DIPEA, etc.) and at least one suitable coupling agent (e.g., HATU, PyBOP, DCC, etc.) in a suitable solvent or solvent mixture (e.g., DCM, MeCN, CHCl3, DMF, DMAc, DMP, etc.) at a temperature ranging from 0°C to 60°C. * Acid 13 * (commercially available or synthesized by procedures known to those skilled in the art) can provide compound B1A1.

[0194] For example, in the presence of a suitable base (e.g., NaH, DIPEA, KOtBu, LiHMDS, etc.) and a suitable coupling reagent (e.g., bis(4-nitrophenyl)carbonate, 4-NPC, CDI, etc.), intermediate 12 can be obtained, for example, in a suitable solvent or solvent mixture (e.g., DMF, THF, dioxane, toluene, etc.) at a temperature ranging, for example, from −20° C. to room temperature. * Alcohol 14 *(commercially available or synthesized by procedures known to those skilled in the art) to give compound B1A2. Alternatively, compounds of general formula B1A2 can be prepared by, for example, coupling with a suitable base (such as DIPEA) in a suitable solvent or solvent mixture (such as DCM, CHCl, THF, DMF, DMAc, dioxane, etc.) at temperatures ranging from -20°C to 60°C to give intermediate 12. * and chloroformate 15 * (commercially available or synthesized by procedures known to those skilled in the art) can be obtained by coupling between

[0195] For example, in the presence of a suitable base (e.g., DIPEA, Et3N, etc.) and a suitable coupling reagent (e.g., bis(4-nitrophenyl)carbonate, 4-NPC, CDI, etc.), in a suitable solvent or solvent mixture (e.g., DCM, CHCl3, THF, DMF, DMAc, dioxane, etc.), at a temperature in the range of, for example, 0°C to 50°C, intermediate 12 can be obtained. * Amine 16 * (commercially available or synthesized by procedures known to those skilled in the art) to give compound B1A3. Alternatively, compounds of general formula B1A3 can be converted to intermediate 12, for example, in the presence of a suitable base (such as DIPEA) in a suitable solvent or solvent mixture (such as DCM, CHCl, THF, DMF, DMAc, dioxane, etc.) at temperatures ranging from -20°C to 60°C. * and isocyanates 17 * (commercially available or synthesized by procedures known to those skilled in the art) can be obtained by coupling between

[0196] For example, intermediate 12 can be prepared in a suitable solvent or solvent mixture (e.g., DCM, CHCl3, THF, DMF, DMAc, dioxane, etc.) at a temperature ranging, for example, from -20°C to 60°C. * Sulfonyl chloride 18 * (commercially available or synthesized by procedures known to those skilled in the art) can provide compound B1A4.

[0197] For example, in the presence of a suitable reducing reagent (e.g., STAB, NaBH4, Pd / C1H2, etc.), for example in a suitable solvent or solvent mixture (e.g., DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.), at a temperature ranging, for example, from room temperature to 60°C, intermediate 12 can be obtained. * and aldehyde 19 * Reductive amination with (commercially available or synthesized by procedures known to those skilled in the art) can provide compound B1A5.

[0198] In some embodiments, compounds of formula B1A1 can be prepared according to the general procedure outlined in Scheme A2.

[0199] [ka] Scheme A2: wherein R 10a Ha-Z 2a -A 2a and R 11a Ha-Y 1a -Z 1a -A 1a and A 1a and Z 1a , Z 2a , Y 1a and A 2a is as described herein For example, in the presence of a suitable base (such as DIPEA) and a suitable coupling agent (such as HATU, PyBOP, DCC), for example, in a suitable solvent or solvent mixture (such as DCM, MeCN, CHCl3, DMF, DMAc, DMP, etc.), at a temperature ranging from, for example, 0°C to 60°C, commercially available compound 3 * Acid 13 * (commercially available or synthesized by procedures known to those skilled in the art) to give the compound of formula 21 * Instead of Boc, other suitable protecting groups such as Fmoc, Ts, etc. can be used. After removal of the Boc protecting group under standard conditions, intermediate 22 can be obtained. *For example, in the presence of a suitable reducing agent (e.g., STAB, NaBH, Pd / CH, etc.), for example, in a suitable solvent or solvent mixture (e.g., DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.), at a temperature ranging from room temperature to 60° C., intermediate 22 can be obtained. * and aldehyde 10 * Reductive amination with (commercially available or synthesized by procedures known to those skilled in the art) can provide compound B1A1.

[0200] In some embodiments, compounds of formula B1A2 can be prepared according to the general procedure outlined in Scheme A3.

[0201] [ka] Scheme A3: wherein A 1a , Z 1a , Z 2a and A 2a is as described herein For example, in the presence of a suitable base (e.g., NaH, DIPEA, KOtBu, LiHMDS, etc.) and a suitable coupling reagent (e.g., bis(4-nitrophenyl)carbonate, 4-NPC, CDI, etc.), for example, in a suitable solvent or solvent mixture (e.g., DMF, THF, toluene, dioxane, etc.), at a temperature ranging from, for example, −20° C. to room temperature, the commercially available compound 3 * Alcohol 14 * (commercially available or synthesized by procedures known to those skilled in the art) to give the compound of formula 24 * Instead of Boc, other suitable protecting groups such as Fmoc, Ts, etc. can be used. After removal of the Boc protecting group under standard conditions, intermediate 25 can be obtained. * For example, in the presence of a reducing agent (e.g., STAB, NaBH4, Pd / CH2, etc.), intermediate 25 can be obtained, for example, in a suitable solvent or solvent mixture (e.g., DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.) at a temperature ranging from room temperature to 60°C. * and aldehyde 10 *Reductive amination with (commercially available or synthesized by procedures known to one skilled in the art) can provide compound B1A2.

[0202] In some embodiments, compounds of formula B1A3 can be prepared according to the general procedure outlined in Scheme A4.

[0203] [ka] Scheme A4: wherein A 1a , Z 1a , Z 2a and A 2a is as described herein For example, in the presence of a suitable base (e.g., DIPEA, Et3N, etc.) and a coupling agent (e.g., bis(4-nitrophenyl)carbonate, 4-NPC, CDI, etc.), for example, in a suitable solvent or solvent mixture (e.g., DCM, CHCl3, THF, DMF, DMAC, dioxane, etc.), at a temperature in the range of, for example, 0°C to 50°C, commercially available compound 3 * Amine 16 * (commercially available or synthesized by procedures known to those skilled in the art) to give the compound of formula 28 * Instead of Boc, other suitable protecting groups such as Fmoc, Ts, etc. may be used. After removal of the Boc protecting group under standard conditions, intermediate 29 can be obtained. * For example, intermediate 29 can be obtained in the presence of a suitable reducing agent (e.g., STAB, NaBH, Pd / CH, etc.), for example, in a suitable solvent or solvent mixture (e.g., DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.) at a temperature ranging from room temperature to 60° C. * and aldehyde 10 * (commercially available or synthesized by procedures known to those skilled in the art) can provide compound B1A3.

[0204] In some embodiments, compounds of formula B1A6 can be prepared according to the general procedure outlined in Scheme A5.

[0205] [ka] Scheme A5: wherein A 1a , Z 1a , R 3a , R 4a , Y 2a , Z 2a and A 2a is as described herein compound 3 * Derivative 30 * Instead of Boc, other suitable protecting groups such as Fmoc, Ts, etc. may be used. After removal of the Boc protecting group under standard conditions, intermediate 31 can be obtained. * 31 * can be subjected to alkylation or reductive amination to give compound B1A6.

[0206] In some embodiments, compounds of Formula B1B1 can be prepared according to the general procedures outlined in Scheme B1.

[0207] [ka] Scheme B1: wherein A 1b , Z 1b , R 3b , R 4b , Y 2b , Z 2b and A 2b is as described herein Commercially available amine derivative 6 * Derivative 33 * After removal of the Boc protecting group under standard conditions, intermediate 34 can be coupled to * 34 * The appropriate aryl aldehyde 8 * to give the final compound B1B1. In some embodiments, derivative 6 * R 4bis H, and if applicable, a group R different from H can be obtained by further reacting B1B1 with a suitable reagent. 4b can be introduced.

[0208] In some embodiments, compounds of Formula B1B2 can be prepared according to the general procedure outlined in Scheme B2.

[0209] [ka] Scheme B2: wherein A 1b , Z 1b , R 3b , R 4b , Y 2b , Z 2b and A 2b is as described herein Commercially available amine derivative 6 * Compound 35 * After removal of the Boc protecting group under standard conditions, intermediate 36 can be coupled to * Amine 36 can be obtained. * From this, reductive amination of the aldehyde or alkylation with an electrophile can give the final compound B1B2. In some embodiments, derivative 6 * R 4b is H, and if applicable, a group R different from H can be obtained by further reaction of B1B2 with a suitable reagent. 4b can be introduced.

[0210] The general schemes depicted above should be considered as non-limiting examples, and it will be understood that compounds of the invention may be obtained through other methods known to those skilled in the art.

[0211] The following examples are provided for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention in any way. [Example]

[0212] [Table 1]

[0213]

Table 2

[0214]

Table 3

[0215]

Table 4

[0216]

Table 5

[0217]

Table 6

[0218]

Table 7

[0219]

Table 8

[0220]

Table 9

[0221]

Table 10

[0222]

Table 11

[0223]

Table 12

[0224]

Table 13

[0225]

Table 14

[0226]

Table 15

[0227] Table 16

[0228]

Table 17

[0229]

Table 18

[0230] Table 19

[0231] Table 20

[0232] Table 21

[0233] Table 22

[0234] Table 23

[0235] Table 24

[0236] Table 25

[0237] Table 26

[0238] Table 27

[0239] Table 28

[0240] Table 29

[0241] Table 30

[0242] Table 31

[0243] Table 32

[0244] [Table 33]

[0245] [Table 34]

[0246] [Table 35]

[0247] [Table 36]

[0248] [Table 37]

[0249] [Table 38]

[0250] [Table 39]

[0251] [Table 40]

[0252] [Table 41]

[0253] Part A represents the preparation of compounds (intermediates and final compounds), while Part B represents pharmacological examples.

[0254] Part A All starting materials not explicitly mentioned were either commercially available (for details of suppliers such as, for example, Aldrich, Combi-Blocks, Enamine, FluoroChem, MatrixScientific, Merck, TCI, reference may be made, for example, to the SciFinder® database), or their synthesis is already precisely described in specialized references (for experimental guidelines reference may be made, for example, to the Reaxys® database or the SciFinder® database, respectively), or could be prepared using conventional methods known to those skilled in the art.

[0255] Reactions were carried out under an inert atmosphere (argon and N2 in most cases) where necessary. The number of equivalents of reagents and the amount of solvent used, as well as the reaction temperature and time, may vary slightly between different reactions carried out by similar methods. Workup and purification methods were adapted according to the characteristic properties of each compound and may vary slightly from similar methods. The yields of the prepared compounds have not been optimized.

[0256] The designation "equivalent" ("eq." or "eq" or "equiv.") means molar equivalent, "RT" or "rt" means room temperature T (23±7°C), "M" is the designation of concentration in mol / l, "sol." means solution, and "conc." means concentrated. Solvent mixture ratios are usually stated as volume / volume ratios.

[0257] Key analytical characterizations were performed for all exemplary compounds and selected intermediates. 1 H-NMR spectroscopy and / or mass spectrometry (MS, [M+H] + and / or [MH] - The analysis was performed using m / z values ​​of 1000 kJ / s.

[0258] The analytical instruments used were, for example, a BRUKER 400MHz (software Topspin) for NMR analysis, an Agilent 1260 Mass:6130 (ESI) (software Open Lab Chemstation) for LC / MS analysis, and a Waters IClass (software MassLynx) for analytical UPLC analysis. For GCMS analysis, an Agilent 6890N was used.

[0259] Preparative HPLC was performed, for example, on an Agilent G6120 or Waters, reversed phase MPLC was performed, for example, on a Revelis.

[0260] Some structures of compounds containing stereocenters are drawn and named with the absolute stereochemistry, if known. When the absolute stereochemistry is unknown, the compound may be either a racemate, a mixture of diastereomers, a pure diastereomer of unknown stereochemistry, or a pure enantiomer of unknown stereochemistry.

[0261] The MS analyses mentioned in the experimental part were performed on a Waters system. Under acidic conditions: Waters IClass; binary pump: UPIBSM, SM: UPISMFTN, SO; UPCMA, PDA: UPPDATC, 210-320 nm; MS: QDa ESI, pos / neg 100-800; column: Waters XSelect CSH C18, 50 × 2.1 mm, 2.5 μm; temperature: 40 °C; flow rate: 0.6 mL / min; gradient: t0 = 5% A, t 2.0min = 98%A, t 2.7min= 98% A, post time: 0.3 min, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water. Under basic conditions: Instrument: Waters IClass; Binary Pump: UPIBSM, SM: UPISMFTN, SO; UPCMA, PDA: UPPDATC, 210-320 nm, MS: QDa ESI, pos / neg 100-800; Column: Waters XSelect CSH C18, 50 × 2.1 mm, 2.5 μm, Temperature: 25 °C, Flow rate: 0.6 mL / min, Gradient: t0 = 5% A, t 2.0min = 98%A, t 2.7min = 98% A, post time: 0.3 min, eluent A: acetonitrile, eluent B: 10 mM ammonium bicarbonate in water (pH = 9.5)

[0262] The GCMS analyses mentioned in the experimental part were carried out on an Agilent 6890N G1530 gas chromatography system coupled with a G2577A 5973 MSD detector (EI-positive, detector temperature: 280 °C) with a mass range of 50-550, a Restek RXi-5MS column (20 m, 180 μm internal diameter, 0.18 μm df), average velocity: 50 cm / s, injection volume: 1 μl, injection temperature: 250 °C, split ratio: 100 / 1, carrier gas: He; initial temperature: 100 °C, initial time: 1.5 min, solvent delay: 1.0 min, velocity: 75 °C / min, final temperature: 250 °C, hold time: 4.3 min.

[0263] The preparative HPLC purifications mentioned in this experimental part were performed under basic conditions on a Waters system: MS instrument type: ACQ-SQD2; HPLC instrument type: Waters modular preparative HPLC system; column: Waters XSelect (C18, 100 x 30 mm, 10 μm); flow rate: 55 ml / min preparative pump; column temperature: room temperature; eluent A: 10 mM ammonium bicarbonate in water pH = 9.5, eluent B: 100% acetonitrile; gradient: t = 0 min 5% B, t = 17 min 100% B; detection: DAD (220-320 nm); detection: MSD (ESI pos / neg) mass range: 100-800; fraction collection was based on MS and DAD.

[0264] The preparative HPLC purification mentioned in this experimental part was carried out on an Agilent system under acidic conditions: MS instrument type: Agilent Technologies G6120AA quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; Column: Waters XSelect CSH (C18, 100 × 30 mm, 10μ); Flow rate: 55 ml / min; Column temperature: room temperature; Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile; Gradient: t = 0 min 5% B, t = 17 min 100% B. Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) mass range: 100-1000; Fraction collection was based on MS and DAD.

[0265] Reversed-phase MPLC purifications mentioned in this experimental part were performed on a Revelis under acidic conditions: Instrument type: Revelis™ Preparative MPLC; Column: Phenomenex LUNA C18(3) (150 × 25 mm, 10 μ); Flow rate: 40 mL / min; Column temperature: room temperature; Eluent A: 0.1% (v / v) formic acid in water, Eluent B: 0.1% (v / v) formic acid in acetonitrile; Gradient: t = 0 min 5% B, t = 20 min 100% B; Detection UV: 220, 254, 280 nm.

[0266] Under basic conditions, the reversed-phase MPLC purifications mentioned in this experimental part were performed on a Revelis: Instrument type: Revelis™ Preparative MPLC; Column: Waters XSelect CSH C18 (145 x 25 mm, 10μ); Flow rate: 40 mL / min; Column temperature: room temperature; Eluent A: 10 mM ammonium bicarbonate in water pH = 9.0); Eluent B: 99% acetonitrile in water + 1% 10 mM ammonium bicarbonate; Gradient: t = 0 min 5% B, t = 20 min 100% B. Detection UV: 220, 254, 280 nm.

[0267] Preparation of intermediates Synthesis of 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone (IB 4-1) [ka] a) tert-butyl 6-(2-(4-chlorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate Tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 0.5 oxalic acid (1 g, 4.11 mmol, Eq: 1.00), and TEA (1.04 g, 1.42 mL, 10.3 mmol, Eq: 2.5) were combined in dry DCM (27.4 mL) to give an off-white suspension. The reaction mixture was cooled to 0 °C. 2-(4-Chlorophenyl)acetyl chloride (777 mg, 601 μL, 4.11 mmol, Eq: 1) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. LCMS showed 80% conversion. The crude reaction mixture was partially concentrated in vacuo, poured into EtOAc, and extracted with HO. The aqueous layer was back-extracted with EtOAc. The crude material was purified by flash chromatography (silica gel, 100 g, 20% to 100% EtOAc in heptane) to give 686 mg (48% yield) of the title product. ESI [M+H] + :351.1.

[0268] b) 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone tert-Butyl 6-(2-(4-chlorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (686 mg, 1.96 mmol, Eq: 1.00) was combined in DCM (13.0 ml) to give a yellow solution. TFA (1.11 g, 749 μl, 9.78 mmol, Eq: 10) was added. After 2 h, the crude reaction mixture was then poured into EtOAc and extracted with Na2CO3. The organic layer was dried over Na2SO4, evaporated, and concentrated in vacuo to give 1.10 g (92% yield) of the title product, which was used directly crude. ESI [M+H] + :251.4.

[0269] Synthesis of 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) [ka] a) tert-butyl 6-(2-(4-fluorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate 2-(4-Fluorophenyl)acetic acid (488 mg, 3.17 mmol, Eq: 2.2), TEA (728 mg, 1.00 ml, 7.19 mmol, Eq: 5) and HATU (1.2 g, 3.17 mmol, Eq: 2.2) were combined in DCM (10 ml).

[0270] The reaction mixture was heated to 45° C. and stirred for 15 minutes. 2,6-Diazaspiro[3.3]heptane-2-carboxylic acid tert-butylhemisoxalate (700 mg, 1.44 mmol, Eq: 1.00) was added, and the reaction mixture was heated to 45° C. and stirred for 1 hour. The reaction mixture was poured into DCM and extracted with saturated NaHCO3. The aqueous layer was back-extracted with DCM. Crude = 1.59 g. The crude material was purified by flash chromatography (silica gel, 70 g, 0% → 10% MeOH in DCM) to give 451 mg (47% yield) of the title product. ESI [M+H] + :335.3.

[0271] b) 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone tert-Butyl 6-(2-(4-fluorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (451 mg, 1.35 mmol, Eq: 1.00) was dissolved in DCM (8.99 ml). TFA (819 mg, 550 μl, 7.18 mmol, Eq: 5.32) was added. The reaction mixture was stirred for 2 hours. An additional 5 equivalents of TFA (550 μl) were added. The reaction mixture was stirred for 4 hours. An additional 5 equivalents of TFA (550 μl) were added. The reaction mixture was stirred for 1.5 hours. The mixture was then concentrated. The crude mixture was then poured into EtOAc and extracted with Na2CO3. The organic layer was dried over Na2SO4 and evaporated to give 281 mg (90% yield) of the title product. ESI [M+H] + :235.1.

[0272] Synthesis of 2-(3,4-difluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-3) [ka] a) tert-butyl 6-(2-(3,4-difluorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate To a solution of 2-(3,4-difluorophenyl)acetic acid (4.68 g, 27.2 mmol, 1.1 eq.) in DMF (200 mL) containing DIPEA (8.63 mL, 49.4 mmol, 2 eq.) was added HATU (11.3 g, 29.7 mmol, 1.2 eq.). The reaction was stirred at room temperature for 20 min, and then a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 0.5 oxalic acid (6 g, 24.7 mmol, 1 eq.) in 50 mL containing 2 eq. of DIPEA was added. The reaction was stirred at room temperature for 4 h. LCMS showed SM and product. Another 1 eq. of 2-(3,4-difluorophenyl)acetic acid and HATU were added, and the reaction was stirred at room temperature for 30 min. LCMS showed the reaction was complete. After extraction with DCM / saturated aqueous NaHCO3, the organic layer was dried over Na2SO4 and evaporated. Silica column purification using heptane / ethyl acetate (1 / 1→0 / 1) gave the desired product. ESI [M+H] + ;353.3.

[0273] b) 2-(3,4-difluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone To a solution of tert-butyl 6-(2-(3,4-difluorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (13.4 g, 30%, 11.4 mmol) was added TFA (13.2 mL, 171 mmol, 15 eq.), and the reaction was stirred at room temperature overnight. Extraction with ethyl acetate / ether and saturated aqueous Na2CO3 gave two layers, and LCMS showed the product in the aqueous layer and an impurity in the organic layer. Concentration of the aqueous layer and extraction with isopropanol / ethyl acetate gave the organic layer, which was dried over Na2SO4 and evaporated, followed by azeotroping with heptane to remove water, to give the product (30%). [M+H] + ;253.2

[0274] Synthesis of N-(6-amino-spiro[3.3]hept-2-yl)-2-(4-fluoro-phenyl)-acetamide (HCl) (IB 7-1) [ka] a) tert-butyl 6-(2-(4-fluorophenyl)acetamido)spiro[3.3]heptan-2-ylcarbamate To a solution of 2-(4-fluorophenyl)acetic acid (1.12 g, 7.29 mmol, 1.1 eq.) in DCM (200 mL) containing TEA (2.77 mL, 19.9 mmol, 3 eq.) was added HATU (3.02 g, 7.95 mmol, 1.2 eq.). The reaction was stirred at 45 °C for 15 min, and then tert-butyl 6-aminospiro[3.3]heptan-2-ylcarbamate (1.5 g, 6.63 mmol, 1 eq.) was added. The reaction was stirred overnight at 45 °C. Extraction with DCM / water gave an organic layer, which was dried over Na2SO4 and evaporated; the product was precipitated in cold DCM and filtered off. ESI [M+H-BOC] + =263.2.

[0275] b) N-(6-amino-spiro[3.3]hept-2-yl)-2-(4-fluoro-phenyl)-acetamide (HCl) tert-Butyl 6-(2-(4-fluorophenyl)acetamido)spiro[3.3]heptan-2-ylcarbamate (110 mg, 0.3 mmol, Eq: 1.00) was dissolved in DCM and 4 M HCl in dioxane (1 mL, 4 mmol, Eq: 13) was added. The reaction mixture was stirred at room temperature for 1 hour. Evaporation of the solvent gave the desired product, which was used directly crude. ESI [MH] - =297.1.

[0276] Synthesis of N-(6-aminospiro[3.3]heptan-2-yl)-2-(4-chlorophenyl)acetamide (HCl) (IB 7-2) [ka] a) tert-butyl 6-(2-(4-chlorophenyl)acetamido)spiro[3.3]heptan-2-ylcarbamate Tert-butyl 6-aminospiro[3.3]heptan-2-ylcarbamate (6 g, 26.5 mmol, Eq: 1.00) and TEA (5.37 g, 7.35 ml, 53.0 mmol, Eq: 2) were combined in DCM (177 ml) to give a white suspension. The solution was cooled to 0 °C. 2-(4-chlorophenyl)acetyl chloride (7.52 g, 5.82 ml, 39.8 mmol, Eq: 1.5) was added at 0 °C to give an orange suspension. The reaction mixture was stirred for 1.5 h, and the reaction mixture was extracted with HO. The crude reaction mixture was concentrated in vacuo. Recrystallization from DCM and MeOH gave a white solid. ESI [M+H-tBu] + =323.3.

[0277] b) N-(6-aminospiro[3.3]heptan-2-yl)-2-(4-chlorophenyl)acetamide (HCl) tert-Butyl 6-(2-(4-chlorophenyl)acetamido)spiro[3.3]heptan-2-ylcarbamate (7.682 g, 20.3 mmol, Eq: 1.00) was dissolved in 100 mL DCM and 4 M HCl in dioxane (35.5 mL, 142 mmol, Eq: 7) was added. The reaction mixture was stirred overnight at room temperature. Evaporation of the solvent and recrystallization from DCM and MeOH gave a white solid, 2.408 g. ESI [M+H] + =279.1.

[0278] Synthesis of 2-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane (IB12-1) [ka] Step 1: To 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl hemioxalate (1 g, 2.055 mmol) in anhydrous DCM (24 mL) / MeOH (8 mL) was added acetic acid (0.471 mL, 8.22 mmol) and 4-fluorobenzaldehyde (0.665 mL, 6.17 mmol). The mixture was purged with nitrogen, and titanium(IV) isopropoxide (2.409 mL, 8.22 mmol) was added. The mixture was stirred at room temperature for 2 hours. STAB (3.48 g, 16.44 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was carefully quenched by the addition of saturated aqueous Na2CO3 and stirred at room temperature for 1 hour. Additional DCM was added to the resulting suspension, and the layers were separated. The aqueous layer was extracted with DCM (2x), and the extracted DCM layer was directly filtered through a Celite path. The combined filtered extracts were collected and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give tert-butyl 6-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.16 g, 3.79 mmol, 92% yield) as a colorless oil. MS (m / e): 307.2 (MH + ).

[0279] Step 2: tert-Butyl 6-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.16 g, 3.79 mmol) was dissolved in DCM (6 ml) and trifluoroacetic acid (3.50 ml, 45.4 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with DCM and concentrated under reduced pressure at low temperature (above water bath). The crude mixture was dissolved in a few mL of DMSO and saturated aqueous Na2CO3 was added until the pH was above 7. The mixture was purified by RP chromatography (50 g column, gradient: 0% → 50% MeCN in 10 mM ammonium bicarbonate in water) to give 2-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane (695 mg, 3.37 mmol, 89% yield) as a slightly yellowish oil. MS (m / e): 207.1 (MH + ).

[0280] In a manner similar to that described for IB 12-1 (using appropriate reagents and purification methods known to those skilled in the art), the following intermediates were prepared: IB 12-2, IB 12-3 and IB 12-4.

[0281] [Table 42]

[0282] Synthesis of 2-(4,4-difluorocyclohexyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (IB 22-1) [ka] Step 1: 2-(4,4-Difluorocyclohexyl)acetic acid (1.007 g, 5.65 mmol) was dissolved in DCM (25 mL), and DIPEA (2.244 mL, 12.85 mmol) and HATU (2.051 g, 5.39 mmol) were added. tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (1.25 g, 2.57 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic fractions were dried over Na2SO4, filtered, and concentrated to give crude tert-butyl 6-(2-(4,4-difluorocyclohexyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a yellow oil. No further purification was performed.

[0283] Step 2: To tert-butyl 6-(2-(4,4-difluorocyclohexyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.842 g, 5.14 mmol) in DCM (40 ml) was added trifluoroacetic acid (5.94 ml, 77 mmol). The mixture was stirred at room temperature for 2 h and then cooled and concentrated on a rotary evaporator. The crude mixture was dissolved in a few mL of DMSO, and saturated aqueous Na2CO3 was added until the pH was above 7. The mixture was purified by RP chromatography (100 g column, gradient: 0% to 100% MeCN in 10 mM ammonium bicarbonate in water) to give 2-(4,4-difluorocyclohexyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one (1.08 g, 4.18 mmol, 81% yield) as an off-white foam. MS(m / e): 259.1(MH + )

[0284] Synthesis of 4,4-difluorocyclohexyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (IB 25-1) [ka] Step 1: To bis(4-nitrophenyl)carbonate (2.345 g, 7.71 mmol) in DMF (dry) (10 mL) was added 4,4-difluorocyclohexan-1-ol (1.119 g, 8.22 mmol) and NaH (60% w / w in mineral oil, 0.668 g, 16.70 mmol). This mixture was stirred at room temperature for 1.5 hours, followed by the addition of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butylhemisoxalate (1.25 g, 2.57 mmol) in DMF (dry) (15 mL) containing DIPEA (1.346 mL, 7.71 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated, and EtOAc, a small amount of water, and saturated aqueous Na2CO3 were added to the residue, and the layers were separated. The aqueous layer was extracted twice more with EtOAc, and the combined organics were washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered, and concentrated to give crude 2-(tert-butyl)6-(4,4-difluorocyclohexyl) 2,6-diazaspiro[3.3]heptane-2,6-dicarboxylate as an orange oil without further purification.

[0285] Step 2: To 2-(tert-butyl)6-(4,4-difluorocyclohexyl)2,6-diazaspiro[3.3]heptane-2,6-dicarboxylate (1.856 g, 5.15 mmol) in DCM (40 ml) was added trifluoroacetic acid (5.95 ml, 77 mmol). The mixture was stirred overnight at room temperature and then cooled and concentrated. The crude mixture was dissolved in a few mL of DMSO and saturated aqueous Na2CO3 was added until the pH was above 7. The mixture was purified by RP chromatography (100 g column, gradient: 0% to 100% MeCN in 10 mM ammonium bicarbonate in water) to give 4,4-difluorocyclohexyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (873 mg, 3.35 mmol, 65.1% yield) as a yellow oil. MS (m / e): 261.2 (MH + )

[0286] In a manner similar to that described for IB 25-1 (using appropriate reagents and purification methods known to those skilled in the art), the following intermediate was prepared: IB25-2

[0287] [Table 43]

[0288] Synthesis of N-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide (IB 29-1) [ka] Step 1: To bis(4-nitrophenyl)carbonate (1.876 g, 6.17 mmol) in DMF (dry) (40 mL) was added (4-fluorophenyl)methanamine (0.752 mL, 6.58 mmol) and DIPEA (2.154 mL, 12.33 mmol). This mixture was stirred at room temperature for 1.5 hours, after which 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl hemioxalate (1 g, 2.055 mmol) was added. The mixture was stirred at room temperature overnight. Saturated aqueous Na2CO3 and EtOAc were added to the mixture, and the layers were separated. The organic layer was washed with additional saturated aqueous Na2CO3 and saturated aqueous NH4Cl. The organic fractions were combined and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40 g silica, wet loading from DCM, heptane / EtOAc = 35:65 → 0:1) to give tert-butyl 6-((4-fluorobenzyl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.11 g, 3.18 mmol, 77% yield) as a white solid. MS (m / e): 350.2 (MH + )

[0289] Step 2: To tert-butyl 6-((4-fluorobenzyl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.11 g, 3.18 mmol) in DCM (6 ml) was added trifluoroacetic acid (3.50 ml, 45.4 mmol). The mixture was stirred at room temperature overnight, then cooled and concentrated. The crude mixture was dissolved in a few mL of DMSO, and saturated aqueous Na2CO3 was added until the pH was above 7. The mixture was purified by RP chromatography (100 g column, gradient: 0% to 100% MeCN in 10 mM ammonium bicarbonate in water) to give N-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide (780 mg, 3.13 mmol, 98% yield) as a slightly yellowish oil. MS (m / e): 250.1 (MH + )

[0290] In a manner similar to that described for IB 29-1 (using appropriate reagents and purification methods known to those skilled in the art), the following intermediates were prepared: IB 29-2, IB 29-3.

[0291] [Table 44]

[0292] Synthesis of N-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl)spiro[3.3]heptane-2,6-diamine hydrochloride (IB 30-1) [ka] a) tert-butyl 6-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-ylamino)spiro[3.3]heptan-2-ylcarbamate To a solution of commercially available tert-butyl 6-aminospiro[3.3]heptan-2-ylcarbamate (1.86 g, 8.2 mmol, Eq. 1.2) in dry DMF (45 ml) was added commercially available 3-chloro-5-(4-fluorobenzyl)-1,2,4-thiadiazole (1.5 g, 6.56 mmol, Eq. 1) and DIPEA (1.6 ml, 9.18 mmol, Eq. 1.4).

[0293] The reaction was stirred under argon at 140° C. for 30 min. The solvent was evaporated and the crude product was dissolved in EtOAc and washed with water. The aqueous layer was extracted again with fresh EtOAc. The organic layer was dried over Na2SO4, concentrated, and purified by flash chromatography using heptane and ethyl acetate to give 2.39 g (87% yield) of the title product. ESI[MH] - ;417.7

[0294] b) N-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl)spiro[3.3]heptane-2,6-diamine hydrochloride To a solution of tert-butyl 6-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-ylamino)spiro[3.3]heptan-2-ylcarbamate (2.19 g, 5.23 mmol, Eq. 1) in dioxane (22 ml) was added HCl in dioxane (4 M, 4 ml, Eq. 7.6). Upon addition of HCl, the reaction mixture changed from a pale yellow suspension to a clear solution. The reaction was stirred at room temperature for 1 hour. LCMS showed no progress so an additional 6 ml of HCl in dioxane (4 M) was added. After a further 3.5 hours, there was still no progress. HCl in dioxane was added until the reaction was complete. The reaction mixture was then concentrated in vacuo and azeotroped twice with toluene. The product was dried under high vacuum overnight to give the title product. ESI [M+H] + ;319.1

[0295] Synthesis of N-(3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl)spiro[3.3]heptane-2,6-diamine TFA salt (IB 30-2) [ka] a) tert-butyl 6-(3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-ylamino)spiro[3.3]heptan-2-ylcarbamate Commercially available tert-butyl 6-aminospiro[3.3]heptan-2-ylcarbamate (3.84 g, 17.0 mmol, Eq: 1), commercially available 5-chloro-3-(4-chlorobenzyl)-1,2,4-thiadiazole (4.1637 g, 17.0 mmol, Eq: 1.00), and DIPEA (4.39 g, 5.93 mL, 34.0 mmol, Eq: 2) were combined with THF (113 mL) to give a yellow solution. The reaction mixture was heated to 110 °C and stirred for 2.5 h, followed by LCMS. The reaction mixture was poured into 400 mL of EtOAc and extracted with HO (1 × 300 mL). The aqueous layer was back-extracted with EtOAc (1 × 100 mL). The organic layer was dried over Na2SO4, concentrated in vacuo, and the crude material was purified by flash chromatography on 330 g silica gel (0% to 50% EtOAc in heptane) to give 5.999 g of the title compound as an off-white solid (81% yield). ESI [M+H] + ;435.3

[0296] b) N-(3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-yl)spiro[3.3]heptane-2,6-diamine TFA salt tert-Butyl 6-(3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-ylamino)spiro[3.3]heptan-2-ylcarbamate (5.999 g, 13.8 mmol, Eq: 1.00) was combined with DCM (25 ml) to give an off-white suspension, and TFA (7.86 g, 5.28 ml, 69.0 mmol, Eq: 5) was added to give an orange solution. The reaction mixture was stirred overnight. The crude reaction mixture was concentrated in vacuo to give an orange oil. Diethyl ether was added to the crude and evaporated four times to give an orange solid, which was dried under high vacuum at 40° C. to give the title compound. ESI [M+H] + ;335.2

[0297] Synthesis of Examples Intermediate 4 * (e.g., IB 4-1, IB 4-2 or IB 4-3) according to general scheme A to prepare final compounds of formula B1A. i) Amine 4 * Aldehyde 5 * (Eq: 1.00) in DCM. The reaction mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (Eq: 1.5) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was poured into DCM and extracted with Na2CO3. The aqueous layer was back-extracted with DCM, and the organic layer was dried over Na2SO4, concentrated in vacuo, and then isolated after silica chromatography using DCM / MeOH.

[0298] or: ii) Amine 4 * Aldehyde 5 * (Eq: 1.00) was combined with triethylamine in EtOH (Eq: 1.5) and acetic acid (Eq: 2). The reaction mixture was stirred for 30 minutes. Sodium cyanoborohydride (Eq: 1.2) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into DCM and extracted with Na2CO3. The aqueous layer was back-extracted with DCM, and the organic layer was dried over Na2SO4, concentrated in vacuo, and then isolated by silica chromatography using DCM / MeOH.

[0299] or: iii) Amine 4 in DMF (1 mL) * (0.15 mmol) and triethylamine (5 eq.), the appropriate halogenated electrophile 5 * The reaction was stirred at room temperature overnight and the resulting product was purified by preparative HPLC.

[0300] Intermediate 7 * Final compound B1B according to general scheme B starting from (e.g. IB 7-1, IB 7-2) Amine 7 * Aldehyde 8 *(Eq: 1.00) and TEA (Eq: 2) were combined in DCE. The reaction mixture was stirred for 5 minutes. Sodium triacetoxyborohydride (Eq: 1.5) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into DCM and extracted with NaHCO3. The aqueous layer was back-extracted with DCM, and the organic layer was dried over Na2SO4 and concentrated in vacuo. It was then isolated by silica chromatography using DCM / MeOH.

[0301] iv) R of compound B1B 4b is hydrogen, for example, compound B1B (wherein R 4b A methyl group can be introduced in this position by combining the methyl group (Eq: 1.5), TEA (Eq: 1), and acetic acid (Eq: 0.4) with formaldehyde (Eq: 1.5), TEA (Eq: 1), and acetic acid (Eq: 0.4) in DCE / MeOH: 4 / 1. The reaction mixture was stirred for 5 minutes. Sodium triacetoxyborohydride (Eq: 2) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was poured into DCM and extracted with NaHCO3. The aqueous layer was back-extracted with DCM, and the organic layer was dried over Na2SO4, concentrated in vacuo, and then isolated using silica chromatography using heptane / ethyl acetate.

[0302] Synthesis of 2-(4-fluorophenyl)-1-(6-(3-phenylpropyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B001) Coupling between the building blocks described herein and aldehydes according to the general procedure for the preparation of B1A i): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) -Aldehyde: 3-phenylpropanal (commercially available) ESI [M+H] + ;353.4

[0303] Synthesis of 1-(6-benzyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-(4-fluorophenyl)ethanone (Cpd B002) Coupling between the building blocks described herein and aldehydes according to the general procedure for the preparation of B1A i): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) -Aldehyde: Benzaldehyde (commercially available) ESI [M+H] + ;325.2

[0304] Synthesis of 1-(6-benzyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-(4-chlorophenyl)ethanone (Cpd B003) Coupling between the building blocks described herein and aldehydes according to the general procedure for the preparation of B1A i): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Aldehyde: Benzaldehyde (commercially available) ESI [M+H] + ;341.0

[0305] Synthesis of 1-(6-(4-chlorobenzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(4-chlorophenyl)ethanone (Cpd B004) Coupling between the building blocks described herein and aldehydes according to the general procedure for the preparation of B1A i): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Aldehyde: 4-chlorobenzaldehyde (commercially available) ESI [M+H] + ;375.0

[0306] Synthesis of 2-(4-chlorophenyl)-1-(6-((2-methoxypyridin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B005) Coupling between the building blocks described herein and aldehydes according to the general procedure for the preparation of B1A i): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Aldehyde: 2-methoxyisonicotinaldehyde (commercially available) ESI [M+H] + ;372.0

[0307] Synthesis of 2-(4-chlorophenyl)-1-(6-(2-methylbenzyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B006) Coupling between the building blocks described herein and aldehydes according to the general procedure for the preparation of B1A i): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Aldehyde: 2-methylbenzaldehyde (commercially available) ESI[M+H]+;355.1

[0308] Synthesis of 1-(6-benzyl-2,6-diazaspiro[3.3]heptan-2-yl)-2-(3,4-difluorophenyl)ethanone (Cpd B007) Coupling between the building blocks described herein and aldehydes according to the general preparation procedure of B1A ii): Building block: 2-(3,4-difluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-3) -Aldehyde: Benzaldehyde (commercially available) ESI [M+H] + ;343.2

[0309] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(3-methoxy-benzyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B008) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(bromomethyl)-3-methoxybenzene (commercially available) ESI [M+H] + ;355.3

[0310] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(4-methyl-benzyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B009) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(bromomethyl)-4-methylbenzene (commercially available) ESI [M+H] + ;339.3

[0311] Synthesis of 2-(4-fluoro-phenyl)-1-(6-pyridin-2-ylmethyl-2,6-diaza-spiro[3.3]hept-2-yl)-ethanone (Cpd B010) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 2-(bromomethyl)pyridine (commercially available) ESI [M+H] + ;326.3

[0312] Synthesis of 1-[6-(3-chloro-benzyl)-2,6-diaza-spiro[3.3]hept-2-yl]-2-(4-fluoro-phenyl)-ethanone (Cpd B011) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(bromomethyl)-3-chlorobenzene (commercially available) ESI [M+H] + ;359.2

[0313] Synthesis of 3-{6-[2-(4-fluoro-phenyl)-acetyl]-2,6-diaza-spiro[3.3]hept-2-ylmethyl}-benzamide (Cpd B012) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) -Halogenated electrophile: 3-(chloromethyl)benzamide (commercially available) ESI [M+H] + ;368.2

[0314] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(2-trifluoromethoxy-benzyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B013) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(bromomethyl)-2-(trifluoromethoxy)benzene (commercially available) ESI [M+H] + ;409.2

[0315] Synthesis of 4-{6-[2-(4-fluoro-phenyl)-acetyl]-2,6-diaza-spiro[3.3]hept-2-ylmethyl}-benzoic acid methyl ester (Cpd B014) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: methyl 4-(bromomethyl)benzoate (commercially available) ESI [M+H] + ;383.2

[0316] Synthesis of 2-(4-fluoro-phenyl)-1-{6-[1-(3-trifluoromethyl-phenyl)-ethyl]-2,6-diaza-spiro[3.3]hept-2-yl}-ethanone (Cpd B015) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(1-bromoethyl)-3-(trifluoromethyl)benzene (commercially available) ESI[M+H]+;407.4

[0317] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(1-phenyl-ethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B016) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) -Halogenated electrophile: (1-bromoethyl)benzene (commercially available) ESI [M+H] + ;339.1

[0318] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(6-methyl-pyridin-2-ylmethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B017) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 2-(bromomethyl)-6-methylpyridine (commercially available) ESI [M+H] + ;340.3

[0319] Synthesis of 1-[6-(2-chloro-benzyl)-2,6-diaza-spiro[3.3]hept-2-yl]-2-(4-fluoro-phenyl)-ethanone (Cpd B018) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(bromomethyl)-2-chlorobenzene (commercially available) ESI [M+H] + ;359.0

[0320] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(2-methyl-thiazol-4-ylmethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B019) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 4-(chloromethyl)-2-methylthiazole hydrochloride (commercially available) ESI [M+H] + ;346.0

[0321] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(1-methyl-1H-imidazol-2-ylmethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B020) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (commercially available) ESI [M+H] + ;329.4

[0322] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(5-methyl-isoxazol-3-ylmethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B021) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 3-(bromomethyl)-5-methylisoxazole (commercially available) ESI [M+H] + ;330.0

[0323] Synthesis of 2-(4-fluoro-phenyl)-1-(6-thiazol-4-ylmethyl-2,6-diaza-spiro[3.3]hept-2-yl)-ethanone (Cpd B022) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) -Halogenated electrophile: 4-(chloromethyl)thiazole (commercially available) ESI [M+H] + ;332.2

[0324] Synthesis of 2-(4-fluoro-phenyl)-1-{6-[2-(3-trifluoromethyl-phenyl)-ethyl]-2,6-diaza-spiro[3.3]hept-2-yl}-ethanone (Cpd B023) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(2-bromoethyl)-3-(trifluoromethyl)benzene (commercially available) ESI [M+H] + ;407.4

[0325] Synthesis of 2-(4-fluoro-phenyl)-1-{6-[2-(3-fluoro-phenyl)-ethyl]-2,6-diaza-spiro[3.3]hept-2-yl}-ethanone (Cpd B024) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): - Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(2-bromoethyl)-3-fluorobenzene (commercially available) ESI [M+H] + ;357.2

[0326] Synthesis of 2-(4-fluoro-phenyl)-1-{6-[2-(4-methoxy-phenyl)-ethyl]-2,6-diaza-spiro[3.3]hept-2-yl}-ethanone (Cpd B025) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(2-bromoethyl)-4-methoxybenzene (commercially available) ESI [M+H] + ;369.2

[0327] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(2-p-tolyl-ethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B026) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) Halogenated electrophile: 1-(2-bromoethyl)-4-methylbenzene (commercially available) ESI [M+H] + ;353.3

[0328] Synthesis of 2-(4-fluoro-phenyl)-1-{6-[2-(4-fluoro-phenyl)-ethyl]-2,6-diaza-spiro[3.3]hept-2-yl}-ethanone (Cpd B027) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(2-bromoethyl)-4-fluorobenzene (commercially available) ESI [M+H] + ;357.2

[0329] Synthesis of 2-(4-fluoro-phenyl)-1-[6-(2-m-tolyl-ethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B028) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(2-bromoethyl)-3-methylbenzene (commercially available) ESI [M+H] + ;353.3

[0330] Synthesis of 2-{6-[2-(4-fluoro-phenyl)-acetyl]-2,6-diaza-spiro[3.3]hept-2-yl}-2-methyl-1-phenyl-propan-1-one (Cpd B029) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 2-bromo-2-methyl-1-phenylpropan-1-one (commercially available) ESI [M+H] + ;381.3

[0331] Synthesis of 2-(4-fluoro-phenyl)-1-(6-phenethyl-2,6-diaza-spiro[3.3]hept-2-yl)-ethanone (Cpd B030) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) -Halogenated electrophile: (2-bromoethyl)benzene (commercially available) ESI [M+H] + ;339.2

[0332] Synthesis of 2-(4-chlorophenyl)-1-(6-(3-methoxybenzyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B031) Coupling between the building blocks described herein above and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(bromomethyl)-3-methoxybenzene (commercially available) ESI [M+H] + ;371.2

[0333] Synthesis of 2-(4-chlorophenyl)-1-(6-(pyridin-2-ylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B032) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 2-(bromomethyl)pyridine (commercially available) ESI [M+H] + ;342.1

[0334] Synthesis of 1-(6-(3-chlorobenzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(4-chlorophenyl)ethanone (Cpd B033) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(bromomethyl)-3-chlorobenzene (commercially available) ESI [M+H] + ;375.3

[0335] Synthesis of 2-(4-chlorophenyl)-1-(6-(2-(trifluoromethoxy)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B034) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(bromomethyl)-2-(trifluoromethoxy)benzene (commercially available) ESI [M+H] + ;424.9

[0336] Synthesis of methyl 4-((6-(2-(4-chlorophenyl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)benzoate (Cpd B035) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: methyl 4-(bromomethyl)benzoate (commercially available) ESI [M+H] + ;399.0

[0337] Synthesis of 2-(4-chlorophenyl)-1-(6-((4,6-dimethoxypyrimidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B036) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 2-(chloromethyl)-4,6-dimethoxypyrimidine (commercially available) ESI [M+H] + ;403.1

[0338] Synthesis of 2-(4-chlorophenyl)-1-(6-(1-(3-(trifluoromethyl)phenyl)ethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B037) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(1-bromoethyl)-3-(trifluoromethyl)benzene (commercially available) ESI [M+H] + ;423.2

[0339] Synthesis of 2-(4-chlorophenyl)-1-(6-((6-methylpyridin-2-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B038) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 2-(bromomethyl)-6-methylpyridine (commercially available) ESI [M+H] + ;356.1

[0340] Synthesis of 2-(4-chlorophenyl)-1-(6-((5-chloropyrimidin-2-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B039) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 5-chloro-2-(chloromethyl)pyrimidine (commercially available) ESI [M+H] + ;377.3

[0341] Synthesis of 2-(4-chloro-phenyl)-1-[6-(5-trifluoromethyl-furan-2-ylmethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B040) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 2-(bromomethyl)-5-(trifluoromethyl)furan (commercially available) ESI [M+H] + ;399.0

[0342] Synthesis of 2-(4-chlorophenyl)-1-(6-((5-methylisoxazol-3-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B041) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 3-(bromomethyl)-5-methylisoxazole (commercially available) ESI [M+H] + ;346.1

[0343] Synthesis of 2-(4-chlorophenyl)-1-(6-propyl-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B042) According to the general procedure for the preparation of IB1A iii): Coupling between the building blocks described herein and halogenated electrophiles Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Halogenated electrophile: 1-iodopropane (commercially available) ESI [M+H] + ;293.1

[0344] Synthesis of 2-(4-chlorophenyl)-1-(6-(thiazol-4-ylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B043) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) Halogenated electrophile: 4-(chloromethyl)thiazole (commercially available) ESI [M+H] + ;348.2

[0345] Synthesis of 2-(4-chlorophenyl)-1-(6-(3-(trifluoromethyl)phenethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B044) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) Halogenated electrophile: 1-(2-bromoethyl)-3-(trifluoromethyl)benzene (commercially available) ESI [M+H] + ;423.2

[0346] Synthesis of 2-(4-chlorophenyl)-1-(6-(3-fluorophenethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B045) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(2-bromoethyl)-3-fluorobenzene (commercially available) ESI [M+H] + ;373.2

[0347] Synthesis of 2-(4-chlorophenyl)-1-(6-(4-methoxyphenethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B046) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(2-bromoethyl)-4-methoxybenzene (commercially available) ESI [M+H] + ;385.2

[0348] Synthesis of 2-(4-chlorophenyl)-1-(6-(4-methylphenethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B047) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(2-bromoethyl)-4-methylbenzene (commercially available) ESI [M+H] + ;369.0

[0349] Synthesis of 2-(4-chlorophenyl)-1-(6-(4-fluorophenethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B048) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenon (IB 4-1) - Halogenated electrophile: 1-(2-bromoethyl)-4-fluorobenzene (commercially available) ESI [M+H] + ;373.0

[0350] Synthesis of 2-(4-chlorophenyl)-1-(6-(3-methylphenethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B049) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(2-bromoethyl)-3-methylbenzene (commercially available) ESI [M+H] + ;369.2

[0351] Synthesis of 2-(6-(2-(4-chlorophenyl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-methyl-1-phenylpropan-1-one (Cpd B050) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 2-bromo-2-methyl-1-phenylpropan-1-one (commercially available) ESI [M+H] + ;397.3

[0352] Synthesis of 2-(4-chlorophenyl)-1-(6-(2-(6-methylpyridin-2-yl)ethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B051) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethenone; (IB 4-1) - Halogenated electrophile: 2-(2-bromoethyl)-6-methylpyridine (commercially available) ESI [M+H] + ;370.3

[0353] Synthesis of 2-(4-chlorophenyl)-1-(6-phenethyl-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B052) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Halogenated electrophile: (2-bromoethyl)benzene (commercially available) ESI [M+H] + ;355.3

[0354] Synthesis of 2-(4-chlorophenyl)-1-(6-isopentyl-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B053) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Halogenated electrophile: 1-iodo-3-methylbutane (commercially available) ESI [M+H] + ;321.3

[0355] Synthesis of 2-(4-chlorophenyl)-1-(6-(1-phenylpropan-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B054) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Halogenated electrophile: (2-bromopropyl)benzene (commercially available) ESI [M+H] + ;369.2

[0356] Synthesis of 2-(4-chlorophenyl)-1-(6-(3,4-difluorobenzyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B055) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 4-(bromomethyl)-1,2-difluorobenzene (commercially available) ESI [M+H] + ;377.3

[0357] Synthesis of 2-(4-chlorophenyl)-1-(6-(cyclohexylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B056) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Halogenated electrophile: (bromomethyl)cyclohexane (commercially available) ESI [M+H] + ;347.2

[0358] Synthesis of 2-(4-chlorophenyl)-1-(6-(2-cyclohexylethyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B057) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) -Halogenated electrophile: (2-bromoethyl)cyclohexane (commercially available) ESI [M+H] + ;361.3

[0359] Synthesis of 2-(4-chlorophenyl)-1-(6-(3-(2-methoxyphenyl)propyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B058) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(3-bromopropyl)-2-methoxybenzene (commercially available) ESI [M+H] + ;399.2

[0360] Synthesis of 2-(4-chlorophenyl)-1-(6-(3-(4-methoxyphenyl)propyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B059) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(3-bromopropyl)-4-methoxybenzene (commercially available) ESI [M+H] + ;399.2

[0361] Synthesis of 2-(4-fluoro-phenyl)-1-{6-[3-(4-methoxy-phenyl)-propyl]-2,6-diaza-spiro[3.3]hept-2-yl}-ethanone (Cpd B060) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(3-bromopropyl)-4-methoxybenzene (commercially available) ESI [M+H] + ;383.3

[0362] Synthesis of 2-(4-chlorophenyl)-1-(6-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptan-2-yl)ethanone (Cpd B061) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(bromomethyl)-4-fluorobenzene (commercially available) ESI [M+H] + ;359.2

[0363] Synthesis of 1-(6-(2-chlorophenethyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(4-chlorophenyl)ethanone (Cpd B062) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1) - Halogenated electrophile: 1-(2-bromoethyl)-2-chlorobenzene (commercially available) ESI [M+H] + ;389.0

[0364] Synthesis of 1-{6-[2-(2-chloro-phenyl)-ethyl]-2,6-diaza-spiro[3.3]hept-2-yl}-2-(4-fluoro-phenyl)-ethanone (Cpd B063) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2) - Halogenated electrophile: 1-(2-bromoethyl)-2-chlorobenzene (commercially available) ESI [M+H] + ;373.2

[0365] Synthesis of 1-[6-(4,6-dimethoxy-pyrimidin-2-ylmethyl)-2,6-diaza-spiro[3.3]hept-2-yl]-2-(4-fluoro-phenyl)-ethanone (Cpd B064) Coupling between the building blocks described herein and halogenated electrophiles according to the general procedure for the preparation of B1A iii): Building ...

Claims

1. Compound of formula (B1A) 【Chemistry 1】 (wherein, A １ａ is selected from the group consisting of C ６～１０ aryl, C ４～６ cycloalkyl and 5- to 6-membered heteroaryl containing at least one N, O and / or S; each of the said groups is unsubstituted or may be substituted by one or more R １ａ and each R １ａ is independently halo, hydrogen, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkoxy, halo C １～６ alkyl, halo C １～６ alkoxy, cyano, hydroxy, carboxyl, C １～６ alkoxycarbonyl, C ３～６ cycloalkyl, (R ５ａ ) ２ N-carbonyl and C １～６ alkylcarbonylamino; and / or two R １ａ together with the atom to which they are attached can form C ３～６ cycloalkyl or a 5- to 10-membered saturated or partially saturated heterocyclyl; X １ａ is -CO- or -SO ２ - Selected from; Y １ａ is -C(R ３ａ ) ２ -, -NR ５ａ - or -O- will be selected; or Y １ａ It is a single bond; Z １ａ is either a single bond or -C(R ３ａ ) ２ -, -NR ５ａ - or -O - is selected; Each R ３ａ These are independently hydrogen, halo, or C １～６ Selected from alkyl groups; Each R ５ａ These are independently hydrogen or C １～６ Selected from alkyl groups; X ２ａ It is a single bond or -CO-; Y ２ａ is -C(R ４ａ ) ２ - and Z ２ａ It is either a single bond or -(C(R ４ａ ) ２ ) ｎ - is true; n is an integer selected from 1 or 2; Each R ４ａ These are, independently, hydrogen, halo, or C １～６ Selected from alkyl groups; or two R groups ４ａ Together with the atoms to which they are bonded, C ３～６ It can form cycloalkyl groups; A ２ａ This includes phenyl, a 5-6 member heteroaryl containing at least one N, O and / or S, and C ５～６ Selected from the group including cycloalkyl groups; each of the groups is either unsubstituted or has one or more R ２ａ It can be replaced by; each R ２ａ These are independently: halo, hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxy, Halo C １～６ Alkyl, Halo C １～６ Alkoxy, cyano, hydroxy, carboxyl, C １～６ Alkoxycarbonyl, (R ５ａ ) ２ N-carbonyl, -SO ２ -R ５ａ , C ３～６ Cycloalkyl and C １～６ Selected from the group including alkylcarbonylaminos; and / or two R ２ａ These, together with the atoms to which they are bonded, can form 5- to 10-membered saturated or partially saturated heterocyclines; However, the aforementioned compound is 2-benzyl-6-(toluene-4-sulfonyl)-2,6-diazaspiro[3.3]heptane; 2-(1,3-benzodioxol-5-ylmethyl)-6-[(4-methylphenyl)sulfonyl-2,6-diazaspiro[3.3]heptane (Assume it is not the case.) or its salts, solvates, hydrates, polymorphs, tautomers, racemates or stereoisomers or prodrugs.

2. A １ａ C ６～１０ Ariel, C ４～６ Selected from the group comprising cycloalkyls and 5- to 6-membered heteroaryls containing at least one N, O and / or S; each of the group is unsubstituted or has one or more R １ａ For example, 1, 2, 3 or 4 R １ａ It can be replaced by each R １ａ These are, independently, hydrogen, halo, and C. １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkyl, Halo C １～６ Alkoxy, cyano, hydroxy, carboxyl, C １～６ Alkoxycarbonyl, C ３～６ Cycloalkyl, (R ５ａ ) ２ N-carbonyl and C １～６ Selected from the group including alkylcarbonylaminos; and / or two R １ａ Together with the atoms to which they are bonded, C ３～６ It can form cycloalkyl or 5- to 9-membered saturated or partially saturated heterocyclines; X １ａ is -CO- or -SO ２ Selected from; Y １ａ is either a single bond or -C(R ３ａ ) ２ -, -NR ５ａ - or -O - is selected; Z １ａ is a single bond or is selected from -C(R ３ａ ), ２ -, -NR ５ａ - or -O-; Each R ３ａ is hydrogen, halo, or C １～４ It is alkyl; Each R ５ａ is hydrogen or C １～４ It is alkyl; X ２ａ It is a single bond or -CO-; Y ２ａ is -C(R ４ａ ) ２ - and Z ２ａ It is either a single bond or -(C(R ４ａ ) ２ ) ｎ - is true; n is an integer selected from 1 or 2; Each R ４ａ These are, independently, hydrogen, halo, or C １～４ Selected from alkyl groups; or two R groups ４ａ Together with the atoms to which they are bonded, C ３～５ It can form cycloalkyl groups; and A ２ａ This includes phenyl, a 5-6 member heteroaryl containing at least one N, O and / or S, and C ５～６ Selected from the group including cycloalkyl groups; each of the groups is either unsubstituted or has one or more R ２ａ For example, 1, 2, 3 or 4 R ２ａ It can be replaced by; each R ２ａ These are, independently, hydrogen, halo, and C. １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkyl, Halo C １～６ Alkoxy, cyano, hydroxy, carboxyl, C １～６ Alkoxycarbonyl, (R ５ａ ) ２ N-carbonyl, -SO ２ -R ５ａ , C ３～６ Cycloalkyl and C １～６ Selected from the group including alkylcarbonylaminos; and / or two R ２ａ The compound according to claim 1, wherein the atoms to which they are bonded can together form a 5-10 member saturated or partially saturated heterocycline.

3. Structural formulas (B1A1), (B1A2), (B1A3), (B1A4), or (B1A6) 【Chemistry 2】 (In the formula, A １ａ , Y １ａ Z １ａ , R ３ａ , R ４ａ Z ２ａ and A ２ａ (This has the same meaning as defined in claim 1.) The compound according to claim 1, having the following characteristics.

4. A １ａ C ６～１０ Ariel, C ５～６ Selected from the group comprising cycloalkyls and 5- to 6-membered heteroaryls containing at least one N, O and / or S; each of the group is unsubstituted or has one or more R １ａ For example, one, two or three R １ａ It can be replaced by each R １ａ These are, independently, hydrogen, halo, and C. １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkyl, Halo C １～６ Alkoxy, cyano, hydroxy, carboxyl, C １～６ Alkoxycarbonyl and C ３～６ Selected from the group including cycloalkyl groups; and / or two R １ａ Together with the atoms to which they are bonded, C ３～６ It can form cycloalkyl or 5-9 member saturated or partially saturated heterocyclines; and A ２ａ This includes phenyl, a 5-6 member heteroaryl containing at least one N, O and / or S, and C ５～６ Selected from the group including cycloalkyl groups; each of the groups is either unsubstituted or has one or more R ２ａ For example, one, two or three R ２ａ It can be replaced by; each R ２ａ These are, independently, hydrogen, halo, and C. １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkyl, Halo C １～６ Alkoxy, cyano, hydroxy, carboxyl, C １～６ Alkoxycarbonyl, (R ５ａ ) ２ N-carbonyl, -SO ２ -R ５ａ , C ３～６ Cycloalkyl and C １～６ Selected from the group including alkylcarbonylaminos; and / or two R ２ａ The compound according to claim 1, wherein the atoms to which they are bonded can together form a 5-10 member saturated or partially saturated heterocycline.

5. Structural formulas (B1A8), (B1A9), (B1A10), (B1A11), (B1A13) 【Transformation 3】 (In the formula, A １ａ , Y １ａ Z １ａ and A ２ａ (This has the same meaning as defined in claim 1.) The compound according to claim 1, having the following characteristics.

6. Structural formulas (B1A14), (B1A15), (B1A16), (B1A17), (B1A18), (B1A19), (B1A20), (B1A21), (B1A22), (B1A23), (B1A24) 【Chemistry 4】 (In the formula, A １ａ and A ２ａ (This has the same meaning as defined in claim 1.) The compound according to claim 1, having the following characteristics.

7. A １ａ Phenylenide, C ５～６ Selected from the group comprising cycloalkyl and 5-6 membered heteroaryls containing at least one N; each of the group is either unsubstituted or has one or more R １ａ For example, one, two or three R １ａ It can be replaced by each R １ａ These are, independently, hydrogen, halo, and C. １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkyl, Halo C １～６ Selected from the group including alkoxy, cyano, and hydroxy; and / or two R １ａ Together with the atoms to which they are bonded, C ３～６ It can form cycloalkyl or 5-9 member saturated or partially saturated heterocyclines; and A ２ａ This includes phenyl, a 5-6 member heteroaryl containing at least one N, O and / or S, and C ５～６ Selected from the group including cycloalkyl groups; each of the groups is either unsubstituted or has one or more R ２ａ For example, one, two or three R ２ａ It can be replaced by; each R ２ａ These are, independently, hydrogen, halo, and C. １～６ Alkyl, C １～６ Alkoxy, Halo C １～６ Alkyl, Halo C １～６ Alkoxy, cyano, hydroxy, carboxyl, C １～６ Alkoxycarbonyl, (R ５ａ ) ２ N-carbonyl, -SO ２ -R ５ａ , C ３～６ Cycloalkyl and C １～６ Selected from the group including alkylcarbonylaminos; and / or two R ２ａ The compound according to claim 1, wherein the atoms to which they are bonded can together form a 5-10 member saturated or partially saturated heterocycline.

8. Structural formulas (B1A25), (B1A26), (B1A27), (B1A28), (B1A29), (B1A30), (B1A31), (B1A32), (B1A33), (B1A34), (B1A35), (B1A36), (B1A37), (B1A38), (B1A39), (B1A40), (B1A41), (B1A42), (B1A43), (B1A44), (B1A45), (B1A46), (B1A47), (B1A48), (B1A49), (B1A50 ), (B1A51), (B1A52), (B1A53), (B1A54), (B1A55), (B1A56), (B1A57), (B1A58), (B1A59), (B1A60), (B1A61), (B1A62), (B1A63 ), (B1A64), (B1A65), (B1A66), (B1A67), (B1A68), (B1A69), (B1A70), (B1A71), (B1A72), (B1A73), (B1A74), (B1A75), (B1A76) 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 (In the formula, R １ａ , Y １ａ Z １ａ , X ２ａ , X １ａ , Y ２ａ Z ２ａ and A ２ａ is defined as having the same meaning as in claim 1, and ma is an integer selected from 1, 2, 3 or 4, and pa is an integer selected from 0 or 1, D １ａ CH ２ And qa is 0, and E １ａ is NH, or qa is 1 and E １ａ (This is either CH or N) The compound according to claim 1, having the following characteristics.

9. Structural formula (B1A77), (B1A78) 【Chemistry 9】 (In the formula, R １ａ and A ２ａ (where has the same meaning as defined in claim 1, and ma is an integer selected from 1, 2, 3, or 4) The compound according to claim 1, having the following characteristics.

10. Structural formula (B1A79), (B1A80) 【Chemistry 10】 (In the formula, R １ａ and R ２ａ is the same as defined in claim 1, and ma is an integer selected from 1, 2, 3 or 4, and na is an integer selected from 1, 2, 3 or 4, and E ２ａ (Selected from CH or N) The compound according to claim 1, having the following characteristics.

11. Compounds selected from the group including Cpd B001 to Cpd B041, Cpd B043 to Cpd B052, Cpd B054 to Cpd B065, Cpd B069 to Cpd B087, Cpd B089 to Cpd B227, Cpd B401 to Cpd B474, Cpd B476 to Cpd B483, Cpd B485 to Cpd B487, Cpd B489 to Cpd B490, Cpd B492 to Cpd B500 and Cpd B503 to Cpd B521, as listed in Table 1B.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and at least one pharmaceutically acceptable carrier.

13. A compound according to any one of claims 1 to 11 for use as a pharmaceutical agent.

14. The pharmaceutical composition according to claim 12 for use in the prevention and / or treatment of neurodegenerative disorders.

15. The pharmaceutical composition according to claim 12 for use in the prevention and / or treatment of a neurodegenerative disorder selected from the group consisting of Parkinson's disease, Alzheimer's disease, diffuse Lewy body disease, amyotrophic lateral sclerosis, Niemann-Pick disease, Haller-Vorden-Spatz syndrome, Down syndrome, Pick's disease, progressive supranuclear palsy, vascular dementia, axonal dystrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy, and Creutzfeldt-Jakob disease, preferably Alzheimer's disease.

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