(Aza) Spiroheptane Derivatives For The Treatment Of Neurodegenerative Disorders

Abstract

The present application relates to compounds of formula (B1A), (B1B), (B1C) or salts, solvates, hydrates, polymorphs, tautomers, racemes or stereoisomers thereof, pharmaceutical compositions comprising such compounds, and these compounds for use as pharmaceuticals, in particular for use in the treatment of neurodegenerative disorders such as Alzheimer's disease. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to (aza)spiroheptane derivatives that can be used for the treatment of certain neurodegenerative disorders, such as neurodegenerative disorders characterized by cytotoxic tau protein misfolding and / or aggregation, and / or amyloid-β aggregation. Background Art

[0002] Tau protein is a protein that can bind to (and thus stabilize and define) the structure and function of microtubules in neurons. The binding of tau protein to microtubules is regulated by tau protein phosphorylation; several tau protein phosphorylation sites and their corresponding kinases have been identified, which can control the phosphorylation state of tau protein, thereby regulating the affinity of tau protein for microtubule binding.

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

[0004] An important aspect of tau protein aggregation is its associated cytotoxicity, which reduces the integrity and functionality of neurons and ultimately leads to disease symptoms. By elucidating the familial mutations of tau protein, the direct role of tau protein in the onset of the disease has been clearly established, and these mutations seem to be the cause of very early and sometimes aggressive tauopathies. Such mutations involve changes in the amino acid sequence of tau protein, which directly or indirectly promote neurotoxic aggregation.

[0005] The best-known of these diseases is Alzheimer's disease, in which tau protein is deposited inside neurons in the form of neurofibrillary tangles (NFTs). These tangles were first described by Alois Alzheimer of the same name in one of his patients suffering from the disorder.

[0006] As used herein, the term "Alzheimer's disease" refers to a chronic progressive neurological disease characterized by neurodegeneration, and the most important (early) symptom is memory loss. As the disease progresses, symptoms may include confusion, irritability and aggressive behavior, mood swings, language disorders, long-term memory loss, and general withdrawal of the patient due to sensory decline. The tangles are formed by the hyperphosphorylation of the microtubule-associated protein called tau protein, resulting in its aggregation in an insoluble form. (These hyperphosphorylated tau protein aggregates are also called PHF or "paired helical filaments"). The exact mechanism of tangle formation is not fully understood, and there is still controversy as to whether the tangles are the main causative factor of the disease or play a more peripheral role. Since there are senile plaques, AD is also classified as amyloidosis.

[0007] Other disorders with common neurofibrillary tangles include: progressive supranuclear palsy, pugilistic dementia (chronic traumatic encephalopathy), chromosome 17-linked frontotemporal dementia associated with related parkinsonism, Lytico-Bodig disease (Guam parkinson-dementia complex), tangle-predominant dementia with NFTs (similar to AD but without plaques), ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

[0008] Non-Alzheimer's tauopathies are sometimes classified as "Pick's complex". In Pick's disease and corticobasal degeneration, tau protein deposits in swollen or "ballooned" neurons in the form of inclusion bodies. Argentophilic grain disease (AGD) (another type of dementia) is characterized by the presence of large numbers of argentophilic grains and coiled bodies in microscopic examination of brain tissue.

[0009] Currently used treatments for tauopathies, including Alzheimer's disease, only provide symptomatic benefits and do not affect underlying neurodegeneration. There is currently no treatment aimed at inhibiting cytotoxic tau protein misfolding and / or aggregation to delay or prevent disease progression.

[0010] Therefore, there is a need for new treatment methods that target the underlying molecular mechanisms of harmful tau protein misfolding and / or aggregation to reduce neuronal cell death and / or degeneration in patients with tauopathies such as Alzheimer's disease (AD). SUMMARY OF THE INVENTION

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

[0012] The object of the present invention is compounds of formula (B1A), (B1B), (B1C), the use of these compounds for the treatment of diseases associated with tau protein biological dysfunction (these diseases include Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia associated with related parkinsonism (chromosome 17-linked, FTDP-17)), the manufacture of these compounds, and drugs for controlling or preventing diseases based on the compounds according to the present invention.

[0013] In a first aspect, the present invention provides a compound of formula (B1A), (B1B), (B1C), or a salt, solvate, hydrate, polymorph, tautomer, racemate or stereoisomer thereof, or a prodrug thereof; wherein

[0014]

[0015] A1a Selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1a substituents, where each R 1a is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0016] X 1a is selected from -CO-, -SO2-, -C(R 3a )2-, or 5-membered heteroarylene;

[0017] Y 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0018] Z 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0019] Each R 3a is independently selected from hydrogen, halo, or C 1-6 alkyl;

[0020] Each R 5a is independently selected from hydrogen or C 1-6 alkyl;

[0021] X 2a is a single bond or -CO-;

[0022] Y 2a is a single bond or -C(R4a )2-,

[0023] Z 2a is a single bond, or is selected from -(C(R 4a 2) n - or -CO-; where n is an integer selected from 1 or 2;

[0024] Each R 4a is independently selected from hydrogen, halo, or C 1-6 alkyl; or two Rs 4a together with the atom to which they are attached can form a C 3-6 cycloalkyl;

[0025] A 2a is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl containing at least one N, O, and / or S, 5-10 membered saturated or partially saturated heterocyclic group, C 3-6 cycloalkyl, and C 1-6 alkyl; where each in the group can be unsubstituted or substituted by one or more Rs 2a where each R 2a is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, C 1-6 alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3-6 cycloalkyl, and C 1-6 alkylcarbonylamino; and / or two Rs 2a together with the atom to which they are attached can form a C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0026]

[0027] A 1b is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; where each in the group can be unsubstituted or substituted by one or more Rs 1b where each R 1bIndependently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached can form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0028] R 3b selected from hydrogen or C 1-6 alkyl;

[0029] Y 1b selected from -CO-, -C(R 5b )2-, or 5-membered heteroarylene;

[0030] Z 1b is -C(R 5b )2-;

[0031] R 4b selected from hydrogen, C 1-6 alkyl, or C 1-6 alkoxycarbonyl;

[0032] each R 5b independently selected from hydrogen, halo or C 1-6 alkyl;

[0033] each R 6b independently selected from hydrogen or C 1-6 alkyl;

[0034] Y 2b is -C(R 5b )2- or a single bond;

[0035] Z 2b is a single bond, or selected from -(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2;

[0036] A 2b selected from the group consisting of: C 6-10 aryl, 5- to 10-membered heteroaryl containing at least one N, O and / or S, 5- to 10-membered saturated or partially saturated heterocyclic group, C 3-6 cycloalkyl, and C1-6 alkyl; wherein each in said group may be unsubstituted or substituted by one or more R 2b substituents, wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which it is attached may form a C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0037]

[0038] A 1c is selected from the group consisting of: 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 heterocyclic group containing at least one N, O and / or S; wherein each in said group may be unsubstituted or substituted by one or more R 1c substituents, wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which it is attached may form a C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0039] R 3c is selected from hydrogen or C 1-6 alkyl;

[0040] Y 1c is a single bond, or is selected from -C(R 4c )2-, -NR 6c -, -O-, or a 5-membered heteroaryl group;

[0041] Z 1c is a single bond, or is selected from -C(R 4c )2- or -O-;

[0042] Each R 4c is independently selected from hydrogen, halo, or C 1-6 alkyl;

[0043] Each R 6c is independently selected from hydrogen or C 1-6 alkyl;

[0044] X 2c is a single bond or -CO-;

[0045] Y 2c is a single bond or -C(R 5c )2-,

[0046] Z 2c is a single bond, or is selected from -(C(R 5c )2) p - or -CO-; where p is an integer selected from 1 or 2;

[0047] Each R 5c is independently selected from hydrogen, halo, or C 1-6 alkyl; or two R 5c together with the atom to which they are attached can form C 3-6 cycloalkyl;

[0048] A 2c is selected from the group consisting of: C 6-10 aryl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S, C 3-6 cycloalkyl, hydrogen, -N(R 6c )2, and C 1-6 alkyl; where each in the group can be unsubstituted or substituted by one or more R 2c ; where each R 2c is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5 - 10 - membered heteroaryl, or 5 - 10 - membered saturated or partially saturated heterocyclic group.

[0049] Preferably, the present invention provides a compound having the formula (B1A), (B1B), (B1C), or a salt, solvate, hydrate, polymorph, tautomer, racemate or stereoisomer thereof, or a prodrug thereof; wherein

[0050]

[0051] A 1a is selected from the group consisting of: 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 heterocyclic group containing at least one N, O and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1a substituents, wherein each R 1a is independently selected from the group consisting of: 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, C 3-6 cycloalkyl, (R 5a )2N - carbonyl, and C 1-6 alkylcarbonylamino; and / or two R 1a together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5 - 10 - membered heteroaryl, or 5 - 10 - membered saturated or partially saturated heterocyclic group;

[0052] X 1a is selected from -CO -, -SO2 -, -C(R 3a )2 -, or a 5 - membered heteroarylene;

[0053] Y 1a is selected from -C(R 3a )2 -, -NR 5a-or -O-; or Y 1a is a single bond;

[0054] Z 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a ]-, or -O-;

[0055] Each R 3a is independently selected from hydrogen, halo, or C 1-6 alkyl;

[0056] Each R 5a is independently selected from hydrogen or C 1-6 alkyl;

[0057] X 2a is a single bond or -CO-;

[0058] Y 2a is -C(R 4a )2- or Y 2a is a single bond,

[0059] Z 2a is a single bond, or is selected from -(C(R 4a )2) n -, or -CO-; where n is an integer selected from 1 or 2;

[0060] Each R 4a is independently selected from hydrogen, halo, or C 1-6 alkyl; or two Rs 4a together with the atom to which they are attached can form a C 3-6 cycloalkyl;

[0061] A 2a is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl containing at least one N, O, and / or S, 5-10 membered saturated or partially saturated heterocyclic group, and C 3-6 cycloalkyl; where each in the group can be unsubstituted or substituted by one or more Rs 2a ; where each R 2a is independently selected from the group consisting of: 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, carboxy, C 1-6 alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a 、C 3-6 cycloalkyl, and C1-6 alkylcarbonylamino; and / or two Rs 2a together with the atom to which it is attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0062] provided that:

[0063] A 1a is not: wherein R 1a1 and R 1a2 are each independently selected from C 1-2 alkyl, or R 1a1 and R 1a2 together with the carbon atom to which it is attached form C3-6 cycloalkyl, wherein R 1a has the same meaning as defined herein, and s is an integer selected from 0, 1, or 2;

[0064] A 2a is not: wherein R 2a has the same meaning as defined herein, and s is an integer selected from 0, 1, or 2;

[0065] provided that the compound is not:

[0066] 2-benzyl-6-(toluene-4-sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0067] 2-(1,3-benzodioxol-5-ylmethyl)-6-[(4-methylphenyl)sulfonyl]-2,6-diazaspiro[3.3]heptane;

[0068] 2-(1,3-benzodioxol-5-ylmethyl)-6-(phenylmethyl)-2,6-diazaspiro[3.3]heptane;

[0069] 2-benzyl-6-(toluenesulfonyl)-2,6-diazaspiro[3.3]heptane;

[0070] 6-benzyl-2,6-diazaspiro[3.3]hept-2-yl)(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methanone;

[0071] (5-cyclohexyl-1H-pyrazol-3-yl)(6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]hept-2-yl)methanone;

[0072] (6-(Cyclopropanecarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)(1-isopropyl-1H-imidazol-4-yl)methanone;

[0073] (5-Isopropyl-1H-pyrazol-3-yl)(6-(1-methylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone;

[0074] (5-Isopropyl-1H-pyrazol-3-yl)(6-(thiophene-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone;

[0075] [2-(4-Fluoro-1-methyl-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone;

[0076]

[0077] A 1b selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1b substituents, wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5-10-membered heteroaryl, or 5-10-membered saturated or partially saturated heterocyclic group;

[0078] R 3b is selected from hydrogen or C 1-6 alkyl;

[0079] Y 1b is selected from -CO-, -C(R 5b )2-, or 5-membered heteroarylene;

[0080] Z1b is -C(R 5b )2-;

[0081] R 4b is selected from hydrogen, C 1-6 alkyl, or C 1-6 alkoxycarbonyl;

[0082] Each R 5b is independently selected from hydrogen, halo, or C 1-6 alkyl;

[0083] Each R 6b is independently selected from hydrogen or C 1-6 alkyl;

[0084] Y 2b is -C(R 5b )2- or a single bond;

[0085] Z 2b is a single bond, or is selected from -(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2;

[0086] A 2b is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl containing at least one N, O, and / or S, 5-10 membered saturated or partially saturated heterocyclic group, C 3-6 cycloalkyl, and C 1-6 alkyl; where each in the group may be unsubstituted or substituted by one or more R 2b substituents, where each R 2b is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0087]

[0088] A1c Selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1c , where each R 1c is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0089] R 3c is selected from hydrogen or C 1-6 alkyl;

[0090] Y 1c is a single bond, or selected from -C(R 4c )2-, -NR 6c -, -O-, or 5-membered heteroarylene;

[0091] Z 1c is a single bond, or selected from -C(R 4c )2- or -O-;

[0092] Each R 4c is independently selected from hydrogen, halo, or C 1-6 alkyl;

[0093] Each R 6c is independently selected from hydrogen or C 1-6 alkyl;

[0094] X 2c is a single bond or -CO-;

[0095] Y 2c is a single bond or -C(R 5c )2-,

[0096] Z 2c is a single bond, or selected from -(C(R5c )2) p - or -CO-; where p is an integer selected from 1 or 2;

[0097] Each R 5c is independently selected from hydrogen, halo, or C 1-6 alkyl; or two Rs 5c together with the atom to which it is attached can form a C 3-6 cycloalkyl;

[0098] A 2c is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl containing at least one N, O, and / or S, 5-10 membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S, C 3-6 cycloalkyl, and -N(R 6c )2; where each in the group can be unsubstituted or substituted by one or more Rs 2c ; where each R 2c is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c , and C 1-6 alkylcarbonylamino; and / or two Rs 2c together with the atom to which it is attached can form a C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group.

[0099] Provided that:

[0100] A 1c is not

[0101] A 2c is not

[0102] Provided that the compound is not:

[0103] N-benzyl-2-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-amine;

[0104] N-(2-(2-Fluorophenyl)-2-azaspiro[3.3]hept-6-yl)-6,7-dimethoxy-2,3-dihydro-1H-cyclopenta[b]quinolin-9-amine;

[0105] 6-((2-((Benzyloxy)carbonyl)-2-azaspiro[3.3]hept-6-yl)amino)-2-chloropyrimidine-4-carboxylic acid;

[0106] Benzyl 6-((2-chloro-6-(methoxycarbonyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate.

[0107] In a second aspect, the present invention also relates to a pharmaceutical composition comprising a compound according to the first aspect of the present invention and at least one pharmaceutically acceptable carrier.

[0108] The present invention also relates to the use of a compound according to the first aspect of the present invention or a pharmaceutical composition according to the second aspect for use as a medicament.

[0109] The compounds and compositions of the present invention can be used to treat certain neurodegenerative disorders, such as neurodegenerative disorders characterized by inhibition of cytotoxic tau protein misfolding and / or aggregation, to delay or prevent 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 disease, 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, preferably the neurodegenerative disorder is Alzheimer's disease.

[0110] The above and other features, characteristics, and advantages of the present invention will become apparent from the following detailed description, which illustrates the principles of the present invention by way of example. Detailed Description

[0111] In describing the present invention, the terms used shall be interpreted according to the following definitions, unless the context indicates otherwise.

[0112] Unless otherwise defined, all terms (including technical and scientific terms) used to disclose the present invention have the meanings commonly understood by those of ordinary skill in the art to which the present invention pertains. Through further guidance, including the definitions of the terms used in the specification, the teachings of the present invention can be better understood. When describing the compounds, methods, articles, and uses of the present invention, the terms used shall be interpreted according to the following definitions, unless the context indicates otherwise.

[0113] As used herein, the singular forms "a / an" and "the" include both singular and plural referents unless the context clearly indicates otherwise. For example, "a compound" means one compound or more than one compound.

[0114] As used herein, the terms "comprising" and "comprised of" are synonymous with "including" or "containing" and are inclusive or open-ended and do not exclude additional, unrecited members, elements or method steps. The terms "comprising" and "comprised of" also include the term "consisting of".

[0115] Numeric ranges expressed by endpoints include all integers and, where appropriate, also fractions within the range (e.g., 1 to 5 may include 1, 2, 3, 4 when referring to, for example, the number of elements and may also include 1.5, 2, 2.75 and 3.80 when referring to, for example, a measured value). The recitation of endpoints also includes the endpoint values themselves (e.g., 1.0 to 5.0 includes both 1.0 and 5.0). Any numeric range recited herein is intended to include all subranges subsumed therein.

[0116] The term "and / or" as used herein will be regarded as a specific disclosure of each of two specified features or components with or without the other specified feature or component. Thus, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B and / or C" is intended to cover each of the following: 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).

[0117] References to "one embodiment" or "an embodiment" throughout the specification mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the phrases "in one embodiment" or "in an embodiment" that appear throughout the specification are not necessarily all referring to the same embodiment, but may. Additionally, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner, as will be clear to those skilled in the art in light of this disclosure. Further, as will be understood by those skilled in the art, although some embodiments described herein include some features but not other features included in other embodiments, combinations of features of different embodiments are intended to be within the scope of the invention and form different embodiments. For example, in the claims and descriptions that follow, any embodiment may be used in any combination.

[0118] As used herein, the term "leaving group" or "LG" refers to a chemical group that is readily replaced by a nucleophile or cleaved or hydrolyzed under basic or acidic conditions. In certain embodiments, the leaving group is selected from a halogen atom (e.g., Cl, Br, I) or a sulfonate group (e.g., mesylate, tosylate, triflate).

[0119] The term "protecting group" or "PG" refers to a moiety that masks or modifies the nature of a functional group or the nature of the entire compound in a compound. The 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 protecting / deprotecting 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 typically used to mask the reactivity of certain functional groups to aid in the efficiency of the desired chemical reaction, such as building and breaking chemical bonds in an orderly and planned manner. The protection of a compound's functional group, in addition to altering the reactivity of the protected functional group, also alters other physical properties, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates themselves may or may not have biological activity.

[0120] When the term "substituted" is used herein, it is intended to indicate that one or more hydrogen atoms on the atom indicated by the use of "substituted" are replaced by a selection from the indicated group, provided that the normal valence of the indicated atom is not exceeded and the substitution results in a chemically stable compound, i.e., a compound that is robust enough to withstand isolation from the reaction mixture.

[0121] The term "halo" or "halogen", as a group or part of a group, refers to the collective term for fluorine, chlorine, bromine, and iodine.

[0122] As used herein, the term "cyano" refers to the group -CN.

[0123] As used herein, the term "hydroxyl" or "hydroxy" refers to the group -OH.

[0124] As used herein, the term "oxo" refers to the group ═O.

[0125] The term "alkyl", as a group or part of a group, refers to a hydrocarbon group having the formula C n H 2n+1 (where n is a number greater than or equal to 1) and having no unsaturated sites. The alkyl group can be straight-chain or branched and can be substituted as shown herein. Generally, the alkyl groups of the present invention contain from 1 to 18 carbon atoms, preferably from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, and even more preferably from 1 to 4 carbon atoms. When a subscript is used after a carbon atom herein, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term "C 1-6 alkyl", as a group or part of a group, refers to a hydrocarbon group having the formula C n H 2n+1 (where n is a number ranging from 1 to 6). Thus, for example, "C 1-6 alkyl" includes all straight-chain or branched alkyl groups having from 1 to 6 carbon atoms and thus includes methyl, ethyl, n-propyl, isopropyl, butyl and its isomers (e.g., n-butyl, isobutyl, and tert-butyl); pentyl and its isomers, hexyl and its isomers, etc. For example, C 1-4 alkyl includes all straight-chain or branched alkyl groups having from 1 to 4 carbon atoms and thus includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, butyl and its isomers (e.g., n-butyl, isobutyl, and tert-butyl), etc. In certain embodiments, the term alkyl refers to C 1-12 alkyl(C 1-12 hydrocarbon), more particularly C 1-9 alkyl(C 1-9 hydrocarbon), more particularly C 1-6 alkyl(C 1-6 hydrocarbon) as further defined herein. Non-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-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.

[0126] When the suffix “ene” is used in combination with an alkyl group, i.e., “alkylene,” it is intended to mean that the alkyl group as defined herein has two single bonds as attachment points to other groups. As used herein, the term “alkylene” is also referred to as “alkanediyl” and, by itself or as part of another substituent, refers to a divalent alkyl group, i.e., having two monovalent group centers (these group centers being obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane), i.e., having two single bonds for attachment to two other groups. The alkylene group can be straight-chain or branched-chain and can be substituted as shown herein. Non-limiting examples of alkylene groups include methylene (-CH2-), ethylene (-CH2-CH2-), methylmethylene (-CH(CH3)-), 1-methylethylene (-CH(CH3)-CH2-), n-propylene (-CH2-CH2-CH2-), 2-methylpropylene (-CH2-CH(CH3)-CH2-), 3-methylpropylene (-CH2-CH2-CH(CH3)-), n-butylene (-CH2-CH2-CH2-CH2-), 2-methylbutylene (-CH2-CH(CH3)-CH2-CH2-), 4-methylbutylene (-CH2-CH2-CH2-CH(CH3)-), pentylene and its chain isomers, hexylene and its chain isomers.

[0127] The term “hydrocarbyl” group is used herein according to the IUPAC-specified definition: a monovalent group formed by removing one hydrogen atom from a hydrocarbon (i.e., a group containing only carbon and hydrogen).

[0128] The term “alkenyl,” as a group or part of a group, refers to an unsaturated hydrocarbyl group that can be straight-chain or branched-chain and contains one or more (usually 1 to 3, preferably 1) unsaturated sites, i.e., at least one sp 2 carbon-sp 2carbon 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, more preferably 2 to 6 carbon atoms. When a subscript is used after a carbon atom herein, the subscript refers to the number of carbon atoms that the named group may contain. C 2-6 Examples of alkenyl groups are vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, etc. The double bond can be in a cis or trans configuration.

[0129] When the suffix “ene” is used in combination with an alkenyl group, i.e., “alkenylene”, it is intended to mean that the alkenyl group as defined herein has two single bonds as attachment points to other groups. As used herein, the term “alkenylene” by itself or as part of another substituent refers to a divalent alkenyl group, i.e., having two monovalent centers (these centers are obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent olefin), i.e., having two single bonds attached to two other groups. The alkenylene group can be straight-chain or branched-chain and can be substituted as shown 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—, etc.

[0130] The term “alkynyl” as a group or part of a group refers to a branched or straight-chain hydrocarbon containing at least one (usually 1 to 3, preferably 1) unsaturated site, i.e., sp 1 carbon-sp 1 carbon triple bond. In certain embodiments, the term alkynyl refers to a branched or straight-chain hydrocarbon having at least one (usually 1 to 3, preferably 1) unsaturated site, i.e., at least one sp 1 carbon-sp 1 carbon triple bond as further defined hereinabove for C 2-12 alkynyl (C 2-12 hydrocarbon), preferably C 2-9 alkynyl (C 2-9 hydrocarbon), still more preferably C 2-6 alkynyl (C 2-6 hydrocarbon). Examples of alkynyl include, but are not limited to: ethynyl (—C≡CH), 3-ethyl-subcyclohept-1-ynyl, and 1-propynyl (propargyl, —CH2C≡CH).

[0131] When the suffix “ene” is used in combination with an alkynyl group, i.e., “alkynylene”, it is intended to mean that the alkynyl group as defined herein has two single bonds as attachment points 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 attached to two other groups. The alkynylene group can be straight-chain or branched-chain and can be substituted as shown herein. Non-limiting examples of alkynylene groups include -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -CH2-CH2-C≡C-, etc.

[0132] The term “cycloalkyl” as a group or part of a group refers to a cyclic alkyl group which is a monovalent saturated hydrocarbon group having one or more cyclic structures and containing 3 to 20 carbon atoms, more preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms; more preferably 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 3-10 monocyclic or C 7-18 polycyclic saturated hydrocarbons such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylethylene, methylenecyclopropyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclooctylmethylene, norbornyl, fenchyl, trimethyltricycloheptyl, decahydronaphthyl, adamantyl, etc. Additional rings of polycyclic cycloalkyls can be fused, bridged and / or linked by one or more spiro atoms. When a subscript is used after a carbon atom herein, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term “C 3-10 cycloalkyl” refers to a cycloalkyl group containing 3 to 10 carbon atoms. For example, the term “C 3-8 cycloalkyl” refers to a cycloalkyl group containing 3 to 8 carbon atoms. For example, the term “C 3-6 cycloalkyl” refers to a cycloalkyl group containing 3 to 6 carbon atoms. To avoid doubt, a fused system of a cycloalkyl ring and a heterocycle is regarded as a heterocycle, regardless of what the ring attached to the core structure is. A fused system of a cycloalkyl ring and an aryl ring is regarded as an aryl, regardless of what the ring attached to the core structure is. A fused system of a cycloalkyl ring and a heteroaryl ring is regarded as a heteroaryl, regardless of what the ring attached to the core structure is.

[0133] The term “alkoxy” or “alkyloxy” as a group or part of a group refers to a group having the formula –OR b wherein R b is an alkyl as defined herein. Non-limiting examples of suitable C 1-6 alkoxys include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0134] The term "aryl", as a group or part of a group, refers to a polyunsaturated aromatic hydrocarbon group having a single ring (i.e., phenyl), or multiple aromatic rings fused together (e.g., naphthyl), or covalently linked, typically containing 6 to 20; preferably 6 to 10 atoms, with at least one ring being aromatic. Typical aryl groups include, but are not limited to, 1 ring, or 2 or 3 rings fused together, which are derived from benzene, naphthalene, anthracene, biphenyl, etc. The aromatic rings may optionally include one or two additional rings. An aryl ring fused system with a cycloalkyl ring, or a cycloalkenyl ring, or a cycloalkynyl ring is considered an aryl, regardless of the ring attached to the core structure. A fused system of an aryl ring with a heterocyclic ring is considered a heterocyclic ring, regardless of the ring attached to the core structure. A fused system of an aryl ring with a heteroaryl ring is considered a heteroaryl ring, 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 aryl. Non-limiting examples of aryl include phenyl, biphenyl, biphenylene, or 1- or 2-naphthanelyl; 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.

[0135] When the suffix “ene” is used in combination with an aryl group, i.e., “arylene”, it is intended to mean that the aryl group as defined herein has two single bonds as attachment points to other groups. As used herein, the term “arylene” by itself or as part of another substituent refers to a divalent aryl group, i.e., having two monovalent centers (these centers are obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent aryl), i.e., having two single bonds attached to two other groups. The arylene group may be substituted as shown herein.

[0136] The term "arylalkyl", as a group or part of a group, refers to an 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-phenyleth-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethyl, etc. The term “C 6-10 aryl C 1-6"Alkyl" means that the alkyl moiety of an arylalkyl group may contain 1 to 6 carbon atoms, and the aryl moiety may contain 6 to 10 carbon atoms.

[0137] The term "aryloxy", as a group or part of a group, refers to a group having the formula –O-R f wherein R f is an aryl as defined herein.

[0138] The term "haloalkyl", as a group or part of a group, refers to an alkyl group having the meaning as defined herein, wherein 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.

[0139] The term "haloalkoxy", as a group or part of a group, refers to a group having the formula -O-R e wherein R e is a haloalkyl as defined herein. Non-limiting examples of suitable haloalkoxy groups 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, 4,4,4-trichlorobutoxy.

[0140] As used herein, the term "heterocyclyl" refers to a non-aromatic, fully saturated or partially unsaturated ring system that contains 3 to 18 atoms (including at least one N, O, S, or P), preferably 3 to 14 atoms (3-14 membered heterocyclyl) (e.g., 3 to 7 membered monocyclic, 7 to 14 membered bicyclic), preferably a total of 3 to 10 ring atoms (3-10 membered heterocyclyl), more preferably 4 to 10 atoms (4-10 membered heterocyclyl), still more preferably 5 to 10 atoms (5-10 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, wherein the N and S heteroatoms may optionally be oxidized, and the N heteroatoms may optionally be quaternized; and wherein at least one carbon atom of the heterocyclyl may be oxidized to form at least one C=O. The heterocyclyl may be attached to any heteroatom or carbon atom of the ring or ring system, provided that the valency permits. The rings of a polycyclic heterocyclyl or heterocycle may be fused, bridged, and / or linked by one or more spiro atoms. A fused system of a heterocycle or heterocyclyl with an aryl ring is regarded as a heterocycle or heterocyclyl, regardless of the ring attached to the core structure. A fused system of a heterocycle or heterocyclyl with a heteroaryl ring is regarded as a heteroaryl, regardless of the ring attached to the core structure.

[0141] 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-dihydrobenz[b]pyranyl), 2H-pyrrolyl, pyrrolinyl (such as 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl), 4H-quinolizinyl, 2-oxopiperazinyl, pyrazolinyl (such as 2-pyrazolinyl, 3-pyrazolinyl), 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-dioxoimidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, indolinyl, tetrahydrothienyl, 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-pyrazinyl, tetrahydro-1,1-dioxothienyl, 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-dihydrobenz[d]oxazolyl, tetrahydro-benzoxazolyl, dihydro-benzoxazinyl, 3,4-dihydro-2H-benz[b][1,4]oxazinyl, tetrahydro-benzoxazinyl, benz[1,3]dioxolyl, benz[1,4]dioxanyl, dihydro-purinyl, tetrahydro-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]heptyl, 2-azabicyclo[2.2.1]heptenyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexyl, 5-azaspiro[2.4]heptyl, 4,7-azaspiro[2.5]octyl, 2,6-azaspiro[3.3]heptyl, 2,5-azaspiro[3.4]octyl, 2,6-azaspiro[3.4]octyl, 2,7-azaspiro[3.5]nonyl, 2,7-azaspiro[4.4]nonyl, 2-azaspiro[4.5]decyl, 2,8-azaspiro[4.5]decyl, 3,6-diazabicyclo[3.2.1]octyl, 1,4-dihydroindeno[1,2-c]pyrazolyl, dihydropyranyl, dihydropyridinyl, dihydroquinolinyl, 8H-indeno[1,2-d]thiazolyl, tetrahydroimidazo[1,2-a] pyridinyl, pyridin-2(1H)-one, 8-azabicyclo[3.2.1]oct-2-enyl. As used herein, the term "aziridinyl" includes aziridin-1-yl and aziridin-2-yl. As used herein, the term "oxiranyl" includes oxiran-2-yl. As used herein, the term "thiiranyl" includes thiiran-2-yl. As used herein, the term "azetidinyl" includes azetidin-1-yl, azetidin-2-yl, and azetidin-3-yl. As used herein, the term "oxetanyl" includes oxetan-2-yl and oxetan-3-yl. As used herein, the term "thietanyl" includes thietan-2-yl and thietan-3-yl. As used herein, the term "pyrrolidinyl" includes pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidin-3-yl. As used herein, the term "tetrahydrofuranyl" includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. As used herein, the term "tetrahydrothienyl" includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. As used herein, the term "succinimidyl" includes succinimid-1-yl and succinimid-3-yl. As used herein, the term "dihydropyrrolyl" 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. As used herein, the term "2H-pyrrolyl" includes 2H-pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl, and 2H-pyrrol-5-yl. As used herein, the term "3H-pyrrolyl" includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl, and 3H-pyrrol-5-yl. As used herein, the term "dihydrofuranyl" includes 2,3-dihydrofuran-2-yl, 2,3-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. As used herein, the term "dihydrothienyl" 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-dihydrothien-5-yl. As used herein, the term "imidazolidinyl" includes imidazolidin-1-yl, imidazolidin-2-yl, and imidazolidin-4-yl. As used herein, the term "pyrazolidinyl" includes pyrazolidin-1-yl, pyrazolidin-3-yl, and pyrazolidin-4-yl. As used herein, the term "imidazolinyl" includes imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl, and imidazolin-5-yl. As used herein, the term "pyrazolinyl" 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. As used herein, the term "dioxolanyl" (also referred to as "1,3-dioxolanyl") includes dioxolan-2-yl, dioxolan-4-yl, and dioxolan-5-yl. As used herein, the term "dioxolenyl" (also referred to as "1,“3-dioxolanyl”) includes dioxolan-2-yl, dioxolan-4-yl, and dioxolan-5-yl. As used herein, the term “oxazolidinyl” includes oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, and oxazolidin-5-yl. As used herein, the term “isoxazolidinyl” includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, and isoxazolidin-5-yl. As used herein, the term “oxazolinyl” includes 2-oxazolin-2-yl, 2-oxazolin-4-yl, 2-oxazolin-5-yl, 3-oxazolin-2-yl, 3-oxazolin-4-yl, 3-oxazolin-5-yl, 4-oxazolin-2-yl, 4-oxazolin-3-yl, 4-oxazolin-4-yl, and 4-oxazolin-5-yl. As used herein, the term “isoxazolinyl” includes 2-isoxazolin-3-yl, 2-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-3-yl, 3-isoxazolin-4-yl, 3-isoxazolin-5-yl, 4-isoxazolin-2-yl, 4-isoxazolin-3-yl, 4-isoxazolin-4-yl, and 4-isoxazolin-5-yl. As used herein, the term “thiazolidinyl” includes thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, and thiazolidin-5-yl. As used herein, the term “isothiazolidinyl” includes isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl, and isothiazolidin-5-yl. As used herein, the term “thiazolinyl” includes 2-thiazolin-2-yl, 2-thiazolin-4-yl, 2-thiazolin-5-yl, 3-thiazolin-2-yl, 3-thiazolin-4-yl, 3-thiazolin-5-yl, 4-thiazolin-2-yl, 4-thiazolin-3-yl, 4-thiazolin-4-yl, and 4-thiazolin-5-yl. As used herein, the term “isothiazolinyl” includes 2-isothiazolin-3-yl, 2-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-3-yl, 3-isothiazolin-4-yl, 3-isothiazolin-5-yl, 4-isothiazolin-2-yl, 4-isothiazolin-3-yl, 4-isothiazolin-4-yl, and 4-isothiazolin-5-yl. As used herein, the term “piperidyl” (also referred to as “piperidinyl”) includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl. As used herein, the term “dihydropyridyl” 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, 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. As used herein, the term "tetrahydropyridyl" 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-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl and 2,3,4,5-tetrahydropyridin-6-yl. As used herein, the term "tetrahydropyranyl" (also referred to as "oxanyl" or "tetrahydro-2H-pyranyl") includes tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl. As used herein, the term "tetrahydrothiopyranyl" (also referred to as "thianyl" or "tetrahydro-2H-thiopyranyl") includes tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl and tetrahydrothiopyran-4-yl. As used herein, the term "2H-pyranyl" includes 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl and 2H-pyran-6-yl. As used herein, the term "4H-pyranyl" includes 4H-pyran-2-yl, 4H-pyran-3-yl and 4H-pyran-4-yl. As used herein, the term "3,4-dihydro-2H-pyranyl" 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. As used herein, the term "3,6-dihydro-2H-pyranyl" 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. As used herein, the term "tetrahydrothienyl" includes tetrahydrothiophen-2-yl, tetrahydrothien-3-yl, and tetrahydrothien-4-yl. As used herein, the term "2H-thiopyranyl" includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl, and 2H-thiopyran-6-yl. As used herein, the term "4H-thiopyranyl" includes 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, and 4H-thiopyran-4-yl. As used herein, the term "3,4-dihydro-2H-thiopyranyl" 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. As used herein, the term "3,6-dihydro-2H-thiopyranyl" 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. As used herein, the term "piperazinyl" (also referred to as "piperazidinyl") includes piperazin-1-yl and piperazin-2-yl. As used herein, the term "morpholinyl" includes morpholin-2-yl, morpholin-3-yl, and morpholin-4-yl. As used herein, the term "thiomorpholinyl" includes thiomorpholin-2-yl, thiomorpholin-3-yl, and thiomorpholin-4-yl. As used herein, the term "dioxolanyl" includes 1,2-dioxolan-3-yl, 1,2-dioxolan-4-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl, 1,3-dioxolan-5-yl, and 1,4-dioxolan-2-yl. As used herein, the term "dithiolanyl" includes 1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, 1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3-dithiolan-5-yl, and 1,4-dithiolan-2-yl. As used herein, the term "oxathiolanyl" includes oxathiolan-2-yl and oxathiolan-3-yl. As used herein, the term "trioxolanyl" includes 1,2,3-trioxolan-4-yl, 1,2,3-trioxolan-5-yl, 1,2,4-trioxolan-3-yl, 1,2,4-trioxolan-5-yl, 1,2,4-trioxolan-6-yl, and 1,3,4 - Trioxan - 2 - yl. As used herein, the term "azepanyl" includes azepan - 1 - yl, azepan - 2 - yl, azepan - 3 - yl, and azepan - 4 - yl. As used herein, the term "homopiperazinyl" includes homopiperazin - 1 - yl, homopiperazin - 2 - yl, homopiperazin - 3 - yl, and homopiperazin - 4 - yl. As used herein, the term "indolinyl" includes indolin - 1 - yl, indolin - 2 - yl, indolin - 3 - yl, indolin - 4 - yl, indolin - 5 - yl, indolin - 6 - yl, and indolin - 7 - yl. As used herein, the term "quinazolinyl" includes quinazolin - 1 - yl, quinazolin - 2 - yl, quinazolin - 3 - yl, and quinazolin - 4 - yl. As used herein, the term "isoindolinyl" includes isoindolin - 1 - yl, isoindolin - 2 - yl, isoindolin - 3 - yl, isoindolin - 4 - yl, isoindolin - 5 - yl, isoindolin - 6 - yl, and isoindolin - 7 - yl. As used herein, the term "3H - indolyl" 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. As used herein, the term "quinazolinyl" includes quinazolin - 1 - yl, quinazolin - 2 - yl, quinazolin - 3 - yl, and quinazolin - 4 - yl. As used herein, the term "quinazolinyl" includes quinazolin - 1 - yl, quinazolin - 2 - yl, quinazolin - 3 - yl, and quinazolin - 4 - yl. As used herein, the term "tetrahydroquinolinyl" 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. As used herein, the term "tetrahydroisoquinolinyl" 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. As used herein, the term "chromanyl" includes chroman - 2 - yl, chroman - 3 - yl, chroman - 4 - yl, chroman - 5 - yl, chroman - 6 - yl, chroman - 7 - yl, and chroman - 8 - yl. As used herein, the term "1H - pyrrolizin" includes 1H - pyrrolizin - 1 - yl, 1H - pyrrolizin - 2 - yl, 1H - pyrrolizin - 3 - yl, 1H - pyrrolizin - 5 - yl, 1H - pyrrolizin - 6 - yl, and 1H - pyrrolizin - 7 - yl. As used herein, the term "3H - pyrrolizin" includes 3H - pyrrolizin - 1 - yl, 3H - pyrrolizin - 2 - yl, 3H - pyrrolizin - 3 - yl, 3H - pyrrolizin - 5 - yl, 3H - pyrrolizin - 6 - yl, and 3H - pyrrolizin - 7 - yl.,

[0142] When the suffix “ene” is used in combination with a heterocyclic group, i.e., “heterocyclylene”, it is intended to mean that the heterocyclic group as defined herein has two single bonds as attachment points to other groups. As used herein, the term “heterocyclylene” by itself or as part of another substituent refers to a divalent heterocyclic group, i.e., having two monovalent centers (these centers are obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent heterocyclic group), i.e., having two single bonds for attachment to two other groups. The heterocyclylene group may be substituted as shown herein.

[0143] The term "heteroaryl" refers to an aromatic ring system containing 5 to 18 atoms, including at least one N, O, S, or P, having 1 or 2 rings that may be fused together or covalently linked, preferably containing 5 to 14 atoms (5- to 14-membered heteroaryl), more preferably 5 to 10 atoms (5- to 10-membered heteroaryl), with each ring typically containing 5 to 6 atoms; at least one of the rings is aromatic, where N and S heteroatoms may optionally be oxidized, N heteroatoms may optionally be quaternized, and where at least one carbon atom in the heteroaryl may be oxidized to form at least one C═O. A fused system of a heteroaryl ring with a cycloalkyl ring or a cycloalkenyl ring or a cycloalkynyl ring is considered a heteroaryl, regardless of the ring attached to the core structure. A fused system of a heteroaryl ring with a heterocyclic ring is considered a heteroaryl, regardless of the ring attached to the core structure. A fused system of a heteroaryl ring with an aryl ring is considered a heteroaryl, regardless of the ring attached to the core structure.Non-limiting examples of such heteroaryl groups include: pyridyl, pyrrolyl, thiophenyl (also known as thienyl), furyl, 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, thiopheno[3,2-b]furyl, thiopheno[3,2-b]thiophenyl, thiopheno[2,3-d][1,3]thiazolyl, thiopheno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridyl, indolyl, indazolyl, isoindolyl, benzofuryl, isobenzofuryl, 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, benzod]oxazol-2(3H)-one, 2,3-dihydro-benzofuryl, thiophenopyridyl, purinyl, 9H-purinyl, imidazo[1,2-a]pyridyl, imidazo[1,2-a]pyrazinyl, imidazo[5,1-a]isoquinolyl, imidazo[1,5-a]pyridyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxo-pyridin-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]isoquinolyl, 8H-indeno[1,2-d]thiazolyl, benzod]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]pyridyl.

[0144] 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, where in some embodiments, the heteroaryl can be, for example, selected from the group consisting of: pyridyl, thiadiazolyl, thiazolyl, imidazolyl, isoxazolyl, pyrimidinyl, thiophenyl or furyl.

[0145] As used herein, the term "pyrrolyl" (also referred to as azolyl) includes pyrrol-1-yl, pyrrol-2-yl, and pyrrol-3-yl. As used herein, the term "furanyl" (also referred to as furyl) includes furan-2-yl and furan-3-yl. As used herein, the term "thiophenyl" (also referred to as thienyl) includes thiophen-2-yl and thiophen-3-yl (also referred to as thien-2-yl and thien-3-yl). As used herein, the term "pyrazolyl" (also referred to as 1H-pyrazolyl and 1,2-diazolyl) includes pyrazol-1-yl, pyrazol-3-yl, 1H-pyrazol-5-yl, pyrazol-4-yl, and pyrazol-5-yl. As used herein, the term "imidazolyl" includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, and imidazol-5-yl. As used herein, the term "oxazolyl" (also referred to as 1,3-oxazolyl) includes oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl. As used herein, the term "isoxazolyl" (also referred to as 1,2-oxazolyl) includes isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl. As used herein, the term "thiazolyl" (also referred to as 1,3-thiazolyl) includes thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl (also referred to as 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl). As used herein, the term "isothiazolyl" (also referred to as 1,2-thiazolyl) includes isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl. As used herein, the term "triazolyl" 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. As used herein, the term "oxadiazolyl" 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.As used herein, the term "thiadiazolyl" 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. As used herein, the term "tetrazolyl" includes 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. As used herein, the term "oxadiazolyl" includes 1,2,3,4-oxadiazol-5-yl and 1,2,3,5-oxadiazol-4-yl. As used herein, the term "thiatriazolyl" includes 1,2,3,4-thiatriazol-5-yl and 1,2,3,5-thiatriazol-4-yl. As used herein, the term "pyridinyl" (also known as "pyridyl") includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl (also known as 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl). As used herein, the term "pyrimidinyl" includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and pyrimidin-6-yl. As used herein, the term "pyrazinyl" includes pyrazin-2-yl and pyrazin-3-yl. As used herein, the term "pyridazinyl" includes pyridazin-3-yl and pyridazin-4-yl. As used herein, the term "oxazinyl" (also known as "1,4-oxazinyl") includes 1,4-oxazin-4-yl and 1,4-oxazin-5-yl. As used herein, the term "dioxinyl" (also known as "1,4-dioxinyl") includes 1,4-dioxin-2-yl and 1,4-dioxin-3-yl. As used herein, the term "thiazinyl" (also known as "1,4-thiazinyl") 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. As used herein, the term "triazinyl" 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. As used herein, the term "imidazo[2,1-b][1,3]thiazolyl" 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. As used herein, the term "thieno[3,2-b]furanyl" 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.As used herein, the term "thieno[3,2-b]thienyl" includes thieno[3,2-b]thiophen-2-yl, thieno[3,2-b]thiophen-3-yl, thieno[3,2-b]thiophen-5-yl, and thieno[3,2-b]thiophen-6-yl. As used herein, the term "thieno[2,3-d][1,3]thiazolyl" 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. As used herein, the term "thieno[2,3-d]imidazolyl" includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl, and thieno[2,3-d]imidazol-5-yl. As used herein, the term "tetrazolo[1,5-a]pyridinyl" 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. As used herein, the term "indolyl" includes indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, and indol-7-yl. As used herein, the term "indazolyl" includes indazol-1-yl, indazol-2-yl, indazol-3-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, and indazol-8-yl. As used herein, the term "isoindolyl" includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl, and isoindol-7-yl. As used herein, the term "benzofuranyl" (also referred to as benz[b]furanyl) includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, and benzofuran-7-yl. As used herein, the term "isobenzofuranyl" (also referred to as benz[c]furanyl) includes isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, and isobenzofuran-7-yl. As used herein, the term "benzothienyl" (also referred to as benz[b]thienyl) includes 2-benz[b]thienyl, 3-benz[b]thienyl, 4-benz[b]thienyl, 5-benz[b]thienyl, 6-benz[b]thienyl, and 7-benz[b]thienyl (also referred to as benzothiophen-2-yl, benzothiophen-3-yl, benzothiophen-4-yl, benzothiophen-5-yl, benzothiophen-6-yl, and benzothiophen-7-yl). As used herein, the term "isobenzothienyl" (also referred to as benz[c]thienyl) includes isobenzothiophen-1-yl, isobenzothiophen-3-yl, isobenzothiophen-4-yl, isobenzothiophen-5-yl, isobenzothiophen-6-yl, and isobenzothiophen-7-yl.As used herein, the term "indazolyl" (also referred to as 1H-indazolyl or 2-azaindolyl) 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. As used herein, the term "benzimidazolyl" includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, and benzimidazol-7-yl. As used herein, the term "1,3-benzoxazolyl" 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. As used herein, the term "1,2-benzisoxazolyl" 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. As used herein, the term "2,1-benzisoxazolyl" 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. As used herein, the term "1,3-benzothiazolyl" 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. As used herein, the term "1,2-benzisothiazolyl" 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. As used herein, the term "2,1-benzisothiazolyl" includes 2,1-benzisothiazol-3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl, and 2,1-benzisothiazol-7-yl. As used herein, the term "benzotriazolyl" includes benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl, and benzotriazol-7-yl. As used herein, the term "1,2,3-benzoxadiazolyl" 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.As used herein, the term "2,1,3-benzoxadiazolyl" 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. As used herein, the term "1,2,3-benzothiadiazolyl" 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. As used herein, the term "2,1,3-benzothiadiazolyl" 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. As used herein, the term "thienopyridyl" includes thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-c]pyridyl, and thieno[3,2-b]pyridyl. As used herein, the term "purinyl" includes purin-2-yl, purin-6-yl, purin-7-yl, and purin-8-yl. As used herein, the term "imidazo[1,2-a]pyridyl" 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. As used herein, the term "1,3-benzodioxolyl" includes 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 1,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl. As used herein, the term "quinolinyl" includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, and quinolin-8-yl. As used herein, the term "isoquinolinyl" includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, and isoquinolin-8-yl. As used herein, the term "cinnolinyl" includes cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl, and cinnolin-8-yl. As used herein, the term "quinazolinyl" includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, and quinazolin-8-yl. As used herein, the term "quinoxalinyl" includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl.

[0146] When the suffix “ene” is used in combination with a heteroaryl group, i.e., “heteroarylene”, it is intended to mean that the heteroaryl group as defined herein has two single bonds as attachment points to other groups. As used herein, the term “heteroarylene” by itself or as part of another substituent refers to a divalent heteroaryl group, i.e., having two monovalent centers (these centers are obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent heteroaryl), i.e., having two single bonds for attachment to two other groups. The heteroarylene group may be substituted as shown herein.

[0147] As used herein, heteroaryl and heterocycle or heterocyclic group include, for example but not limited to, those groups described in the following: Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), especially volumes 1, 3, 4, 6, 7 and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to date), 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.

[0148] The term “carbonyl” as a group or part of a group refers to the group -C(=O)-, also written as -CO-.

[0149] The term “carboxy / carboxyl” or “hydroxycarbonyl” as a group or part of a group refers to the group -C(=O)-OH.

[0150] The term “alkoxycarbonyl” or “alkyloxycarbonyl” as a group or part of a group refers to a group having the formula -C(=O)-O-R b wherein R b is an alkyl as defined herein.

[0151] The term “amino” as a group or part of a group refers to the -NH2 group.

[0152] The term "mono- or di-alkylamino", as a group or part of a group, refers to a group having the formula -N(R l )(R b ), where R l is hydrogen or alkyl and R b is alkyl (as defined herein). Thus, such a term includes mono-alkylamino groups (e.g., mono-alkylamino groups such as methylamino and ethylamino) and di-alkylamino groups (e.g., di-alkylamino groups such as dimethylamino and diethylamino). Non-limiting examples of suitable mono- or di-alkylamino groups include n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, n-hexylamino, di-n-propylamino, di-isopropylamino, ethylmethylamino, methyl-n-propylamino, methyl-isopropylamino, n-butylmethylamino, isobutylmethylamino, tert-butylmethylamino, ethyl-n-propylamino, ethyl-isopropylamino, n-butylethylamino, isobutylethylamino, tert-butylethylamino, di-n-butylamino, di-isobutylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, etc.

[0153] The term "alkylcarbonylamino", as a group or part of a group, refers to a group having the formula -N(R l )-C(=O)-R b , where R l is hydrogen or alkyl and R b is alkyl (as defined herein).

[0154] As used herein, the term "single bond" for connecting groups (i.e., the manner in which a certain connecting group in the formulas herein is selected from single bonds, etc.) refers to a molecule in which there is no connecting group and thus refers to a compound in which two moieties connected by the connecting group are directly connected by a single bond.

[0155] Any substituent designation found at more than one site in the compounds of the present invention should be independently selected.

[0156] Substituents are optionally designated as having or not having a bond. Regardless of the bond indication, if a substituent is polyvalent (based on its position in the structure mentioned), any and all possible orientations of the substituent are contemplated.

[0157] Unless otherwise expressly stated, any reference to "compounds according to the present invention" or "compounds having formula (I)" also includes isomers (such as stereoisomers and tautomers), salts (such as pharmaceutically and / or physiologically acceptable salts), hydrates, solvates, polymorphs of such compounds.

[0158] As used herein and unless otherwise indicated, the term "solvate" includes any combination that can be formed by a derivative of the present invention with a suitable inorganic solvent (such as a hydrate) or an organic solvent (such as, but not limited to, alcohols, ketones, esters, ethers, nitriles, etc.).

[0159] Preferred statements (features) and examples of the methods, compositions, and uses of the present invention are listed below. Each statement and example of the present invention so defined can be combined with any other statement and / or example, unless explicitly stated to the contrary. In particular, any feature indicated as preferred or advantageous can be combined with any other feature or statement indicated as preferred or advantageous. Thus, the present invention is particularly embodied by any one of the following numbered statements and examples, or any combination of one or more of the following numbered statements and examples with any other aspect and / or example.

[0160] 1. A compound having the formula (B1A), (B1B), or (B1C), or a salt, solvate, hydrate, polymorph, tautomer, racemate, or stereoisomer thereof; or a prodrug thereof, wherein

[0161]

[0162] A 1a is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1a is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1a is selected from the group consisting of: C 6-10 aryl, C 4-6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O, and / or S, and 5-6 membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1a is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O, and / or S;

[0163] wherein each in the group can be unsubstituted or substituted by one or more R 1a substituents, wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C2-6 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, C 3-6 Cycloalkyl, (R 5a )2N - carbonyl, and C 1-6 Alkylcarbonylamino; and / or two R 1a Together with the atom to which it is attached can form C 6-10 Aryl, C 3-6 Cycloalkyl, 5 - 10 - membered heteroaryl, or 5 - 10 - membered saturated or partially saturated heterocyclic group;

[0164] X 1a Selected from - CO -, - SO2 -, - C(R 3a )2 -, or 5 - membered heteroarylene;

[0165] Y 1a Is a single bond, or selected from - C(R 3a )2 -, - NR 5a -, or - O -;

[0166] Z 1a Is a single bond, or selected from - C(R 3a )2 -, - NR 5a -, or - O -;

[0167] Each R 3a Independently selected from hydrogen, halo, or C 1-6 Alkyl;

[0168] Each R 5a Independently selected from hydrogen or C 1-6 Alkyl;

[0169] X 2a Is a single bond or - CO -;

[0170] Y 2a Is a single bond or - C(R 4a )2 -,

[0171] Z 2a Is a single bond, or selected from -(C(R 4a )2) n -, or - CO -; where n is an integer selected from 1 or 2;

[0172] Each R 4a Independently selected from hydrogen, halo, or C 1-6 Alkyl; or two R 4aTogether with the atom to which it is attached, can form a C 3-6 cycloalkyl;

[0173] A 2a is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclic group, C 3-6 cycloalkyl, and C 1-6 alkyl; preferably A 2a is selected from the group consisting of: 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 selected from the group consisting of: 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 selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S and C 5-6 cycloalkyl;

[0174] wherein each in the group may be unsubstituted or substituted by one or more R 2a substituents; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached can form a C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0175]

[0176] A 1b is selected from the group consisting of: C 6-10 aryl, C 3-6Cycloalkyl, a 5-10 membered heteroaryl containing at least one N, O, and / or S, and a 5-10 membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1b Selected from the group consisting of: C 6-10 Aryl, C 3-6 Cycloalkyl, a 5-9 membered heteroaryl containing at least one N, O, and / or S, and a 5-9 membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1b Selected from the group consisting of: C 6-10 Aryl, C 4-6 Cycloalkyl, a 5-6 membered heteroaryl containing at least one N, O, and / or S, and a 5-6 membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1b Selected from the group consisting of: C 6-10 Aryl, C 5-6 Cycloalkyl, a 5-6 membered heteroaryl containing at least one N, O, and / or S; preferably A 1b Is phenyl;

[0177] Wherein each in the group may be unsubstituted or substituted by one or more R 1b Substituted, wherein each R 1b Independently selected from the group consisting of: hydrogen, halo, 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 6b )2N-carbonyl, and C 1-6 Alkylcarbonylamino; and / or two R 1b Together with the atom to which it is attached may form C 6-10 Aryl, a 5-10 membered heteroaryl, or a 5-10 membered saturated or partially saturated heterocyclic group;

[0178] R 3b Selected from hydrogen or C 1-6 Alkyl;

[0179] Y 1b Selected from -CO-, -C(R 5b )2-, or a 5-membered heteroarylene;

[0180] Z 1b Is -C(R 5b )2-;

[0181] R4b Selected from hydrogen, C 1-6 alkyl, or C 1-6 alkoxycarbonyl;

[0182] Each R 5b is independently selected from hydrogen, halo, or C 1-6 alkyl;

[0183] Each R 6b is independently selected from hydrogen or C 1-6 alkyl;

[0184] Y 2b is -C(R 5b )2- or a single bond;

[0185] Z 2b is a single bond, or selected from –(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2;

[0186] A 2b is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl containing at least one N, O, and / or S, 5-10 membered saturated or partially saturated heterocyclic group, C 3-6 cycloalkyl, and C 1-6 alkyl; preferably A 2b is selected from the group consisting of: 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 selected from the group consisting of: 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 selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O, and / or S and C 5-6 cycloalkyl; preferably A 2b is phenyl;

[0187] where each in the group may be unsubstituted or substituted by one or more R 2b substituents, where each R 2b is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, C1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two Rs 2b together with the atom to which it is attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0188]

[0189] A 1c is selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S;

[0190] wherein each in the group may be unsubstituted or substituted by one or more Rs 1c substituted, wherein each R 1c is independently selected from the group consisting of: 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, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6c )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two Rs 1c together with the atom to which it is attached may form a C6-10 an aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered saturated or partially saturated heterocyclic group;

[0191] R 3c is selected from hydrogen or C 1-6 alkyl;

[0192] Y 1c is a single bond, or is selected from -C(R 4c )2-, -NR 6c -, -O-, or a 5-membered heteroarylene group;

[0193] Z 1c is a single bond, or is selected from -C(R 4c )2- or -O-;

[0194] Each R 4c is independently selected from hydrogen, halo, or C 1-6 alkyl;

[0195] Each R 6c is independently selected from hydrogen or C 1-6 alkyl;

[0196] X 2c is a single bond or -CO-;

[0197] Y 2c is a single bond or -C(R 5c )2-,

[0198] Z 2c is a single bond, or is selected from -(C(R 5c )2) p - or -CO-; where p is an integer selected from 1 or 2;

[0199] Each R 5c is independently selected from hydrogen, halo, or C 1-6 alkyl; or two R 5c together with the atom to which they are attached can form a C 3-6 cycloalkyl;

[0200] A 2c is selected from the group consisting of: C 6-10 aryl, a 5- to 10-membered heteroaryl containing at least one N, O, and / or S, a 5- to 10-membered saturated or partially saturated heterocyclic group 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 selected from the group consisting of: C 6-10 aryl, a 5- to 9-membered heteroaryl containing at least one N, O, and / or S, C 3-6Naphthenyl, and C 1-4 alkyl; preferably A 2c is selected from the group consisting of: C 6-10 aryl, 5- or 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 naphthenyl; preferably A 2c is selected from the group consisting of: phenyl, 5- or 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 naphthenyl;

[0201] wherein each in the group may be unsubstituted or substituted by one or more R 2c substituents; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, 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 naphthenyl, (R 6c )2N-carbonyl, -SO2-R 6c , and C 1-6 alkylcarbonylamino; and / or two R 2c together with the atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

[0202] 2. A compound having formula (B1A), (B1B), or (B1C), or a salt, solvate, hydrate, polymorph, tautomer, racemate, or stereoisomer thereof; or a prodrug thereof, wherein

[0203]

[0204] A 1a is selected from the group consisting of: C 6-10 aryl, C 3-6 naphthenyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1a substituents, wherein each R 1a is independently selected from the group consisting of: halo, hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo C1-6 alkyl, halo-C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached can form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0205] X 1a is selected from -CO-, -SO2-, -C(R 3a )2-, or a 5-membered heteroarylene;

[0206] Y 1a is selected from -C(R 3a )2-, -NR 5a -, or -O-; or Y 1a is a single bond;

[0207] Z 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0208] Each R 3a is independently selected from hydrogen, halo, or C 1-6 alkyl;

[0209] Each R 5a is independently selected from hydrogen or C 1-6 alkyl;

[0210] X 2a is a single bond or -CO-;

[0211] Y 2a is -C(R 4a )2- or Y 2a is a single bond,

[0212] Z 2a is a single bond, or is selected from -(C(R 4a )2) n -, or -CO-; where n is an integer selected from 1 or 2;

[0213] Each R 4a is independently selected from hydrogen, halo, or C 1-6 alkyl; or two R 4a together with the atom to which they are attached can form C 3-6 cycloalkyl;

[0214] A 2a selected from the group consisting of: C 6-10 aryl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, 5- to 10-membered saturated or partially saturated heterocyclic group, and C 3-6 cycloalkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2a substituents; wherein each R 2a is independently selected from the group consisting of: 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0215] Provided that:

[0216] A 1a is not: wherein R 1a1 and R 1a2 are each independently selected from C 1-2 alkyl, or R 1a1 and R 1a2 together with the carbon atom to which they are attached form C3-6 cycloalkyl, wherein R 1a has the same meaning as defined herein, and s is an integer selected from 0, 1, or 2;

[0217] A 2a is not: wherein R 2a has the same meaning as defined herein, and s is an integer selected from 0, 1, or 2;

[0218] Provided that the compound is not:

[0219] 2-benzyl-6-(toluene-4-sulfonyl)-2,6-diazaspiro[3.3]heptane;

[0220] 2-(1,3-Benzodioxol-5-ylmethyl)-6-[(4-methylphenyl)sulfonyl]-2,6-diazaspiro[3.3]heptane;

[0221] 2-(1,3-Benzodioxol-5-ylmethyl)-6-(phenylmethyl)-2,6-diazaspiro[3.3]heptane;

[0222] 2-Benzyl-6-(tosyl)-2,6-diazaspiro[3.3]heptane;

[0223] (6-Benzyl-2,6-diazaspiro[3.3]hept-2-yl)(3,3,5-trimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)methanone;

[0224] (5-Cyclohexyl-1H-pyrazol-3-yl)(6-(cyclopropanecarbonyl)-2,6-diazaspiro[3.3]hept-2-yl)methanone;

[0225] (6-(Cyclopropanecarbonyl)-2,6-diazaspiro[3.3]hept-2-yl)(1-isopropyl-1H-imidazol-4-yl)methanone;

[0226] (5-Isopropyl-1H-pyrazol-3-yl)(6-(1-methylcyclopropane-1-carbonyl)-2,6-diazaspiro[3.3]hept-2-yl)methanone;

[0227] (5-Isopropyl-1H-pyrazol-3-yl)(6-(thiophene-2-carbonyl)-2,6-diazaspiro[3.3]hept-2-yl)methanone;

[0228] [2-(4-Fluoro-1-methyl-pyrazole-3-carbonyl)-2,6-diazaspiro[3.3]hept-6-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone;

[0229]

[0230] A 1b selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1b substituents, wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6Alkynyl, C 1-6 Alkoxy, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached can form C 6-10 Aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0231] R 3b Is selected from hydrogen or C 1-6 Alkyl;

[0232] Y 1b Is selected from -CO-, -C(R 5b )2-, or 5-membered heteroarylene;

[0233] Z 1b Is -C(R 5b )2-;

[0234] R 4b Is selected from hydrogen, C 1-6 Alkyl, or C 1-6 Alkoxycarbonyl;

[0235] Each R 5b Independently is selected from hydrogen, halo, or C 1-6 Alkyl;

[0236] Each R 6b Independently is selected from hydrogen or C 1-6 Alkyl;

[0237] Y 2b Is -C(R 5b )2- or a single bond;

[0238] Z 2b Is a single bond, or is selected from -(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2;

[0239] A 2b Is selected from the group consisting of: C 6-10 Aryl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, 5- to 10-membered saturated or partially saturated heterocyclic group, C 3-6 Cycloalkyl, and C 1-6 Alkyl; where each in the group can be unsubstituted or substituted by one or more R 2b Substituted, where each R2b independently selected from the group consisting of: 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, carboxy, 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 atom to which it is attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0240]

[0241] A 1c selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1c substituents, wherein each R 1c independently selected from the group consisting of: 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, carboxy, 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 atom to which it is attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0242] R 3c selected from hydrogen or C 1-6 alkyl;

[0243] Y 1c is a single bond, or selected from -C(R 4c )2-, -NR 6c-O- or a 5-membered heteroaryl;

[0244] Z 1c is a single bond or is selected from -C(R 4c )2- or -O-;

[0245] Each R 4c is independently selected from hydrogen, halo or C 1-6 alkyl;

[0246] Each R 6c is independently selected from hydrogen or C 1-6 alkyl;

[0247] X 2c is a single bond or -CO-;

[0248] Y 2c is a single bond or -C(R 5c )2-,

[0249] Z 2c is a single bond or is selected from -(C(R 5c )2) p - or -CO-; where p is an integer selected from 1 or 2;

[0250] Each R 5c is independently selected from hydrogen, halo or C 1-6 alkyl; or two Rs 5c together with the atom to which they are attached can form a C 3-6 cycloalkyl;

[0251] A 2c is selected from the group consisting of: C 6-10 aryl, a 5- to 10-membered heteroaryl containing at least one N, O and / or S, a 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O and / or S, C 3-6 cycloalkyl, and -N(R 6c )2; where each in the group can be unsubstituted or substituted by one or more Rs 2c ; where each R 2c is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c , and C 1-6Alkylcarbonylamino; and / or two Rs 2c Together with the atom to which it is attached, can form a C 6-10 Aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

[0252] Provided that:

[0253] A 1c is not

[0254] A 2c is not

[0255] Provided that the compound is not:

[0256] N-Benzyl-2-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-amine;

[0257] N-(2-(2-Fluorophenyl)-2-azaspiro[3.3]heptan-6-yl)-6,7-dimethoxy-2,3-dihydro-1H-cyclopenta[b]quinolin-9-amine;

[0258] 6-((2-((Benzyloxy)carbonyl)-2-azaspiro[3.3]heptan-6-yl)amino)-2-chloropyrimidine-4-carboxylic acid;

[0259] 6-((2-Chloro-6-(methoxycarbonyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid benzyl ester.

[0260] 3. The compound according to statement 1 or 2, wherein

[0261] A 1a is selected from the group consisting of: C 6-10 Aryl, C 4-6 Cycloalkyl, 5- to 9-membered heteroaryl containing at least one N, O, and / or S, and 5- to 9-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1a is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1a is selected from the group consisting of: C 6-10 Aryl, C 5-6 Cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S;

[0262] Each in said group may be unsubstituted or substituted by one or more R 1a where each R 1a is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group; preferably each in said group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, 3 or 4 R 1a where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; preferably each in said group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two R1a can form a C together with the attached atom 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group can be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1a can form a C together with the attached atom 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group can be unsubstituted or substituted by one or more R 1a , for example 1 or 2 R 1a , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano; and / or two R 1a can form a C together with the attached atom 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group;

[0263] X 1a is selected from -CO-, -SO2-, -C(R 3a )2-, or 5-membered heteroarylene; preferably X 1a is selected from -CO-, -SO2-, -C(R 3a )2-, or 1,2,4-thiadiazolyl; preferably X 1a is selected from -CO-, -SO2-, or -C(R 3a )2-;

[0264] Y 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0265] Z 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a-, or -O-;

[0266] Each R 3a is independently selected from 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 alkyl;

[0267] Each R 5a is independently selected from hydrogen or C 1-6 alkyl; preferably each R 5a is hydrogen or C 1-4 alkyl; preferably each R 5a is hydrogen or C 1-2 alkyl;

[0268] X 2a is a single bond or -CO-;

[0269] Y 2a is a single bond or -C(R 4a )2-,

[0270] Z 2a is a single bond, or is selected from –(C(R 4a )2) n - or -CO-; where n is an integer selected from 1 or 2;

[0271] Each R 4a is independently selected from hydrogen, halo, or C 1-6 alkyl; or two Rs 4a together with the atom to which they are attached can form a C 3-6 cycloalkyl; preferably each R 4a is independently selected from hydrogen, halo, or C 1-4 alkyl; or two Rs 4a together with the atom to which they are attached can form a C 3-5 cycloalkyl; preferably each R 4a is independently selected from hydrogen, halo, or C 1-2 alkyl; or two Rs 4a together with the atom to which they are attached can form a C 3-4 cycloalkyl;

[0272] A 2a is selected from the group consisting of: 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 selected from the group consisting of: C 6-10 aryl, 5-6 membered heteroaryl containing at least one N, O, and / or S, and C4-6 Cycloalkyl; preferably A 2a Selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5-6 Cycloalkyl;

[0273] wherein each in the group may be unsubstituted or substituted by one or more R 2a substituents; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which it is attached may form C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group; preferably wherein each in the group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, 3 or 4 R 2a substituents; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached may form C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group; preferably wherein each in the group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, or 3 R 2a substituents; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6Alkyl, halo-C 1-6 Alkoxy, cyano, hydroxy, carboxy, C 1-6 Alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3-6 Cycloalkyl, and C 1-6 Alkylcarbonylamino; and / or two Rs 2a Together with the atom to which it is attached can form C 6-10 Aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0274] A 1b Is selected from the group consisting of: C 6-10 Aryl, C 3-6 Cycloalkyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1b Is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1b Is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1b Is selected from the group consisting of: C 6-10 Aryl, C 5-6 Cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S; preferably A 1b Is phenyl;

[0275] Wherein each in the group can be unsubstituted or substituted by one or more Rs 1b Where each R 1b Is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, C 1-6 Alkoxycarbonyl, C 3-6 Cycloalkyl, (R 6b )2N-carbonyl, and C 1-6 Alkylcarbonylamino; and / or two Rs 1bTogether with the attached atom, it can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example, 1, 2, 3 or 4 R 1b , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 attached atom can form a C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example, 1, 2, or 3 R 1b , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two R 1b together with the attached atom can form a C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example, 1, 2 or 3 R 1b , where each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1b together with the attached atom can form a C 6-10 aryl, C 3-6a cycloalkyl group, a 5- to 9-membered heteroaryl group, or a 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example 1 or 2 R 1b , wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano; and / or two R 1b together with the atom to which they are attached may form a C 6-10 aryl, C 3-6 cycloalkyl group, a 5- to 9-membered heteroaryl group, or a 5- to 9-membered saturated or partially saturated heterocyclic group;

[0276] R 3b is selected from 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 alkyl;

[0277] Y 1b is selected from -CO-, -C(R 5b )2-, or a 5-membered heteroarylene group; preferably Y 1b is selected from -CO-, -C(R 5b )2-, or 1,2,4-thiadiazolyl;

[0278] Z 1b is -C(R 5b )2-;

[0279] R 4b is selected from hydrogen, C 1-6 alkyl, or C 1-6 alkoxycarbonyl; preferably R 4b is selected from hydrogen, C 1-4 alkyl, or C 1-4 alkoxycarbonyl; preferably R 4b is selected from hydrogen, C 1-2 alkyl, or C 1-2 alkoxycarbonyl;

[0280] each R 5b is independently selected from hydrogen, halo or C 1-6 alkyl; preferably each R 5b is independently selected from hydrogen, halo or C 1-4 alkyl; preferably each R 5b is independently selected from hydrogen, halo or C 1-2 alkyl; preferably each R5b Independently selected from hydrogen or C 1-2 alkyl;

[0281] Each R 6b Independently selected from hydrogen or C 1-6 alkyl; preferably each R 6b Independently selected from hydrogen or C 1-4 alkyl; preferably each R 6b Independently selected from hydrogen or C 1-2 alkyl;

[0282] Y 2b is -C(R 5b )2- or a single bond;

[0283] Z 2b is a single bond, or selected from –(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2;

[0284] A 2b is selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclic group, C 3-6 cycloalkyl, and C 1-6 alkyl; preferably A 2b is selected from the group consisting of: 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 selected from the group consisting of: 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 selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S and C 5-6 cycloalkyl; preferably A 2b is phenyl;

[0285] Wherein each in the group may be unsubstituted or substituted by one or more R 2b substituents, where each R 2b is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, C 1-6Alkoxycarbonyl, C 3-6 (R 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two R 2b together with the atom to which it is attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each of the groups may be unsubstituted or substituted by one or more R 2b , for example 1, 2, 3, or 4 R 2b , where each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, C 3-6 (R 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two R 2b together with the atom to which it is attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each of the groups may be unsubstituted or substituted by one or more R 2b , for example 1, 2, or 3 R 2b , where each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, C 3-6 (R 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two R 2b together with the atom to which it is attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each of the groups may be unsubstituted or substituted by one or more R 2b , for example 1 or 2 R 2b , where each R 2b is independently selected from the group consisting of: hydrogen, halo, C1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two Rs 2b together with the atoms to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0286] A 1c is selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S;

[0287] wherein each in the group may be unsubstituted or substituted by one or more Rs 1c substituted, where each R 1c is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6c )2N-carbonyl, and C 1-6alkylcarbonylamino; and / or two R 1c together with the atom(s) to which it is attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in said group can be unsubstituted or substituted by one or more R 1c , for example 1, 2, 3, or 4 R 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom(s) to which it is attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in said group can be unsubstituted or substituted by one or more R 1c , for example 1, 2, or 3 R 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, and C 3-6 cycloalkyl; and / or two R 1c together with the atom(s) to which it is attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in said group can be unsubstituted or substituted by one or more R 1c , for example 1 or 2 R 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, and cyano; and / or two R 1c together with the atom(s) to which it is attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0288] R3c Selected from 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 alkyl;

[0289] Y 1c is a single bond, or selected from -C(R 4c )2-, -NR 6c -, -O-, or a 5-membered heteroaryl; preferably Y 1c is a single bond, or selected from -C(R 4c )2-, -NR 6c -, -O-, or 1,2,4-thiadiazolyl;

[0290] Z 1c is a single bond, or selected from -C(R 4c )2- or -O-;

[0291] Each R 4c is independently selected from 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 alkyl;

[0292] Each R 6c is independently selected from 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 alkyl;

[0293] X 2c is a single bond or -CO-;

[0294] Y 2c is a single bond or -C(R 5c )2-,

[0295] Z 2c is a single bond, or selected from –(C(R 5c )2) p - or -CO-; where p is an integer selected from 1 or 2;

[0296] Each R 5c is independently selected from hydrogen, halo, or C 1-6 alkyl; or two Rs 5c together with the atom to which they are attached can form C 3-6 cycloalkyl; preferably each R5c Independently selected from hydrogen, halo or C 1-4 alkyl; or two R 5c together with the atom to which it is attached may form a C 3-5 cycloalkyl; preferably each R 5c independently selected from hydrogen, halo or C 1-2 alkyl; or two R 5c together with the atom to which it is attached may form a C 3-4 cycloalkyl;

[0297] A 2c selected from the group consisting of: C 6-10 aryl, 5-10 membered heteroaryl containing at least one N, O and / or S, 5-10 membered saturated or partially saturated heterocyclic group containing at least one N, O and / or S, C 3-6 cycloalkyl, and -N(R 6c )2; preferably A 2c selected from the group consisting of: 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 selected from the group consisting of: 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 selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S and C 5-6 cycloalkyl;

[0298] wherein each in the group may be unsubstituted or substituted by one or more R 2c substituted; wherein each R 2c independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which it is attached may form a C 6-10An aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 2c , for example 1, 2, 3 or 4 R 2c ; where each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form a C 6-10 aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 2c , for example 1, 2, or 3 R 2c ; where each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 6c )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two R 2c together with the atom to which they are attached may form a C 6-10 aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered saturated or partially saturated heterocyclic group.

[0299] 4. The compound according to any one of statements 1-3, wherein

[0300] A 1a is selected from the group consisting of: C 6-10 aryl, C 4-6 cycloalkyl, a 5- to 6-membered heteroaryl containing at least one N, O and / or S, and a 5- to 6-membered saturated or partially saturated heterocyclic group containing at least one N, O and / or S; preferably A 1a is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, a 5- to 6-membered heteroaryl containing at least one N, O and / or S;

[0301] Each in the group may be unsubstituted or substituted by one or more R 1a , such as 1, 2, 3 or 4 R 1a , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1a , such as 1, 2, or 3 R 1a , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two R 1a together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1a , such as 1, 2, or 3 R 1a , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1a together with the atom to which they are attached may form C 6-10 aryl, C 3-6A cycloalkyl group, a 5-9 membered heteroaryl group, or a 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1a , for example 1 or 2 R 1a , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano; and / or two R 1a together with the atom to which they are attached may form a C 6-10 aryl, C 3-6 cycloalkyl, a 5-9 membered heteroaryl group, or a 5-9 membered saturated or partially saturated heterocyclic group;

[0302] X 1a is selected from -CO-, -SO2-, -C(R 3a )2-, or 1,2,4-thiadiazolyl; preferably X 1a is selected from -CO-, -SO2-, or -C(R 3a )2-;

[0303] Y 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0304] Z 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0305] Each R 3a is hydrogen, halo or C 1-4 alkyl; preferably each R 3a is hydrogen, halo or C 1-2 alkyl;

[0306] Each R 5a is hydrogen or C 1-4 alkyl; preferably each R 5a is hydrogen or C 1-2 alkyl;

[0307] X 2a is a single bond or -CO-;

[0308] Y 2a is a single bond or -C(R 4a )2-,

[0309] Z 2a is a single bond, or is selected from –(C(R4a )2) n - or -CO-; where n is an integer selected from 1 or 2;

[0310] Each R 4a is independently selected from hydrogen, halo, or C 1-4 alkyl; or two Rs 4a together with the atom to which it is attached can form a C 3-5 cycloalkyl; preferably each R 4a is independently selected from hydrogen, halo, or C 1-2 alkyl; or two Rs 4a together with the atom to which it is attached can form a C 3-4 cycloalkyl;

[0311] A 2a is selected from the group consisting of: 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 selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0312] where each in the group can be unsubstituted or substituted by one or more Rs 2a , for example 1, 2, 3, or 4 Rs 2a ; where each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3-6 cycloalkyl, and C 1-6 alkylcarbonylamino; and / or two Rs 2a together with the atom to which it is attached can form a C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group; preferably where each in the group can be unsubstituted or substituted by one or more Rs 2a , for example 1, 2, or 3 Rs 2a ; where each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 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 atom to which it is attached can form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0313] A 1b is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1b is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1b is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S; preferably A 1b is phenyl;

[0314] each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2, 3, or 4 R 1b , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, 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, C 3-6 cycloalkyl, (R 5a )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two R 1b together with the atom to which it is attached can form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2, or 3 R1b is substituted, wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two Rs 1b together with the atom to which they are attached can form a C 6-10 aryl, C 3-6 cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more Rs 1b , for example 1, 2 or 3 Rs 1b substituted, wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, and hydroxy; and / or two Rs 1b together with the atom to which they are attached can form a C 6-10 aryl, C 3-6 cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more Rs 1b , for example 1 or 2 Rs 1b substituted, wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, and cyano; and / or two Rs 1b together with the atom to which they are attached can form a C 6-10 aryl, C 3-6 cycloalkyl, a 5- to 9-membered heteroaryl, or a 5- to 9-membered saturated or partially saturated heterocyclic group;

[0315] Each R 3b is hydrogen or C 1-4 alkyl; preferably each R 3b is hydrogen or C 1-2 alkyl;

[0316] Y 1b is selected from -CO-, -C(R 5b )2-, or 1,2,4-thiadiazolyl;

[0317] Z 1b is -C(R 5b )2-;

[0318] R 4b is selected from hydrogen, C 1-4 alkyl, or C 1-4 alkoxycarbonyl; preferably R 4b is selected from hydrogen, C 1-2 alkyl, or C 1-2 alkoxycarbonyl;

[0319] Each R 5b is independently selected from hydrogen, halo, or C 1-4 alkyl; preferably each R 5b is independently selected from hydrogen, halo, or C 1-2 alkyl; preferably each R 5b is independently selected from hydrogen or C 1-2 alkyl;

[0320] Each R 6b is independently selected from hydrogen or C 1-4 alkyl; preferably each R 6b is independently selected from hydrogen or C 1-2 alkyl;

[0321] Y 2b is -C(R 5b )2- or a single bond;

[0322] Z 2b is a single bond, or is selected from –(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2;

[0323] A 2b is selected from the group consisting of: 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 selected from the group consisting of: 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 selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl; preferably A 2b is phenyl;

[0324] where each in the group may be unsubstituted or substituted by one or more R 2b , for example 1, 2, 3, or 4 R's2b is substituted, wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two Rs 2b together with the atoms to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably wherein each in said group may be unsubstituted or substituted by one or more Rs 2b , for example 1, 2, or 3 Rs 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two Rs 2b together with the atoms to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably wherein each in said group may be unsubstituted or substituted by one or more Rs 2b , for example 1 or 2 Rs 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two Rs 2b together with the atoms to which they are attached may form a C6-10 an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclic group;

[0325] A 1c selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, a 5- to 9-membered heteroaryl containing at least one N, O, and / or S, and a 5- to 9-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1c selected from the group consisting of: C 6-10 aryl, C 4-6 cycloalkyl, a 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and a 5- to 6-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1c selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, a 5- to 6-membered heteroaryl containing at least one N, O, and / or S;

[0326] wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, 3, or 4 R 1c substituents, where each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclic group; preferably wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, or 3 R 1c substituents, where each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, and C 3-6 cycloalkyl; and / or two R 1c together with the atom to which they are attached may form C 6-10an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1c , for example 1 or 2 Rs 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano; and / or two Rs 1c together with the atom to which they are attached may form a C 6-10 aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclic group;

[0327] each R 3c is hydrogen or C 1-4 alkyl; preferably each R 3c is hydrogen or C 1-2 alkyl;

[0328] Y 1c is a single bond, or selected from -C(R 4c )2-, -NR 6c -, -O-, or 1,2,4-thiadiazolyl;

[0329] Z 1c is a single bond, or selected from -C(R 4c )2- or -O-;

[0330] each R 4c is hydrogen, halo or C 1-4 alkyl; preferably each R 4c is hydrogen, halo or C 1-2 alkyl;

[0331] each R 6c is hydrogen or C 1-4 alkyl; preferably each R 6c is hydrogen or C 1-2 alkyl;

[0332] X 2c is a single bond or -CO-;

[0333] Y 2c is a single bond or -C(R 5c )2-,

[0334] Z 2c is a single bond, or selected from –(C(R 5c )2) p - or -CO-; wherein p is an integer selected from 1 or 2;

[0335] Each R 5c is independently selected from hydrogen, halo, or C 1-4 alkyl; or two Rs 5c together with the atom to which they are attached can form a C 3-5 cycloalkyl; preferably each R 5c is independently selected from hydrogen, halo, or C 1-2 alkyl; or two Rs 5c together with the atom to which they are attached can form a C 3-4 cycloalkyl;

[0336] A 2c is selected from the group consisting of: C 6-10 aryl, 5- to 9-membered heteroaryl containing at least one N, O, and / or S, and C 3-6 cycloalkyl; preferably A 2c is selected from the group consisting of: C 6-10 aryl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 cycloalkyl; preferably A 2c is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0337] wherein each in the group can be unsubstituted or substituted by one or more Rs 2c , for example 1, 2, 3, or 4 Rs 2c ; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, (R 6c )2N-carbonyl, -SO2-R 6c , and C 1-6 alkylcarbonylamino; and / or two Rs 2c together with the atom to which they are attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably wherein each in the group can be unsubstituted or substituted by one or more Rs 2c , for example 1, 2, or 3 Rs 2c ; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6alkyl, halo-C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 6c )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two Rs 2c together with the atom to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

[0338] 5. A compound according to any one of statements 1-4, wherein

[0339] A 1a is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1a is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S;

[0340] each in the group may be unsubstituted or substituted by one or more Rs 1a , for example 1, 2, 3, or 4 Rs 1a wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, (R 5a )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two Rs 1a together with the atom to which they are attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more Rs 1a , for example 1, 2, or 3 Rs 1a wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two R 1a together with the atom to which it is attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a ; wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, and hydroxy; and / or two R 1a together with the atom to which it is attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1a , for example 1 or 2 R 1a ; wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, and cyano; and / or two R 1a together with the atom to which it is attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group;

[0341] A 2a is selected from the group consisting of: C 6-10 aryl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 cycloalkyl; preferably A 2a is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0342] wherein each in the group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, 3, or 4 R 2a ; wherein each R 2aIndependently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached can form a C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group; preferably each in said group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, or 3 R 2a ; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached can form a C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0343] A 1b is selected from the group consisting of: 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 heterocyclic group containing at least one N, O and / or S; preferably A 1b is selected from the group consisting of: C 6-10 aryl, C 4-6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated or partially saturated heterocyclic group containing at least one N, O and / or S; preferably A 1b is selected from the group consisting of: 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;

[0344] Each in the group may be unsubstituted or substituted by one or more Rs 1b , such as 1, 2, 3 or 4 Rs 1b , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, (R 5a )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two Rs 1b together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, a 5-9 membered heteroaryl, or a 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more Rs 1b , such as 1, 2, or 3 Rs 1b , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two Rs 1b together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, a 5-9 membered heteroaryl, or a 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more Rs 1b , such as 1, 2 or 3 Rs 1b , wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two Rs 1b together with the atom to which it is attached may form a C 6-10 aryl, C 3-6a cycloalkyl group, a 5- to 9-membered heteroaryl group, or a 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example 1 or 2 R 1b , wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano; and / or two R 1b together with the atom to which they are attached may form a C 6-10 aryl, C 3-6 cycloalkyl group, a 5- to 9-membered heteroaryl group, or a 5- to 9-membered saturated or partially saturated heterocyclic group;

[0345] A 2b is selected from the group consisting of: C 6-10 aryl, a 5- to 9-membered heteroaryl group containing at least one N, O, and / or S, C 3-6 cycloalkyl, and C 1-4 alkyl; preferably A 2b is selected from the group consisting of: C 6-10 aryl, a 5- to 6-membered heteroaryl group containing at least one N, O, and / or S, and C 4-6 cycloalkyl; preferably A 2b is selected from the group consisting of: phenyl, a 5- to 6-membered heteroaryl group containing at least one N, O, and / or S, and C 5-6 cycloalkyl; preferably A 2b is phenyl;

[0346] wherein each in the group may be unsubstituted or substituted by one or more R 2b , for example 1, 2, 3, or 4 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form a C 6-10An aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 2b , such as 1, 2, or 3 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form a C 6-10 aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 2b , such as 1 or 2 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form a C 6-10 aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered saturated or partially saturated heterocyclic group;

[0347] A 1c is selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, a 5- to 9-membered heteroaryl containing at least one N, O, and / or S, and a 5- to 9-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: C 6-10 aryl, C 4-6A cycloalkyl group, a 5- or 6-membered heteroaryl group containing at least one N, O, and / or S, and a 5- or 6-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; preferably A 1c Selected from the group consisting of: C 6-10 An aryl group, C 5-6 A cycloalkyl group, a 5- or 6-membered heteroaryl group containing at least one N, O, and / or S;

[0348] Wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, 3, or 4 R 1c Substituents, wherein each R 1c Is independently selected from the group consisting of: hydrogen, halo, C 1-6 An alkyl group, C 1-6 An alkoxy group, halo C 1-6 An alkyl group, halo C 1-6 An alkoxy group, cyano, hydroxy, carboxy, C 1-6 An alkoxycarbonyl group, C 3-6 A cycloalkyl group, (R 6c )2N-carbonyl, and C 1-6 An alkylcarbonylamino group; and / or two R 1c Together with the atom to which they are attached can form C 6-10 An aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered saturated or partially saturated heterocyclic group; preferably wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, or 3 R 1c Substituents, wherein each R 1c Is independently selected from the group consisting of: hydrogen, halo, C 1-6 An alkyl group, C 1-6 An alkoxy group, halo C 1-6 An alkyl group, halo C 1-6 An alkoxy group, cyano, hydroxy, carboxy, and C 3-6 A cycloalkyl group; and / or two R 1c Together with the atom to which they are attached can form C 6-10 An aryl group, a 5- to 10-membered heteroaryl group, or a 5- to 10-membered saturated or partially saturated heterocyclic group; preferably wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1 or 2 R 1c Substituents, wherein each R 1c Is independently selected from the group consisting of: hydrogen, halo, C 1-6 An alkyl group, C 1-6 An alkoxy group, halo C 1-6 An alkyl group, halo C 1-6 An alkoxy group, and cyano; and / or two R 1cTogether with the atom to which it is attached, can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0349] A 2c is selected from the group consisting of: C 6-10 aryl, 5- to 9-membered heteroaryl containing at least one N, O, and / or S, and C 3-6 cycloalkyl; preferably A 2c is selected from the group consisting of: C 6-10 aryl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 cycloalkyl; preferably A 2c is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0350] wherein each in the group may be unsubstituted or substituted by one or more R 2c , for example 1, 2, 3, or 4 R 2c substituents; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably wherein each in the group may be unsubstituted or substituted by one or more R 2c , for example 1, 2, or 3 R 2c substituents; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 6c )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two R 2c together with the atom to which they are attached can form a C6-10 An aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclic group.

[0351] 6. The compound according to any one of statements 1-5, wherein

[0352] X 1a is selected from -CO-, -SO2-, -C(R 3a )2-, or 1,2,4-thiadiazolyl;

[0353] Y 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0354] Z 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0355] Each R 3a is hydrogen, halo, or C 1-2 alkyl;

[0356] Each R 5a is hydrogen or C 1-2 alkyl;

[0357] X 2a is a single bond or -CO-;

[0358] Y 2a is a single bond or -C(R 4a )2-,

[0359] Z 2a is a single bond, or is selected from –(C(R 4a )2) n -, or -CO-; where n is an integer selected from 1 or 2;

[0360] Each R 4a is independently selected from hydrogen, halo, or C 1-2 alkyl; or two R 4a together with the atom to which they are attached can form C 3-4 cycloalkyl.

[0361] 7. The compound according to any one of statements 1-5, wherein

[0362] Each R 3b is hydrogen or C 1-2 alkyl;

[0363] Y 1b is selected from -CO-, -C(R 5b) 2-, or 1,2,4-thiadiazolyl;

[0364] Z 1b is -C(R 5b )2-;

[0365] R 4b is selected from hydrogen, C 1-2 alkyl, or C 1-2 alkoxycarbonyl;

[0366] Each R 5b is independently selected from hydrogen, halo, or C 1-2 alkyl; preferably each R 5b is independently selected from hydrogen or C 1-2 alkyl;

[0367] Each R 6b is independently selected from hydrogen or C 1-2 alkyl;

[0368] Y 2b is -C(R 5b )2- or a single bond;

[0369] Z 2b is a single bond, or selected from –(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2.

[0370] 8. The compound according to any one of statements 1-5, wherein

[0371] Each R 3c is hydrogen or C 1-2 alkyl;

[0372] Y 1c is a single bond, or selected from -C(R 4c )2-, -NR 6c -, -O-, or 1,2,4-thiadiazolyl;

[0373] Z 1c is a single bond, or selected from -C(R 4c )2- or -O-;

[0374] Each R 4c is hydrogen, halo, or C 1-2 alkyl;

[0375] Each R 6c is hydrogen or C 1-2 alkyl;

[0376] X 2c is a single bond or -CO-;

[0377] Y2c is a single bond or -C(R 5c )2-

[0378] Z 2c is a single bond, or is selected from –(C(R 5c )2) p - or -CO-; where p is an integer selected from 1 or 2;

[0379] Each R 5c is independently selected from hydrogen, halo, or C 1-2 alkyl; or two Rs 5c together with the atom to which they are attached can form C 3-4 cycloalkyl.

[0380] 9. The compound according to any one of statements 1 - 6, wherein

[0381] X 1a is selected from -CO-, -SO2-, or -C(R 3a )2-;

[0382] Y 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0383] Z 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0384] Each R 3a is hydrogen; each R 5a is hydrogen;

[0385] X 2a is a single bond or -CO-;

[0386] Y 2a is a single bond or -C(R 4a )2-

[0387] Z 2a is a single bond, or is selected from –(C(R 4a )2) n - or -CO-; where n is an integer selected from 1 or 2; each R 4a is independently selected from hydrogen.

[0388] 10. The compound according to any one of statements 1 - 5, 7, wherein

[0389] Each R 3b is hydrogen;

[0390] Y 1bSelected from -CO-, -C(R 5b )2-;

[0391] Z 1b is -C(R 5b )2-;

[0392] R 4b is selected from hydrogen;

[0393] Each R 5b is hydrogen;

[0394] Each R 6b is hydrogen;

[0395] Y 2b is -C(R 5b )2- or a single bond;

[0396] Z 2b is a single bond, or selected from –(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2. 11. The compound according to any one of statements 1-5, 8, wherein

[0397] Each R 3c is hydrogen;

[0398] Y 1c is a single bond, or selected from -C(R 4c )2-, -NR 6c -, or -O-;

[0399] Z 1c is a single bond, or selected from -C(R 4c )2- or -O-;

[0400] Each R 4c is hydrogen;

[0401] Each R 6c is hydrogen;

[0402] X 2c is a single bond or -CO-;

[0403] Y 2c is a single bond or -C(R 5c )2-,

[0404] Z 2c is a single bond, or selected from –(C(R 5c )2) p - or -CO-; where p is an integer selected from 1 or 2; each R 5c is hydrogen.

[0405] 12. A compound according to any one of statements 1 - 11, the compound having the structural formulas (B1A1), (B1A2), (B1A3), (B1A4), (B1A5), (B1A6), (B1B1), (B1B2),

[0406]

[0407] wherein A 1a , Y 1a , Z 1a , R 2a , R 3a , R 4a , Y 2a , Z 2a , A 2a , A 1b , Y 1b , Z 1b , R 2b , 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 have the same meanings 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.

[0408] 13. A compound according to any one of statements 1 - 12, wherein

[0409] A 1a is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5 - 6 - membered heteroaryl containing at least one N, O, and / or S;

[0410] each in the group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two Rs 1a together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more Rs 1a , such as 1, 2, or 3 Rs 1a , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, and hydroxy; and / or two Rs 1a together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more Rs 1a , such as 1 or 2 Rs 1a , where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, and cyano; and / or two Rs 1a together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group;

[0411] A 2a is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0412] where each in the group may be unsubstituted or substituted by one or more Rs 2a , such as 1, 2, or 3 Rs 2a , where each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached can form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0413] A 1b is selected from the group consisting of: 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 heterocyclic group containing at least one N, O and / or S; preferably A 1b is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S; preferably A 1b is phenyl;

[0414] each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2, or 3 R 1b , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two R 1b together with the atom to which it is attached can form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2 or 3 R 1b , wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1b together with the atom to which it is attached can form C 6-10Aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example 1 or 2 R 1b , wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano; and / or two R 1b together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group;

[0415] A 2b is selected from the group consisting of: C 6-10 aryl, 5- to 6-membered heteroaryl containing at least one N, O and / or S, and C 4-6 cycloalkyl; preferably A 2b is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O and / or S and C 5-6 cycloalkyl; preferably A 2b is phenyl;

[0416] wherein each in the group may be unsubstituted or substituted by one or more R 2b , for example 1, 2, or 3 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, 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 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two R 2b together with the atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably wherein each in the group may be unsubstituted or substituted by one or more R 2b , for example 1 or 2 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0417] A 1c is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S;

[0418] wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, or 3 R 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, cyano, hydroxy, carboxy, and C 3-6 cycloalkyl; and / or two R 1c together with the atom to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1 or 2 R 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, and cyano; and / or two R 1c together with the atom to which they are attached may form a C6-10 an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclic group;

[0419] A 2c selected from the group consisting of: C 6-10 an aryl, a 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 a cycloalkyl; preferably A 2c selected from the group consisting of: phenyl, a 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 a cycloalkyl;

[0420] wherein each in the group may be unsubstituted or substituted by one or more R 2c , for example, 1, 2, or 3 R 2c ; wherein each R 2c is independently selected from the group consisting of: 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 atom to which they are attached may form C 6-10 an aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclic group.

[0421] 14. The compound according to any one of statements 1-13, the compound having the structural formula (B1A8), (B1A9), (B1A10), (B1A11), (B1A12), (B1A13),

[0422]

[0423] wherein A 1a , Y 1a , Z 1a , and A 2a have the same meanings as defined in any one of statements 1-13.

[0424] 15. The compound according to any one of statements 1-14, the compound having the structural formula (B1A14), (B1A15), (B1A16), (B1A17), (B1A18), (B1A19), (B1A20), (B1A21), (B1A22), (B1A23), (B1A24),

[0425]

[0426] wherein A 1a and A 2a have the same meaning as defined in any one of Statements 1-14.

[0427] 16. A compound according to any one of Statements 1-15, wherein

[0428] A 1a is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S;

[0429] each in the group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two R 1a together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1a together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1a , for example 1 or 2 R 1a , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C1-6 alkyl, halo-C 1-6 alkoxy, and cyano; and / or two R 1a together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5-9-membered heteroaryl, or 5-9-membered saturated or partially saturated heterocyclic group;

[0430] A 2a is selected from the group consisting of: C 6-10 aryl, 5-6-membered heteroaryl containing at least one N, O and / or S, and C 5-6 cycloalkyl;

[0431] wherein each in the group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, or 3 R 2a substituted; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached may form a C 6-10 aryl, 5-10-membered heteroaryl, or 5-10-membered saturated or partially saturated heterocyclic group;

[0432] A 1b is selected from the group consisting of: C 6-10 aryl, C 4-6 cycloalkyl, 5-6-membered heteroaryl containing at least one N, O and / or S, and 5-6-membered saturated or partially saturated heterocyclic group containing at least one N, O and / or S; preferably A 1b is selected from the group consisting of: 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;

[0433] each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2 or 3 R 1b substituted, wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1b together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example 1 or 2 R 1b substituents, where each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, and cyano; and / or two R 1b together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group;

[0434] A 2b is selected from the group consisting of: 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 selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S and C 5-6 cycloalkyl; preferably A 2b is phenyl;

[0435] where each in the group may be unsubstituted or substituted by one or more R 2b , for example 1, 2, or 3 R 2b substituents, where each R 2b is independently selected from the group consisting of: hydrogen, halo, 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 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two R 2b together with the atom to which it is attached may form a C 6-10aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 2b , such as 1 or 2 R 2b , where each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, 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 may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0436] A 1c is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S;

[0437] where each in the group may be unsubstituted or substituted by one or more R 1c , such as 1, 2, or 3 R 1c , where each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, and C 3-6 cycloalkyl; and / or two R 1c together with the atoms to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably where each in the group may be unsubstituted or substituted by one or more R 1c , such as 1 or 2 R 1c , where each R 1cIndependently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano; and / or two R 1c together with the atom to which it is attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0438] A 2c selected from the group consisting of: C 6-10 aryl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 cycloalkyl; preferably A 2c selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0439] wherein each in the group can be unsubstituted or substituted by one or more R 2c , for example 1, 2, or 3 R 2c substituents; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 6c )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two R 2c together with the atom to which it is attached can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

[0440] 17. The compound according to any one of statements 1-16, wherein

[0441] A 1a is selected from the group consisting of: phenyl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N;

[0442] each in the group can be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a substituents, wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C1-6 alkyl, halo-C 1-6 alkoxy, cyano, and hydroxy; and / or two Rs 1a together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more Rs 1a , for example 1 or 2 Rs 1a substituted, where each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, and cyano; and / or two Rs 1a together with the atom to which it is attached may form a C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group;

[0443] A 2a is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0444] where each in the group may be unsubstituted or substituted by one or more Rs 2a , for example 1, 2, or 3 Rs 2a substituted; where each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 5a )2N-carbonyl, -SO2-R 5a , C 3-6 cycloalkyl, and C 1-6 alkylcarbonylamino; and / or two Rs 2a together with the atom to which it is attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0445] A 1b is selected from the group consisting of: phenyl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S; preferably A 1b is phenyl;

[0446] Each in the group may be unsubstituted or substituted by one or more R 1b , for example, 1, 2 or 3 R 1b , wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1b together with the atom to which it is attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; preferably each in the group may be unsubstituted or substituted by one or more R 1b , for example, 1 or 2 R 1b , wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano; and / or two R 1b together with the atom to which it is attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group;

[0447] A 2b is selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and C 5-6 cycloalkyl; preferably A 2b is phenyl;

[0448] wherein each in the group may be unsubstituted or substituted by one or more R 2b , for example, 1, 2, or 3 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, 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 6b )2N-carbonyl, -SO2-R 6b , and C 1-6 alkylcarbonylamino; and / or two R2b Together with the attached atom, it can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in the group can be unsubstituted or substituted by one or more R 2b , for example 1 or 2 R 2b substituents, where each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 attached atom can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0449] A 1c is selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; preferably A 1c is selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S;

[0450] where each in the group can be unsubstituted or substituted by one or more R 1c , for example 1, 2, or 3 R 1c substituents, where each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, and C 3-6 cycloalkyl; and / or two R 1c together with the attached atom can form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; preferably each in the group can be unsubstituted or substituted by one or more R 1c , for example 1 or 2 R1c is substituted, wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, and cyano; and / or two Rs 1c together with the atom to which it is attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group;

[0451] A 2c is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 cycloalkyl; preferably A 2c is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0452] wherein each in the group may be unsubstituted or substituted by one or more Rs 2c , for example 1, 2, or 3 Rs 2c ; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 6c )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two Rs 2c together with the atom to which it is attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

[0453] 18. The compound according to any one of statements 1-17, the compound having the structural formula (B1A25), (B1A26),

[0454]

[0455] wherein R 1a , Y 1a , Z 1a , X 2a , X 1a , Y 2a , Z 2a and A 2ahas the same meaning as defined in any one of Statements 1-17, 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, D 1a is selected from CH2, O, or NH, and E 1a is selected from CH, N, O, or S.

[0456] 19. A compound according to any one of Statements 1-18, the compound having structural formulas (B1A27), (B1A28),

[0457]

[0458] wherein 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 1-18, 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, D 1a is selected from CH2, O, or NH, and E 1a is selected from CH, N, O, or S.

[0459] 20. A compound according to any one of Statements 1-19, the compound having structural formulas (B1A29), (B1A30), (B1A31), (B1A32),

[0460]

[0461]

[0462] wherein 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 1-19, 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, D 1a is selected from CH2, O, or NH, and E 1a is selected from CH, N, O, or S.

[0463] 21. A compound according to any one of statements 1 - 20, the compound having structural formulas (B1A33), (B1A34), (B1A35), (B1A36), (B1A37), (B1A38), (B1A39), (B1A40), (B1A41), (B1A42), (B1A43),

[0464]

[0465]

[0466] wherein R 1a and A 2a have the same meanings as defined in any one of statements 1 - 20, and ma is an integer selected from 1, 2, 3 or 4, pa is an integer selected from 0 or 1, D 1a is selected from CH2, O or NH.

[0467] 22. A compound according to any one of statements 1 - 21, the compound having structural formulas (B1A44), (B1A45), (B1A46), (B1A47), (B1A48), (B1A49), (B1A50), (B1A51), (B1A52), (B1A53), (B1A54),

[0468]

[0469]

[0470] wherein R 1a and A 2a have the same meanings as defined in any one of statements 1 - 21, and ma is an integer selected from 1, 2, 3 or 4, qa is an integer selected from 0 or 1, E 1a is selected from CH, O or N.

[0471] 23. A compound according to any one of statements 1 - 22, the compound having structural formulas (B1A55), (B1A56), (B1A57), (B1A58), (B1A59), (B1A60), (B1A61), (B1A62), (B1A63), (B1A64), (B1A65),

[0472]

[0473]

[0474] wherein R 1a and A 2aHas the same meaning as defined in any one of Statements 1-22, and ma is an integer selected from 1, 2, 3, or 4.

[0475] 24. A compound according to any one of Statements 1-23, the compound having a structural formula (B1A66), (B1A67), (B1A68), (B1A69), (B1A70), (B1A71), (B1A72), (B1A73), (B1A74), (B1A75), (B1A76),

[0476]

[0477]

[0478] wherein R 1a and A 2a Have the same meaning as defined in any one of Statements 1-23, and ma is an integer selected from 1, 2, 3, or 4.

[0479] 25. A compound according to any one of Statements 1-24, the compound having a structural formula (B1A77), (B1A78),

[0480]

[0481] wherein R 1a and A 2a Have the same meaning as defined in any one of Statements 1-24, and ma is an integer selected from 1, 2, 3, or 4.

[0482] 26. A compound according to any one of Statements 1-25, the compound having a structural formula (B1A79), (B1A80),

[0483]

[0484]

[0485] wherein R 1a 、R 2a and A 2a Have the same meaning as defined in any one of Statements 1-25, and ma is an integer selected from 1, 2, 3, or 4, na is an integer selected from 1, 2, 3, or 4, E 1a Is selected from CH, O, or N.

[0486] 27. A compound according to any one of Statements 1-26, wherein the compound is selected from the group consisting of the compounds listed in Table 1B.

[0487] 28. A pharmaceutical composition comprising a compound according to any one of statements 1-27 and at least one pharmaceutically acceptable carrier.

[0488] 29. A compound according to any one of statements 1-27 or a pharmaceutical composition according to statement 28 for use as a medicament or drug.

[0489] 30. A compound according to any one of statements 1-27 for use as a therapeutically active substance.

[0490] 31. A compound according to any one of statements 1-27 or a pharmaceutical composition according to statement 28 for use in the prevention and / or treatment of neurodegenerative disorders such as neurodegenerative disorders characterized by cytotoxic tau protein misfolding and / or aggregation to delay or prevent the progression of such diseases.

[0491] 32. The compound or pharmaceutical composition for use according to statement 31, 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 disease, 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, preferably the neurodegenerative disorder is Alzheimer's disease.

[0492] 33. A compound according to any one of statements 1-27 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 disease, 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, preferably the neurodegenerative disorder is Alzheimer's disease.

[0493] 34. A method for preventing and / or treating a neurodegenerative disorder such as a neurodegenerative disorder characterized by cytotoxic tau protein misfolding and / or aggregation to delay or prevent the progression of such a disease, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of statements 1-27.

[0494] 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 disease, Down syndrome, Pick's disease, progressive supranuclear palsy, vascular dementia, neuronal ceroid lipofuscinosis, Huntington's disease, frontotemporal lobar degeneration (FTLD), multiple system atrophy, and Creutzfeldt-Jakob disease, preferably the neurodegenerative disorder is Alzheimer's disease.

[0495] The present invention provides novel compounds of formula (B1A), (B1B), or (B1C) as defined herein (including all embodiments thereof as described herein).

[0496] In some embodiments of the compound of formula (B1A) as defined herein (including all embodiments thereof as described herein),

[0497] A 1a is selected from the group consisting of: phenyl, C 5-6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O, and / or S;

[0498] wherein each in the group may be unsubstituted or substituted by one, two, or three R 1a substituents, wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxyl, C 3-6 cycloalkyl; and / or two R 1a together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0499] X 1a is selected from -CO-, -SO2-, -C(R 3a )2-, or 1,2,4-thiadiazolyl;

[0500] Y 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0501] Z 1a is a single bond, or is selected from -C(R 3a )2-, -NR 5a -, or -O-;

[0502] Each R3a is hydrogen;

[0503] Each R 5a is hydrogen;

[0504] X 2a is a single bond or -CO-;

[0505] Y 2a is a single bond or -C(R 4a )2-,

[0506] Z 2a is a single bond, or is selected from –(C(R 4a )2) n - or -CO-; where n is an integer selected from 1 or 2;

[0507] Each R 4a is hydrogen;

[0508] A 2a is selected from the group consisting of: phenyl, or a 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0509] where each in the group may be unsubstituted or substituted by one, two, or three R 2a substituents; where each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered saturated or partially saturated heterocyclic group;

[0510] In some embodiments (including all embodiments as described herein) of the compounds having formula (B1B) as defined herein,

[0511] A 1b is selected from the group consisting of: phenyl, C 5-6 cycloalkyl, a 5- to 6-membered heteroaryl containing at least one N, O, and / or S; preferably A 1b is phenyl;

[0512] Each in the group may be unsubstituted or substituted by one, two or three R 1b where each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached may form C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0513] R 3b is hydrogen;

[0514] Y 1b is selected from -CO-, -C(R 5b )2-, or 1,2,4-thiadiazolyl;

[0515] Z 1b is -C(R 5b )2-;

[0516] R 4b is hydrogen; each R 5b is hydrogen; each R 6b is hydrogen;

[0517] Y 2b is -C(R 5b )2- or a single bond;

[0518] Z 2b is a single bond, or selected from –(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2;

[0519] A 2b is selected from the group consisting of: phenyl, 5-6 membered heteroaryl containing at least one N, O and / or S and C 5-6 cycloalkyl; preferably A 2b is phenyl;

[0520] Each in the group may be unsubstituted or substituted by one, two or three R 2b where each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halo-C 1-6 Alkyl, halo-C 1-6 Alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached can form C 6-10 Aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group.

[0521] In some embodiments of the compounds having formula (B1C) as defined herein (including all embodiments thereof as described herein),

[0522] A 1c is selected from the group consisting of: phenyl, C 5-6 Cycloalkyl, 5-6 membered heteroaryl containing at least one N, O, and / or S;

[0523] wherein each in the group can be unsubstituted or substituted by one, two, or three R 1c substituents, wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 Alkyl, C 1-6 Alkoxy, halo-C 1-6 Alkyl, halo-C 1-6 Alkoxy, cyano, hydroxy, carboxy, 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 atom to which it is attached can form C 6-10 Aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group;

[0524] R 3c is hydrogen;

[0525] Y 1c is a single bond, or is selected from -C(R 4c )2-, -NR 6c -, -O-, or 1,2,4-thiadiazolyl;

[0526] Z 1c is a single bond, or is selected from -C(R 4c )2- or -O-;

[0527] Each R 4c is hydrogen; each R 6c is hydrogen;

[0528] X 2c is a single bond or -CO-;

[0529] Y 2c is a single bond or -C(R 5c )2-,

[0530] Z 2c is a single bond, or is selected from –(C(R 5c )2) p - or -CO-; where p is an integer selected from 1 or 2;

[0531] Each R 5c is hydrogen;

[0532] A 2c is selected from the group consisting of: phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl;

[0533] where each in the group may be unsubstituted or substituted by one, two, or three R 2c ; where each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

[0534] In a preferred embodiment of the present invention, the compound is selected from the group consisting of: the compounds listed in Table 1B below or salts, solvates, hydrates, polymorphs, tautomers, racemates, stereoisomers, or prodrugs thereof.

[0535] Unless expressly stated otherwise, any reference to a compound of formula (B1A), (B1B) or (B1C) as defined herein (including all embodiments thereof as described herein) also includes isomers (such as stereoisomers and tautomers), salts (such as pharmaceutically and / or physiologically acceptable salts), hydrates, solvates, polymorphs and prodrugs of such compounds.

[0536] As used herein, the term "isomer" means all possible isomeric forms, including tautomeric and stereochemical forms, wherein compounds having the formula herein may have positional isomers, but positional isomers are not included. Typically, the structures shown herein illustrate one tautomeric or resonance form of the compound, but the corresponding alternative configurations are also contemplated.

[0537] Depending on its substitution pattern, the 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 or may not 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 indicated, the chemical name of the compound represents a mixture of all possible stereochemical isomeric forms, the mixture containing all diastereomers and enantiomers of the basic molecular structure (because the compound with the formula herein can have at least one chiral center), as well as stereochemically pure or enriched compounds. More particularly, the stereocenter can have an R- or S-configuration, and multiple bonds can have a cis- or trans-configuration. The term R- or S-configuration is used herein according to Chemical Abstracts nomenclature. The terms cis and trans are used herein according to Chemical Abstracts nomenclature, and these terms include reference to the position of the substituents on the ring portion. 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.

[0538] The term "pharmaceutically acceptable salt" relates to any salt that a compound may form, which is suitable for administration to a subject according to the present invention, in particular a human subject. Thus, the compounds of the present invention optionally include salts of the compounds herein, in particular containing, for example, Na + , Li + , K + , Ca 2+ and Mg 2+Pharmaceutically acceptable non-toxic salts thereof. Such salts can include those obtained by combining a suitable cation (such as an alkali metal ion, an alkaline earth metal ion, or an ammonium and quaternary ammonium ion) with an acidic anionic moiety (typically a carboxylic acid). The compounds of the present invention can carry multiple positive or negative charges. The net charge of the compounds of the present invention can be positive or negative. Any associated counterion is typically determined by the method of synthesis and / or isolation of the compound. Typical counterions include, but are not limited to, ammonium ion, sodium ion, potassium ion, lithium ion, halide ion, acetate ion, trifluoroacetate ion, etc., and mixtures thereof. Organic bases from which salts can be derived include, for example, primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc., particularly such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, etc. It should be understood that the identity of any associated counterion is not a key feature of the present invention, and the present invention encompasses compounds associated with any type of counterion. In addition, since the compounds can exist in various different forms, the present invention not only aims to cover the forms of compounds associated with counterions (e.g., dry salt), but also aims to cover the forms of compounds not associated with counterions (e.g., aqueous solution or organic solution). Metal salts are typically prepared by reacting a metal hydroxide with the compound of the present invention. Examples of metal salts prepared in this way are salts containing Li + 、Na + 、and K + . Less soluble metal salts can be precipitated from more soluble salt solutions by adding a suitable metal compound. In addition, salts can be formed by the addition of certain organic and inorganic acids to basic centers (typically amines) or acidic groups. Examples of such suitable acids include, for example, inorganic acids (such as hydrohalic acids (such as hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.); or organic acids (such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic 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, cyclohexylaminosulfonic acid, salicylic acid (i.e., 2-hydroxybenzoic acid), p-aminosalicylic acid, etc.). In addition, this term also includes solvates, such as hydrates, alcoholates, etc., that the compounds of the present invention having the formulas herein and their salts can form. Finally, it should be understood that the compositions herein contain the compounds of the present invention in non-ionic as well as zwitterionic forms, in combination with stoichiometric amounts of water (in hydrates).

[0539] The scope of the present invention also includes salts of the parent compound with one or more amino acids (especially naturally occurring amino acids found as components of proteins). The amino acids are typically amino acids with side chains bearing basic or acidic groups (such as lysine, arginine or glutamic acid) or amino acids with side chains bearing neutral groups (such as glycine, serine, threonine, alanine, isoleucine or leucine).

[0540] The compounds of the present invention as defined herein (including all embodiments thereof as described herein) also include their physiologically acceptable salts. Examples of physiologically acceptable salts of the compounds of the present invention include salts derived from suitable bases such as alkali metals (such as sodium), alkaline earth metals (such as magnesium), ammonium and NX4 + (wherein X is C1-C4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts with organic carboxylic acids such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, 2-hydroxyethanesulfonic 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 combinations of the anions of said compounds with suitable cations such as Na + and NX4 + (wherein X is typically independently selected from H or C1-C4 alkyl groups). However, salts of physiologically unacceptable acids or bases may also be used, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of the present invention.

[0541] Non-limiting examples of suitable salts of this kind include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as 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-ethanedisulfonic acid, 2-hydroxyethanesulfonic 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, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucic acid. Other salts include 2,2-dichloroacetate, adipate, alginate, ascorbate, aspartate, 2-acetamidobenzoate, caproate, caprylate, camphorate, cyclohexylsulfamate, lauryl sulfate, ethanedisulfonate, ethanesulfonate, hydroxyethanesulfonate, formate, galactarate, gentisate, glucoheptonate, glucuronate, ketoglutarate, hippurate, lactobionate, naphthalenedisulfonate, cinchomeronate, nicotinate, oleate, lactobionate, oxalate, palmitate, enolinate, pyruvate, p-aminosalicylate, sebacate, tannate, thiocyanate, undecylenate, etc.; or salts formed when the acidic protons present in the parent compound are replaced by, for example, ammonia, arginine, benzathine penicillin, benzylpenicillin, calcium, choline, danthron, diethanolamine, diethylamine, ethanolamine, ethylenediamine, glucosamine, glycine, hydrabamine, imidazole, lysine, magnesium, hydroxyethylmorpholine, piperazine, potassium, epolamine, sodium, triethanolamine, tromethamine, or zinc.

[0542] The present invention includes within its scope solvates of the compounds as defined herein (including all embodiments thereof as described herein). The term "solvate" refers to a crystal formed by an active compound and a second component (a solvent), which is in a liquid state at room temperature in the separated form. Such solvates can be formed with common organic solvents such as hydrocarbon solvents like benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcohol 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.

[0543] Another embodiment of the present invention relates to various precursors 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 chemical substances that are not themselves significantly bioactive, but which, when delivered to an animal, mammal or human, will undergo a chemical reaction catalyzed by the normal functions of the fish body (especially enzymes present in the stomach or serum), said chemical reaction having the effect of releasing the compounds as defined herein. Generally, such prodrugs will be functional derivatives of the compounds described herein, which functional derivatives are readily converted in vivo, for example, by endogenous enzymes in the intestine or blood, into the desired GPR17 modulating compounds described herein. Thus, the term "prodrug" refers to these substances that are converted in vivo into the active pharmaceutical ingredient.

[0544] The prodrugs of the compounds of the present invention as defined herein (including all of its embodiments as described herein) can have any form suitable for the formulator. For example, esters are a common prodrug form without limitation. However, in this case, the prodrug may need to be in a form in which the covalent bond is cleaved by an enzyme at the target site. For example, a C-C covalent bond can be selectively cleaved by one or more enzymes at the target site. Thus, other forms of prodrugs than those that are readily hydrolyzable precursors can be used, especially esters, amides, etc. The counterpart of the active pharmaceutical ingredient in the prodrug can have a different structure, such as an amino acid or peptide structure, an alkyl chain, a sugar moiety, and other structures known in the art.

[0545] For the purposes of the present invention, the term "therapeutically suitable prodrug" can be defined herein as a compound modified in such a way that, when brought into contact with the tissues of an animal, mammal or human to which the prodrug is administered, whether by single or multiple biotransformations, it is converted in vivo into a therapeutically active form and has no undue toxicity, irritation or allergic reaction and achieves the desired therapeutic result.

[0546] More particularly, as used herein, the term "prodrug" refers to an inactive or significantly less active derivative of a compound as shown by the structural formula described herein, which derivative undergoes spontaneous or enzymatic conversion in vivo 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).

[0547] The compounds of the present invention as defined herein (including all of its embodiments as described herein) can also exist in different crystal forms (i.e., polymorphs and mixtures thereof), all of which are encompassed by the present invention.

[0548] The term "polymorph" refers to a specific crystalline form of a compound that can crystallize into different crystal forms, which have different arrangements and / or conformations of molecules in the crystal lattice. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stabilities, and solubilities. Although polymorphs can have the same chemical composition, their compositions can also differ due to the presence or absence of co-crystallized water or other molecules, which may be weakly or strongly bound in the crystal lattice. The chemical, physical, and biological properties of polymorphs, such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspension, dissolution rate, and bioavailability, may vary. Those skilled in the art will understand that polymorphs of the compounds described herein may exhibit beneficial effects (e.g., suitability for preparing useful formulations, improved biological properties) relative to another polymorph or mixture of polymorphs of the same compound. The preparation and isolation of a specific polymorph of a compound can be achieved by methods known to those skilled in the art, including, for example, crystallization using selected solvents and temperatures. The recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystal form to predominate. The various polymorphs of a compound can be prepared by crystallization under different conditions. A comprehensive discussion of polymorphism can be found in Rolf Hilfiker, editor, Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006.

[0549] The present invention also encompasses pharmaceutical compositions comprising at least one compound according to the invention as defined herein (including all its embodiments as described herein) and at least one pharmaceutically acceptable carrier.

[0550] The term "pharmaceutically acceptable carrier" 1 ' refers to a diluent, adjuvant, excipient, or carrier, or other ingredients administered with the compounds of the present invention and understood by those skilled in the art to be pharmaceutically acceptable.

[0551] Tablets will contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in a sterile form and are generally isotonic when intended to be delivered by a route other than oral administration. The formulations optionally contain excipients such as those listed in "Handbook of Pharmaceutical Excipients" (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.

[0552] Subsequently, as used herein, the term "pharmaceutically acceptable carrier" means any material or substance formulated with an active ingredient to facilitate its application or diffusion to the site to be treated, for example by dissolving, dispersing or diffusing the composition, and / or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier can be solid, liquid or a gas compressed to form a liquid. For example, the compositions of the present invention can be suitably used as concentrates, emulsions, solutions, granules, powders, sprays, aerosols, suspensions, ointments, creams, tablets, pills or powders.

[0553] Suitable pharmaceutical carriers for use in the pharmaceutical compositions and their formulations are well known to those skilled in the art and there is no particular limitation on their selection within the present invention. The pharmaceutical carrier can also include additives such as wetting agents, dispersing agents, adhesives, binders, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (such as phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride), etc., provided that they conform to pharmaceutical practice, for example carriers and additives that do not cause permanent damage to mammals. The pharmaceutical compositions of the present invention can be prepared in any known manner, for example by uniformly mixing, coating and / or grinding the active ingredient with the selected carrier material and (where appropriate) other additives (such as surfactants) in one or more step procedures, and can also be prepared by micronization, for example in view of obtaining them in the form of microspheres having a generally diameter of about 1 to 10 μm, i.e., for manufacturing microcapsules for controlled or sustained release of the active ingredient.

[0554] Suitable surfactants (also known as emulgents or emulsifiers) for use in the pharmaceutical compositions of the present invention are nonionic, cationic and / or anionic materials having good emulsifying, dispersing and / or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surfactants. Suitable soaps are higher fatty acids (C 10 -C 22Alkali metal or alkaline earth metal salts, unsubstituted or substituted ammonium salts, such as sodium or potassium salts of oleic acid or stearic acid, or sodium or potassium salts of natural fatty acid mixtures obtained from coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acid; fatty sulfonates and sulfates; sulfonated benzimidazole derivatives and alkylaryl sulfonates. 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 sodium or calcium salts of lignosulfonic acid or dodecylsulfonic acid, or mixtures of fatty alcohol sulfates obtained from natural fatty acids, sulfuric or sulfonic acid esters (such as sodium dodecyl sulfate) and alkali metal or alkaline earth metal salts of sulfonic acids of fatty alcohol / ethylene oxide adducts. Suitable sulfonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylaryl sulfonates are sodium, calcium or alkanolamine salts of dodecylbenzenesulfonic acid or dibutyl-naphthalenesulfonic acid or naphthalenesulfonic acid / formaldehyde condensation products. Corresponding phosphates (such as phosphoric acid esters and salts of adducts of nonylphenol with ethylene oxide and / or propylene oxide) or phospholipids are also suitable. Suitable phospholipids for this purpose are natural (derived from animal or plant cells) or synthetic phospholipids of the cephalin or lecithin type, such as, for example, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, lysophosphatidylcholine, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphosphatidylcholine and mixtures thereof.

[0555] Suitable nonionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides having at least 12 carbon atoms in the molecule, alkylarene sulfonates and dialkyl sulfosuccinates, such as polyethylene glycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, which preferably contain 3 to 10 ethylene glycol ether groups and 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 water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediamine polypropylene glycol (having 1 to 10 carbon atoms in the alkyl chain), which adducts contain 20 to 250 ethylene glycol ether groups and / or 10 to 100 propylene glycol ether groups. Such compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit. Representative examples of nonionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolic ether, polypropylene oxide / polyethylene oxide adducts, tributylphenoxy polyethoxyethanol, polyethylene glycol and octylphenoxy polyethoxyethanol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitol, sucrose and pentaerythritol are also suitable nonionic surfactants.

[0556] Suitable cationic surfactants include quaternary ammonium salts (especially halides) having 4 hydrocarbon groups optionally substituted by halogen, phenyl, substituted phenyl or hydroxy; for example, quaternary ammonium salts containing at least one C 8-22 alkyl group (such as cetyl, dodecyl, palmitoyl, myristoyl, oleyl, etc.) as the N-substituent, and unsubstituted or halogenated lower alkyl, benzyl and / or hydroxy lower alkyl as additional substituents.

[0557] A more detailed description of the surfactants suitable for this purpose can be found, for example, in the following: "McCutcheon's Detergents and Emulsifiers Annual", (MC Publishing Crop., Ridgewood, New Jersey, 1981), "Tensid-Taschenbucw", 2nd edition (Hanser Verlag, Vienna, 1981) and "Encyclopaedia of Surfactants", (Chemical Publishing Co., New York, 1981).

[0558] The compounds of the invention as defined herein (including all embodiments thereof as described herein) and their pharmaceutically acceptable salts (collectively hereinafter referred to as the active ingredients) can be administered by any route suitable for the disorder being treated, suitable routes including oral, rectal, nasal, topical (including ocular, 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 disorder of the recipient.

[0559] Although it is possible to administer the active ingredients individually, it is preferred to present them in the form of pharmaceutical formulations. The formulations according to the invention for veterinary use and for human use contain at least one active ingredient as described above, and thus together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic ingredients. The carrier is optimally "acceptable", meaning compatible with the other ingredients of the formulation and not harmful to its recipient. The 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. The formulations can conveniently be presented in unit dosage forms and can be prepared by any method well known in the pharmaceutical art. Such methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0560] The formulations according to the invention suitable for oral administration can be presented in discrete unit forms, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous liquids or non-aqueous liquids; or water-in-oil liquid emulsions or oil-in-water liquid emulsions. The active ingredient can also be presented in boluses, lozenges or pastes.

[0561] Tablets can be prepared by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, a preservative, a surfactant or a dispersing agent. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated or scored and can be formulated so as to provide slow or controlled release of the active ingredient therein. When formulated as an ointment, the active ingredient can be used with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can include, for example, polyols, such as alcohols having two or more hydroxyl groups, such as propylene glycol, 1,3-butanediol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof. Topical formulations can desirably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such transdermal penetration enhancers include dimethyl sulfoxide and related analogues.

[0562] The oil phase of the emulsion of the present invention can be composed of known components in a known manner. Although this phase can contain only one emulsifier (or one emulsifying agent), it is desirable that it contains at least one emulsifier and a fat or an oil or a mixture of both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier acting as a stabilizer. It also preferably includes both an oil and a fat. The emulsifier with or without a stabilizer together forms the so-called emulsifying wax, and this wax together with the oil and fat forms the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

[0563] Since the solubility of the active compound in most of the oils that may be used in pharmaceutical emulsion formulations is very low, the selection of a suitable oil or fat for the formulation is based on achieving the desired cosmetic properties. Thus, the cream should optionally be a non-greasy, non-staining and washable product with an appropriate consistency to avoid leakage from tubes or other containers. Straight-chain or branched-chain, mono- or di-alkyl esters can be used, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched-chain esters called Crodamol CAP, the latter three being preferred esters. Depending on the desired properties, these esters can be used alone or in combination. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

[0564] Formulations suitable for topical administration to the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. Formulations suitable for topical administration to the oral cavity include lozenges (active ingredient contained in a flavored matrix, usually sucrose and gum arabic or tragacanth); soft lozenges containing the active ingredient in an inert matrix (such as gelatin and glycerin, or sucrose and gum arabic); and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0565] Formulations for rectal administration can be presented as suppositories with a suitable matrix (containing, for example, cocoa butter or salicylate). Formulations suitable for nasal administration, where the carrier is a solid, include, for example, coarse powders with a particle size range of 20 to 500 μm (including particle sizes in the range of 20 to 500 μm, incremented by 5 μm, such as 30 μm, 35 μm, etc.), which are administered in the manner of taking snuff (e.g., rapidly inhaled through the nasal passage from a powder container close to the nose). Suitable formulations with a liquid carrier 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 can be prepared according to conventional methods and can be delivered together with other therapeutic agents.

[0566] Formulations suitable for vaginal administration can be presented as vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations, which contain, in addition to the active ingredient, suitable carriers known in the art.

[0567] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions (which may contain antioxidants, buffers, bacteriostatic agents and solutes rendering the formulation isotonic with the blood of the intended recipient); and aqueous and non-aqueous sterile suspensions, which may include suspending and thickening agents. The formulations can be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the immediate addition of a sterile liquid carrier, such as water for injection, prior to use. Temporary injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the aforementioned types.

[0568] Preferred unit-dose formulations are those containing the active ingredient in the daily dose or unit daily sub-dose, or an appropriate fraction thereof, as described above.

[0569] It should be understood that, in addition to the components specifically mentioned above, depending on the type of formulation under discussion, the formulations of the present invention may include other reagents commonly used in the art, for example, those suitable for oral administration may include flavoring agents.

[0570] The compounds of the present 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 of the compounds of the present invention as the active ingredient, wherein the release of the active ingredient can be controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given compound of the present invention. Controlled-release formulations suitable for oral administration (wherein the discrete units contain one or more compounds of the present invention) can be prepared according to conventional methods.

[0571] Additional ingredients may be included to control the duration of action of the active ingredient in the composition. Thus, controlled-release compositions can be achieved by selecting suitable polymeric carriers such as, for example, polyesters, polyamino acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylcellulose, protamine sulfate, and the like. The rate of drug release and duration of action can also be controlled by incorporating the active ingredient into particles (such as microcapsules) of polymeric materials (such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethylmethacrylate, and other aforementioned polymers). Such methods include colloidal drug delivery systems such as liposomes, microspheres, microemulsions, nanoparticles, nanocapsules, and the like. Depending on the route of administration, the pharmaceutical composition may require a protective coating. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for their temporary preparation. Thus, typical carriers for this purpose include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol, and the like, and mixtures thereof.

[0572] In view of the fact that when several active ingredients are used in combination, they do not necessarily directly exert their combined therapeutic effect simultaneously in the mammal being treated, the corresponding composition may also be in the form of a medical kit or package that contains the two ingredients in separate but adjacent reservoirs or compartments. Thus, in the latter case, each active ingredient can be formulated in a manner suitable for a route of administration different from that of the other ingredient. For example, one can be in the form of an oral or parenteral formulation, while the other can be in the form of an intravenous injection ampoule or an aerosol.

[0573] The compounds of the invention as defined herein (including all embodiments thereof as described herein) can be used for the prevention and / or treatment of neurodegenerative diseases or disorders such as, but not limited to, neurodegenerative diseases or disorders characterized by cytotoxic tau protein misfolding and / or aggregation, and / or amyloid-β aggregation, to delay or stop the progression of such diseases or disorders in a subject (such as an animal, particularly a human), as described herein.

[0574] As used herein, the term "preventing" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., preventing at least one of the clinical symptoms of the disease from developing in a subject (particularly a human subject) who may be exposed to or susceptible to the disease but has not yet experienced or exhibited symptoms of the disease).

[0575] In one embodiment, the term "treating" or "treatment" of any disease or disorder includes ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least alleviating one of the clinical symptoms of the disease). In another embodiment, "treating" refers to ameliorating at least one physical parameter, which may or may not be discernible by a subject (particularly a human subject), but is based on or associated with the disease or disorder to be treated. In yet another embodiment, "treating" refers to modulating or alleviating the disease or disorder physically (e.g., stabilizing discernible or indiscernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, "treating" refers to delaying the onset or progression of the disease or disorder. Thus, "treating" includes any causal treatment of an underlying disease or disorder (i.e., disease modification), as well as any treatment of the signs and symptoms of the disease or disorder (with or without disease modification), and any alleviation or amelioration of the disease or disorder or its signs and symptoms. The terms "disease" and "disorder" are used interchangeably herein for the most part.

[0576] In one embodiment, as used herein, the term "diagnosis", "diagnoses" or "diagnosing" of a disease or disorder includes identifying and measuring signs and symptoms associated with the disease.

[0577] The term "subject" refers to an animal in need of such treatment, preferably a mammalian patient such as a human. The term also refers to an animal, preferably a mammalian, and most preferably a human being used as an object of treatment, observation or experiment. Unless otherwise specified, the terms "human", "patient" and "human subject" are typically used interchangeably herein.

[0578] The present invention also relates to a method for treating a disease or disorder in an animal (particularly a human disease or disorder as described in more detail herein), the method comprising administering a therapeutically effective amount of a compound of the present invention as defined herein (including all embodiments thereof as described herein).

[0579] As used herein, the term "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that, when administered to a subject, elicits a biological or pharmaceutical response in a tissue system or subject, which is sought by a researcher, veterinarian, physician or other clinician, including alleviating or partially alleviating 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 to be treated (particularly a human subject).

[0580] The compounds of the present invention as defined herein (including all embodiments thereof as described herein) are useful for treating or preventing neurodegenerative disorders.

[0581] Unless otherwise indicated, as used herein, the term "neurodegenerative disorder" refers to a disease, disorder, or condition characterized by the degeneration of neurons (e.g., including loss of function and eventual cell death) in an individual's brain and / or nervous system. Progressive damage to nerve cells and nervous system connections can have a significant impact on mobility, coordination, strength, sensation, and / or cognition.

[0582] In certain embodiments, a neurodegenerative disorder can include the occurrence of or can be characterized by cognitive dysfunction in a subject.

[0583] In certain embodiments, a neurodegenerative disorder can include dementia or dementia symptoms, or can be characterized by dementia or dementia symptoms. Dementia can be diagnosed by any method known in the art, such as by cognitive and neuropsychological tests (e.g., memory, language skills). Neurodegenerative dementia is progressive and irreversible due to the deterioration of nerve cells and their interconnections. Neurodegenerative dementia includes, but is not limited to, Alzheimer's disease dementia, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia. Thus, a neurodegenerative disorder can be Alzheimer's disease dementia, dementia with Lewy bodies, vascular dementia, and / or frontotemporal dementia (FTD), can include it, or can be characterized by it.

[0584] In certain embodiments, a neurodegenerative disorder (such as a neurodegenerative disorder that includes or is characterized by dementia as one of its primary symptoms) can include protein aggregation or can be characterized by protein aggregation. In certain embodiments, a neurodegenerative disorder may include or be characterized by the aggregation of tau protein or amyloid-beta (Aβ). In additional certain embodiments, a neurodegenerative disorder can include tau protein aggregation and / or beta-amyloid aggregation (i.e., the formation of beta-amyloid plaques) or can be characterized by it. In other words, in certain embodiments, a neurodegenerative disorder can be an amyloid-beta (Aβ) and / or tau protein-driven neurodegenerative disorder. In additional certain embodiments, a neurodegenerative disorder can include tau protein and / or Aβ-driven neurotoxicity or can be characterized by it. In additional certain embodiments, a neurodegenerative disorder can be a tauopathy (e.g., Alzheimer's disease, Pick's disease, frontotemporal lobar degeneration (FTLD)) or a beta-amyloidopathy (e.g., Alzheimer's disease, Down syndrome).

[0585] In certain embodiments, the neurodegenerative disorder can be a tauopathy and / or an alpha-synucleopathy, and thus includes but is not limited to Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with associated parkinsonism (chromosome 17-linked, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis (ALS), Niemann-Pick disease, Hallervorden-Spatz disease, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy.

[0586] In additional specific embodiments, the neurodegenerative disorder can be a tauopathy, beta-amyloidosis, and / or an alpha-synucleopathy.

[0587] Unless otherwise indicated, as used herein, the term "tauopathy" refers to a disease characterized by tau protein dysfunction (e.g., manifested as insoluble aggregates or polymers of the protein). The exact molecular mechanisms involved in tau protein aggregation are not well understood but may involve partial denaturation or misfolding of tau protein in a conformation that has a high propensity to self-organize into higher-order structures. The misfolding and aggregation may be triggered by hyperphosphorylation of tau protein, but it cannot be excluded at present that such abnormal phosphorylation is a consequence rather than a cause of aggregation.

[0588] The compounds of the present invention (including all embodiments thereof as described herein) are particularly suitable for treating certain neurodegenerative disorders (including those characterized by or involving cytotoxic tau protein misfolding and / or aggregation) to delay or prevent the progression of such diseases. Such diseases can be subsumed under the term tauopathy, as described elsewhere in this specification.

[0589] Tau protein is a protein capable of binding (and thus stabilizing and defining) the microtubule structure and function in neurons. The binding of tau protein to microtubules is regulated by tau protein phosphorylation; several tau protein phosphorylation sites and their corresponding kinases have been identified, which can control the phosphorylation state of tau protein and thus regulate the affinity of tau protein for microtubule binding.

[0590] An important aspect of tau protein aggregation is its associated cytotoxicity, which reduces neuronal integrity and functionality and ultimately leads to disease symptoms. By elucidating the familial mutations of tau protein, a direct role of tau protein in disease onset has been clearly established, and these mutations appear to be the cause of very early and sometimes aggressive tauopathies. Such mutations involve alterations in the amino acid sequence of tau protein that directly or indirectly promote neurotoxic aggregation.

[0591] The most well-known of these diseases is Alzheimer's disease, in which tau protein deposits within neurons in the form of neurofibrillary tangles (NFTs). These tangles were first described by Alois Alzheimer, after whom the disorder is named, in one of his patients suffering from the disorder. As used herein, the term "Alzheimer's disease" refers to a chronic progressive neurological disease characterized by neurodegeneration, and the most important (early) symptom is memory loss. As the disease progresses, symptoms may include confusion, irritability and aggressive behavior, mood swings, language disturbances, long-term memory loss, and general withdrawal of the patient due to sensory decline.

[0592] The tangles are formed by the hyperphosphorylation of microtubule-associated proteins known as tau proteins, leading to their aggregation in an insoluble form. (These hyperphosphorylated tau protein aggregates are also known as PHF or "paired helical filaments"). The exact mechanism of tangle formation is not fully understood, and there is still controversy as to whether the tangles are the primary causative factor of the disease or play a more peripheral role. AD is also classified as an amyloidosis due to the presence of senile plaques.

[0593] Other disorders in which neurofibrillary tangles are common include: progressive supranuclear palsy, pugilistic dementia (chronic traumatic encephalopathy), chromosome 17-linked frontotemporal dementia with associated parkinsonism, Lytico-Bodig disease (Guam parkinson-dementia complex), tangle-predominant dementia with NFTs (similar to AD but without plaques), ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, tuberous sclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

[0594] Non-Alzheimer's tauopathies are sometimes classified as "Pick's complex". In Pick's disease and corticobasal degeneration, tau protein deposits in swollen or "ballooned" neurons in the form of inclusion bodies. Argentophilic grain disease (AGD) (another type of dementia) is characterized by the presence of large numbers of argentophilic grains and coiled bodies in microscopic examination of brain tissue.

[0595] The compounds of the present invention (including all of its embodiments as described herein) are particularly suitable for preventing and / or treating diseases associated with tau protein biological dysfunction, which may include Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with associated parkinsonism (chromosome 17-linked, FTDP-17). The preferred indication is Alzheimer's disease.

[0596] The present invention also encompasses the compounds of the present invention (including all of its embodiments as described herein) for use in a method for preventing and / or treating a disease associated with tau protein biological dysfunction, which disease may include Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with associated parkinsonism (chromosome 17-linked, FTDP-17), the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of the present invention.

[0597] The present invention also encompasses a method for preventing and / or treating a disease associated with tau protein biological dysfunction, which disease may include Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with associated parkinsonism (chromosome 17-linked, FTDP-17), the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of the present invention (including all of its embodiments as described herein).

[0598] Unless otherwise indicated, as used herein, the term "amyloidosis" refers to both systemic and local amyloid protein-related diseases and prion-related encephalopathy, and thus includes, but is not limited to, type II diabetes, Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia with associated parkinsonism (chromosome 17-linked, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz disease, Down syndrome, neuroaxonal dystrophy, cataract, Creutzfeldt-Jakob disease, cystic fibrosis, phenylketonuria, Huntington's disease, Marfan syndrome, osteogenesis imperfecta, sickle cell anemia, Tay-Sachs disease, alpha-1 antitrypsin deficiency, cerebral amyloid angiopathy, retinitis pigmentosa, amyloid A amyloidosis, AL amyloidosis, familial transthyretin-related amyloidosis, familial Mediterranean fever, amyloidosis associated with long-term hemodialysis, amyloidosis associated with medullary thyroid carcinoma, and multiple system atrophy. For example, amyloidosis may be beta-amyloidosis.

[0599] Unless otherwise indicated, as used herein, the term "alpha-synucleinopathy" refers to a disease characterized by the pathological deposition of insoluble alpha-synuclein polymers or aggregates, either intracellularly and / or extracellularly. Such diseases include, but are not limited to, Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz disease, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy.

[0600] The present invention further encompasses the compounds of the present invention for use in the prevention and / or treatment of brain diseases or disorders.

[0601] In certain embodiments, the brain disease or disorder may include or be characterized by dementia, which is, but not limited to, Alzheimer's disease-related dementia, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, alcohol-related dementia, Down syndrome-related dementia, HIV-related dementia, and chronic traumatic encephalopathy (CTE) dementia.

[0602] In certain embodiments, the brain disease or disorder may include or be characterized by protein aggregation (such as the aggregation of tau protein and / or amyloid-beta (Aβ)) (but not limited to this).

[0603] In certain embodiments, the brain disease or disorder may be a neurodegenerative disorder and / or a vascular disorder (such as a neurovascular disorder). For example, the brain disease or disorder may be a neurovascular disorder that includes or is characterized by amyloid-beta (Aβ) aggregation, such as cerebral amyloid angiopathy.

[0604] In certain embodiments, the brain disease or disorder may be a tauopathy. For example, the brain disease or disorder may be primary age-related tauopathy (PART) dementia, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chromosome 17-linked frontotemporal dementia with associated parkinsonism (FTDP-17), vacuolar tauopathy, Lytico-Bodig disease (Guam Parkinson-dementia complex), ganglioglioma and gangliocytoma, meningeal hemangiomatosis, or post-encephalitic parkinsonism.

[0605] In certain 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 associated parkinsonism (chromosome 17-linked, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis (ALS), Niemann-Pick disease, Hallervorden-Spatz disease, Down syndrome, neuroaxonal dystrophy, multiple system atrophy, Huntington's disease, frontotemporal lobar degeneration (FTLD), cystic fibrosis, and Creutzfeldt-Jakob disease.

[0606] In further certain 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 disease, 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, preferably the neurodegenerative disorder is Alzheimer's disease.

[0607] In certain embodiments, neurodegenerative disorders are characterized by Ca 2+ homeostatic imbalance.

[0608] In certain embodiments, the neurodegenerative disorder is Alzheimer's disease.

[0609] The compounds of the 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 together constitute a method for preparing the compounds and are further exemplified. The methods further described are only intended as examples and are not intended to limit the scope of the invention.

[0610] The abbreviations used in the specification (especially the schemes and examples) are as follows: Boc - tert - butoxycarbonyl, CDI - carbonyldiimidazole, DCC - N,N - dicyclohexylcarbodiimide, CHCl3 - chloroform, DCE - dichloroethane, DCM - dichloromethane, DIPEA - diisopropylethylamine, DMAc - dimethylacetamide, DMF - N,N - dimethylformamide, DMSO - dimethyl sulfoxide, DPPA - diphenylphosphoryl azide, Et3N - triethylamine, EtOAc - ethyl acetate, EtOH - ethanol, Eq. - equivalent, Fmoc - fluorenylmethoxycarbonyl chloride, h - hour, HATU - O-(7 - azabenzotriazol - 1 - yl)-N,N,N′,N′ - tetramethyluronium hexafluorophosphate, HPLC - high performance liquid chromatography, KOtBu - potassium tert - butoxide, LCMS - liquid chromatography - mass spectrometry, LiHDMS - lithium bis(trimethylsilyl)amide, MeCN(CH3CN)-ACN - acetonitrile, MeOH - methanol, min. - minute, mL - ml - milliliter, MPLC - medium pressure liquid chromatography, NaBH4 - sodium borohydride, Na2CO3 - sodium carbonate, Na2SO4 - sodium sulfate, NH4Cl - ammonium chloride, NH3 - ammonia, NMP - 1 - methyl - 2 - pyrrolidone, NMR - nuclear magnetic resonance, 4 - NPC - 4 - nitrophenyl chloroformate, PyBOP - benzotriazol - 1 - yloxytris(pyrrolidino)phosphonium hexafluorophosphate, RP - reverse phase, RT - room temperature, sat. - saturated, STAB - sodium triacetoxyborohydride, TEA - triethylamine, TFA - trifluoroacetic acid, THF - tetrahydrofuran.

[0611] The preparation of the compounds of the invention as defined herein (including all embodiments thereof as described herein) can be carried out according to sequential or convergent synthetic routes.

[0612] Examples for the synthesis of the compounds of the invention as defined herein (including all embodiments thereof as described herein) are shown in the following schemes.

[0613] The techniques required for carrying out the reaction and purifying the resulting product are known to those skilled in the art. The substituents and indicators used in the following method descriptions have the meanings given above, unless stated to the contrary.

[0614] More specifically, the compounds as defined herein (including all embodiments thereof as described herein) can be made by the methods given below, the methods given in the examples, or similar methods. The appropriate reaction conditions for each reaction step are known to those skilled in the art. The order of the reaction steps is not limited to the order shown in the schemes, but rather the order of the reaction steps can be freely changed according to the starting materials and their respective reactivities. The starting materials can be commercially available or can be prepared by methods similar to the methods given below, by the methods described in the references cited in the specification or examples, or by methods known in the art.

[0615] In some embodiments, the compound having the formula B1A can be prepared according to the general procedure outlined in Scheme A.

[0616]

[0617] Scheme A: wherein A 1a , Z 1a , Y 1a , X 1a , R 3ab , R 4a , X 2a , Y 2a , Z 2a and A 2a as described herein

[0618] The commercially available amine derivative 3* can be coupled with the derivative *2. Other suitable protecting groups can be used instead of Boc, such as Ts, etc. After removing the protecting group under standard conditions, the intermediate 4* can be obtained. The compound B1A can be obtained by alkylating or reductive amination of 4*, wherein LG is a suitable leaving group, such as an aldehyde or a halogen, for example.

[0619] In some embodiments, the compound having the formula B1B can be prepared according to the general procedure outlined in Scheme B.

[0620]

[0621] Scheme B: wherein A 1b , Z 1b , R 3b , R 4b , Y 4b , Z 2b and A 2b as described herein

[0622] A commercially available amine derivative 6* can be coupled with derivative 9*. Other suitable protecting groups can be used instead of Boc, such as Ts, etc. After removing the Boc-protecting group under standard conditions, intermediate 7* can be obtained. Intermediate 7* can be coupled with a suitable aryl aldehyde 8* to obtain compound B1B. In some embodiments, R in derivative 6* 4b is H, and a group R other than H can be introduced by further reacting B1B with a suitable reagent (when applicable). 4b .

[0623] In some embodiments, compounds having the formulae B1A1, B1A2, B1A3, B1A4, B1A5 can be prepared according to the general procedures outlined in Scheme A1.

[0624]

[0625] Scheme A1: wherein A 1a , Y 1a , Z 1a , Z 2a and A 2a as described herein

[0626] Compound 3* (commercially available) can be coupled with aldehyde 10* (commercially available or synthesized by procedures known to those skilled in the art) via reductive amination in the presence of a suitable reducing reagent (such as STAB, NaBH4, Pd / C H2, etc.), for example, in a suitable solvent or solvent mixture (such as DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.), for example, at a temperature in the range of RT to 60 °C, to provide an intermediate having the formula 11*. Other suitable protecting groups can be used instead of Boc, such as Fmoc, Ts, etc. After removing the Boc-protecting group under standard conditions, intermediate 12* can be obtained. Intermediate 12* can be coupled with acid 13* (commercially available or synthesized by procedures known to those skilled in the art) to obtain compound B1A1, for example, in the presence of a suitable base (such as DIPEA, etc.) and at least one suitable coupling agent (such as HATU, PyBOP, DCC, etc.), for example, in a suitable solvent or solvent mixture (such as DCM, MeCN, CHCl3, DMF, DMAc, DMP, etc.), for example, at a temperature in the range of 0 °C to 60 °C.

[0627] Compound B1A2 can be obtained by coupling intermediate 12* with alcohol 14* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of, for example, a suitable base (such as NaH, DIPEA, KOtBu, LiHMDS, etc.) and a suitable coupling reagent (such as bis(4-nitrophenyl) carbonate, 4-NPC, CDI, etc.), in a suitable solvent or solvent mixture (such as DMF, THF, dioxane, toluene, etc.), at a temperature in the range of -20 °C to RT. Alternatively, compound B1A2 with the general formula can be obtained by coupling between intermediate 12* and chloroformate 15* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of, for example, a suitable base (such as DIPEA, etc.), in a suitable solvent or solvent mixture (such as DCM, CHCl3, THF, DMF, DMAc, dioxane, etc.), at a temperature in the range of -20 °C to 60 °C.

[0628] Compound B1A3 can be obtained by coupling intermediate 12* with amine 16* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of, for example, a suitable base (such as DIPEA, Et3N, etc.) and a suitable coupling reagent (such as bis(4-nitrophenyl) carbonate, 4-NPC, CDI, etc.), in a suitable solvent or solvent mixture (such as DCM, CHCl3, THF, DMF, DMAc, dioxane, etc.), at a temperature in the range of 0 °C to 50 °C. Alternatively, compound B1A3 with the general formula can be obtained by coupling between intermediate 12* and isocyanate 17* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of, for example, a suitable base (such as DIPEA, etc.), in a suitable solvent or solvent mixture (such as DCM, CHCl3, THF, DMF, DMAc, dioxane, etc.), at a temperature in the range of -20 °C to 60 °C.

[0629] Compound B1A4 can be obtained by coupling intermediate 12* with sulfonyl chloride 18* (commercially available or synthesized by procedures known to those skilled in the art) in a suitable solvent or solvent mixture (such as DCM, CHCl3, THF, DMF, DMAc, dioxane, etc.), at a temperature in the range of -20 °C to 60 °C.

[0630] Compound B1A5 can be obtained by reductive amination of intermediate 12* with aldehyde 19* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of a suitable reducing agent (such as STAB, NaBH4, Pd / C H2, etc.), for example, in a suitable solvent or solvent mixture (such as DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.), for example, at a temperature in the range of RT to 60 °C.

[0631] In some embodiments, compounds having the formula B1A1 can be prepared according to the general procedures outlined in Scheme A2.

[0632]

[0633] Scheme A2: wherein R 10a is -Z 2a -A 2a , R 11a is -Y 1a -Z 1a -A 1a and A 1a 、Z 1a 、Z 2a 、Y 1a and A 2a as described herein

[0634] Compound 3* (commercially available) can be coupled with acid 13* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of a suitable base (such as DIPEA, etc.) and a suitable coupling agent (such as HATU, PyBOP, DCC, etc.), for example, in a suitable solvent or solvent mixture (such as DCM, MeCN, CHCl3, DMF, DMAc, DMP, etc.), for example, at a temperature in the range of 0 °C to 60 °C, to provide an intermediate having the formula 21*. Other suitable protecting groups can be used instead of Boc, such as Fmoc, Ts, etc. After removing the Boc-protecting group under standard conditions, intermediate 22* is obtained. Compound B1A1 can be obtained by reductive amination of intermediate 22* with aldehyde 10* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of a suitable reducing agent (such as STAB, NaBH4, Pd / C H2, etc.), for example, in a suitable solvent or solvent mixture (such as DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.), for example, at a temperature in the range of RT to 60 °C.

[0635] In some embodiments, compounds having the formula B1A2 can be prepared according to the general procedures outlined in Scheme A3.

[0636]

[0637] Scheme A3: wherein A 1a , Z 1a , Z 2a and A 2a as described herein

[0638] Compound 3* (commercially available) can be coupled with alcohol 14* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of, for example, a suitable base (such as NaH, DIPEA, KOtBu, LiHMDS, etc.) and a suitable coupling reagent (such as bis(4-nitrophenyl) carbonate, 4-NPC, CDI, etc.), for example, in a suitable solvent or solvent mixture (such as DMF, THF, toluene, dioxane, etc.), for example, at a temperature in the range of -20 °C to RT, to provide an intermediate having formula 24*. Other suitable protecting groups can be used instead of Boc, such as Fmoc, Ts, etc. After removing the Boc-protecting group under standard conditions, intermediate 25* is obtained. Intermediate 25* can be reductive aminated with aldehyde 10* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of, for example, a reducing agent (such as STAB, NaBH4, Pd / C H2, etc.), for example, in a suitable solvent or solvent mixture (such as DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.), for example, at a temperature in the range of RT to 60 °C to obtain compound B1A2.

[0639] In some embodiments, compounds having formula B1A3 can be prepared according to the general procedure outlined in Scheme A4.

[0640]

[0641] Scheme A4: wherein A 1a , Z 1a , Z 2a and A 2a as described herein

[0642] Compound 3* (commercially available) can be coupled with amine 16* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of, for example, a suitable base (such as DIPEA, Et3N, etc.) and a coupling agent (such as bis(4-nitrophenyl) carbonate, 4-NPC, CDI, etc.), for example, in a suitable solvent or solvent mixture (such as DCM, CHCl3, THF, DMF, DMAC, dioxane, etc.), for example, at a temperature in the range of 0 °C to 50 °C, to provide an intermediate having formula 28*. Other suitable protecting groups can be used instead of Boc, such as Fmoc, Ts, etc. After removing the Boc-protecting group under standard conditions, intermediate 29* can be obtained. Intermediate 29* can be reductively aminated with aldehyde 10* (commercially available or synthesized by procedures known to those skilled in the art) in the presence of, for example, a suitable reducing agent (such as STAB, NaBH4, Pd / C H2, etc.), for example, in a suitable solvent or solvent mixture (such as DCM, MeOH, DMF, DMAc, toluene, dioxane, water, etc.), for example, at a temperature in the range of RT to 60 °C to obtain compound B1A3.

[0643] In some embodiments, a compound having formula B1A6 can be prepared according to the general procedure outlined in Scheme A5.

[0644]

[0645] Scheme A5: wherein A 1a , Z 1a , R 3a , R 4a , Y 2a , Z 2a and A 2a as described herein

[0646] Compound 3* can be coupled with derivative 30*. Other suitable protecting groups can be used instead of Boc, such as Fmoc, Ts, etc. After removing the Boc-protecting group under standard conditions, intermediate 31* can be obtained. Intermediate 31* can be alkylated or reductively aminated to obtain compound B1A6.

[0647] In some embodiments, a compound having formula B1B1 can be prepared according to the general procedure outlined in Scheme B1.

[0648]

[0649] Scheme B1: wherein A 1b , Z 1b , R 3b , R 4b , Y 2b , Z 2b and A2b As described herein

[0650] A commercially available amine derivative 6* can be coupled with derivative 33*. After removing the Boc-protecting group under standard conditions, intermediate 34* can be obtained. 34* can be coupled with a suitable aryl aldehyde 8* to obtain the final compound B1B1. In some embodiments, R in derivative 6* 4b is H, and a group R other than H can be introduced by further reacting B1B1 with a suitable reagent (when applicable). 4b .

[0651] In some embodiments, compounds having the formula B1B2 can be prepared according to the general procedure outlined in Scheme B2.

[0652]

[0653] Scheme B2: wherein A 1b , Z 1b , R 3b , R 4b , Y 2b , Z 2b and A 2b as described herein

[0654] A commercially available amine derivative 6* can be coupled with compound 35*. After removing the Boc-protecting group under standard conditions, intermediate 36* can be obtained. The final compound B1B2 can be obtained from amine 36* by reductive amination of an aldehyde or alkylation with an electrophile. In some embodiments, R in derivative 6* 4b is H, and a group R other than H can be introduced by further reacting B1B2 with a suitable reagent (when applicable). 4b .

[0655] The general schemes described above should be considered non-limiting examples. It should be understood that the compounds of the present invention can be obtained by other methods known to those skilled in the art.

[0656] The following examples are provided for illustrative purposes of the present invention and should not be construed as limiting the scope of the present invention.

[0657] Example

[0658] Table 1B: Structures of the compounds of the present invention and their corresponding codes

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704] Part A represents the preparation of the compounds (intermediates and final compounds), while Part B represents the pharmacological examples.

[0705] Part A

[0706] All starting materials not specifically described are commercially available (e.g., supplier details can be found in databases such as, for example, Aldrich, Combi-Blocks, Enamine, FluoroChem, Matrix Scientific, Merck, TCI, etc.), or their synthesis has been precisely described in the professional literature (e.g., experimental guidelines can be found in databases or databases), or can be prepared using conventional methods known to those skilled in the art.

[0707] If desired, the reaction is carried out under an inert atmosphere (mainly argon and N2). The reagent equivalents, solvent amounts, reaction temperature, and time may vary slightly between different reactions carried out by similar methods. The work-up and purification methods are adjusted according to the characteristic properties of each compound and may vary slightly for similar methods. The yields of the prepared compounds have not been optimized.

[0708] The indication “equivalents (equivalents, eq., or eq or equiv.)” means molar equivalents, “RT” or “rt” means room temperature T (23 °C ± 7 °C), “M” indicates concentration (mol / l), “sol.” means solution, “conc.” means concentrated. The mixing ratio of solvents is usually expressed as a volume / volume ratio.

[0709] Key analytical characterizations of all exemplary compounds and selected intermediate products were performed by 1 1H-NMR spectroscopy and / or mass spectrometry (MS, for m / z of [M+H] + and / or [M-H] – .

[0710] The analytical instruments used were, for example, BRUKER 400 MHz (Topspin software) for NMR analysis. LC / MS analysis was carried out using, for example, Agilent 1260, Mass: 6130 (ESI) (Open Lab Chemstation software). Analytical UPLC was measured, for example, on Waters IClass (MassLynx software). GCMS analysis was performed using, for example, Agilent 6890N.

[0711] Preparative HPLC was carried out, for example, on Agilent G6120 or Waters, and reverse-phase MPLC was carried out, for example, on Reveleris.

[0712] If known, the structures of some compounds containing stereocenters were drawn and named according to the absolute stereochemistry. In cases where the absolute stereochemistry is unknown, the compounds can be racemic, mixtures of diastereoisomers, pure diastereoisomers with unknown stereochemistry, or pure enantiomers with unknown stereochemistry.

[0713] The MS analysis mentioned in the experimental section was performed on a Waters system. Acidic conditions: Waters IClass; binary pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210 - 320 nm, MS: QDa ESI, pos / neg 100 - 800; column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 μ, temperature: 40 °C, flow rate: 0.6 mL / min, gradient: t0 = 5% A, t 2.0min = 98% A, t 2.7min = 98% A, post - run time: 0.3 min, eluent A: 0.1% formic acid in acetonitrile, eluent B: 0.1% formic acid in water. Basic conditions: Equipment: Waters IClass; binary pump: UPIBSM, SM: UPISMFTN with SO; UPCMA, PDA: UPPDATC, 210 - 320 nm, MS: QDa ESI, pos / neg 100 - 800; column: Waters XSelect CSH C18, 50 x 2.1 mm, 2.5 μ, temperature: 25 °C, flow rate: 0.6 mL / min, gradient: t0 = 5% A, t 2.0min = 98% A, t 2.7min = 98% A, post - run time: 0.3 min, eluent A: acetonitrile, eluent B: 10 mM ammonium bicarbonate in water (pH = 9.5)

[0714] The GCMS analysis mentioned in the experimental section was performed on an Agilent 6890N G1530 gas chromatography system coupled with a G2577A5973 MSD detector (EI - positive, detection temperature: 280 °C), mass range: 50 - 550, column: Restek RXi - 5MS (20 m ID 180 μm, df 0.18 μm), average velocity: 50 cm / s, injection volume: 1 μl, injector temperature: 250 °C, split ratio: 100 / 1, carrier gas: He; initial temperature: 100 °C, initial time: 1.5 min, solvent delay: 1.0 min, rate: 75 °C / min, final temperature: 250 °C, hold time: 4.3 min.

[0715] The preparative HPLC purification under basic conditions mentioned in this experimental section was carried out using a Waters system: MS instrument type: ACQ-SQD2; HPLC instrument type: Waters modular preparative HPLC system; column: Waters XSelect (C18, 100x30 mm, 10 μm); flow rate: 55 ml / min for the preparative pump; column temperature: RT; 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 based on MS and DAD.

[0716] The preparative HPLC purification under acidic conditions mentioned in this experimental section was carried out using an Agilent system: MS instrument type: Agilent Technologies G6120AA quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; column: Waters XSelect CSH (C18, 100x30 mm, 10 μ); flow rate: 55 ml / min; column temperature: RT; 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 based on MS and DAD.

[0717] The reversed-phase MPLC purification under acidic conditions mentioned in this experimental section was carried out using Reveleris: Instrument type: Reveleris TM Preparative MPLC; column: Phenomenex LUNA C18(3) (150x25 mm, 10 μ); flow rate: 40 mL / min; column temperature: rt.; 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.

[0718] The reversed-phase MPLC purification under basic conditions mentioned in this experimental section was carried out using Reveleris: Instrument type: Reveleris TMPreparative MPLC; Column: Waters XSelect CSH C18 (145x25mm, 10μ); Flow rate: 40 mL / min; Column temperature: rt.; Eluent A: 10 mM ammonium bicarbonate in water (pH = 9.0); Eluent B: 99% acetonitrile + 1% 10 mM ammonium bicarbonate in water; Gradient: t = 0 min 5% B, t = 20 min 100% B, Detection UV: 220, 254, 280 nm.

[0719] Preparation Examples of Intermediates

[0720] Synthesis of 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethenone (IB4-1)

[0721]

[0722] a) tert-Butyl 6-(2-(4-chlorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0723] tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 0.5 oxalic acid (1 g, 4.11 mmol, equivalent: 1.00) and TEA (1.04 g, 1.42 ml, 10.3 mmol, equivalent: 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, equivalent: 1) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. LCMS showed a conversion of 80%. The crude reaction mixture was concentrated in part under reduced pressure, poured into EtOAc, and extracted with H2O. 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 of the title product (48% yield). ESI [M+H] + : 351.1.

[0724] b) 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethanone

[0725] tert-Butyl 6-(2-(4-chlorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (686 mg, 1.96 mmol, equivalent: 1.00) was combined in DCM (13.0 ml) to give a yellow solution. TFA (1.11 g, 749 μl, 9.78 mmol, equivalent: 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 and evaporated, concentrated in vacuo, to give 1.10 g of the title product used directly as a crude (92% yield). ESI [M+H] + : 251.4.

[0726] Synthesis of 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethanone (IB 4-2)

[0727]

[0728] a) tert-Butyl 6-(2-(4-fluorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0729] 2-(4-Fluorophenyl)acetic acid (488 mg, 3.17 mmol, equivalent: 2.2), TEA (728 mg, 1.00 ml, 7.19 mmol, equivalent: 5), and HATU (1.2 g, 3.17 mmol, equivalent: 2.2) were combined in DCM (10 ml).

[0730] The reaction mixture was heated to 45 °C and stirred for 15 min. tert-Butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (700 mg, 1.44 mmol, equivalent: 1.00) was added, and the reaction mixture was heated to 45 °C and stirred for 1 h. 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% to 10% MeOH in DCM) to give 451 mg of the title product (yield 47%). ESI [M+H] + : 335.3.

[0731] b) 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethanone

[0732] tert-Butyl 6-(2-(4-fluorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (451 mg, 1.35 mmol, equivalent: 1.00) was dissolved in DCM (8.99 ml). TFA (819 mg, 550 μl, 7.18 mmol, equivalent: 5.32) was added. The reaction mixture was stirred for 2 h. Another 5 equivalents of TFA (550 μl) were added. The reaction mixture was stirred for 4 h. Another 5 equivalents of TFA (550 μl) were added. The reaction mixture was stirred for 1.5 h. Then the mixture was concentrated. Then the crude mixture was poured into EtOAc and extracted with Na2CO3. The organic layer was dried over Na2SO4 and evaporated to give 281 mg of the title product (yield 90%). ESI [M+H] + : 235.1.

[0733] Synthesis of 2-(3,4-difluorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethanone (IB 4-3)

[0734]

[0735] a) tert-Butyl 6-(2-(3,4-difluorophenyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0736] To a solution of 2-(3,4-difluorophenyl)acetic acid (4.68 g, 27.2 mmol, 1.1 eq) in DMF (200 mL) was added HATU (11.3 g, 29.7 mmol, 1.2 eq) in DIPEA (8.63 mL, 49.4 mmol, 2 eq). The reaction was stirred at RT for 20 min, then a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, 0.5 oxalate (6 g, 24.7 mmol, 1 eq) in 2 eq DIPEA (50 mL) was added. The reaction was stirred at RT for 4 h. LCMS showed the SM and the product. Another equivalent of 2-(3,4-difluorophenyl)acetic acid and HATU were added and the reaction was stirred at RT 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 gel column with heptane / ethyl acetate (1 / 1 to 0 / 1) gave the desired product. ESI [M+H] + : 353.3.

[0737] b) 2-(3,4-difluorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethanone

[0738] 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 RT overnight. Extraction was carried out with ethyl acetate / ether and saturated aqueous Na2CO3. Two layers were obtained, where LCMS showed the product in the aqueous layer and the impurities in the organic layer. The aqueous layer was concentrated and extracted with isopropanol / ethyl acetate to give the organic layer, which was dried over Na2SO4 and evaporated, then azeotroped with heptane to remove water and give the product (30%).

[0739] [M+H] + : 253.2

[0740] Synthesis of N-(6-amino-spiro[3.3]hept-2-yl)-2-(4-fluoro-phenyl)-acetamide (HCl) (IB 7-1)

[0741]

[0742] a ) tert-Butyl 6-(2-(4-fluorophenyl)acetamido)spiro[3.3]hept-2-ylcarbamate

[0743] To a solution of 2-(4-fluorophenyl)acetic acid (1.12 g, 7.29 mmol, 1.1 eq) in DCM (200 mL) was added HATU (3.02 g, 7.95 mmol, 1.2 eq) in TEA (2.77 mL, 19.9 mmol, 3 eq). The reaction was stirred at 45 °C for 15 min, then 6-aminospiro[3.3]heptan-2-yl carbamate tert-butyl ester (1.5 g, 6.63 mmol, 1 eq) was added. The reaction was stirred at 45 °C overnight. Extraction with DCM / water provided the 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.

[0744] b) N-(6-amino-spiro[3.3]hept-2-yl)-2-(4-fluoro-phenyl)-acetamide (HCl)

[0745] 6-(2-(4-Fluorophenyl)acetamido)spiro[3.3]heptan-2-yl carbamate tert-butyl ester (110 mg, 0.3 mmol, equivalent: 1.00) was dissolved in DCM and 4M HCl in dioxane (1 mL, 4 mmol, equivalent: 13) was added. The reaction mixture was stirred at RT for 1 h. The solvent was evaporated, giving the desired product to be used directly as a crude. ESI [M-H] - = 297.1.

[0746] Synthesis of N-(6-aminospiro[3.3]hept-2-yl)-2-(4-chlorophenyl)acetamide (HCl) (IB 7-2)

[0747]

[0748] a) tert-Butyl 6-(2-(4-chlorophenyl)acetamido)spiro[3.3]hept-2-ylcarbamate

[0749] 6-Aminospiro[3.3]heptan-2-yl carbamate tert-butyl ester (6 g, 26.5 mmol, equivalent: 1.00) and TEA (5.37 g, 7.35 ml, 53.0 mmol, equivalent: 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, equivalent: 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 H2O. The crude reaction mixture was concentrated in vacuo. Recrystallization from DCM and MeOH gave a white solid. ESI [M+H-tBu] + = 323.3.

[0750] b) N-(6-aminospiro[3.3]hept-2-yl)-2-(4-chlorophenyl)acetamide (HCl)

[0751] Dissolve tert-butyl 6-(2-(4-chlorophenyl)acetamido)spiro[3.3]heptan-2-ylcarbamate (7.682 g, 20.3 mmol, equivalent: 1.00) in 100 mL of DCM and add 4 M HCl in dioxane (35.5 mL, 142 mmol, equivalent: 7). Stir the reaction mixture overnight at RT. Evaporate the solvent and recrystallize from DCM and MeOH to obtain a white solid (2.408 g). ESI[M+H] + = 279.1.

[0752] Synthesis of 2-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane (IB12-1)

[0753]

[0754] Step 1: To tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (1 g, 2.055 mmol) in anhydrous DCM (24 ml) / MeOH (8 ml), add acetic acid (0.471 ml, 8.22 mmol) and 4-fluorobenzaldehyde (0.665 ml, 6.17 mmol). Purge the mixture with nitrogen and add titanium(IV) isopropoxide (2.409 ml, 8.22 mmol). Stir the mixture for 2 h at rt. Add STAB (3.48 g, 16.44 mmol) and stir the mixture overnight at RT. Quench the mixture carefully by adding aqueous saturated Na2CO3 and stir for 1 h at RT. Add more DCM to the resulting suspension and separate the layers. Extract the aqueous layer with DCM (2x) and filter the extracted DCM layers directly through a celite path. Collect the combined and filtered extracts and concentrate under reduced pressure. Purify the crude product by flash column chromatography to obtain tert-butyl 6-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a colorless oil (1.16 g, 3.79 mmol, 92% yield). MS (m / e): 307.2 (MH + ).

[0755] Step 2: Dissolve tert-butyl 6-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.16 g, 3.79 mmol) in DCM (6 ml) and add trifluoroacetic acid (3.50 ml, 45.4 mmol). Stir the mixture overnight at RT. Dilute the mixture with DCM and concentrate it cold under reduced pressure (on a water bath). Dissolve the crude mixture in a few mL of DMSO and add saturated aqueous Na2CO3 until pH > 7. Purify the mixture by RP chromatography (50 g column, gradient: 0% to 50% MeCN in 10 mM aqueous ammonium bicarbonate) to obtain 2-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane as a pale yellow oil (695 mg, 3.37 mmol, 89% yield). MS (m / e): 207.1 (MH + ).

[0756] Prepare the following intermediates in a similar manner as described for IB 12-1 (using appropriate reagents and purification methods known to those skilled in the art): IB 12-2, IB 12-3, and IB 12-4.

[0757]

[0758] Synthesis of 2-(4,4-difluorocyclohexyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethan-1-one (IB22-1)

[0759]

[0760] Step 1: Dissolve 2-(4,4-difluorocyclohexyl)acetic acid (1.007 g, 5.65 mmol) in DCM (25 ml) and add DIPEA (2.244 ml, 12.85 mmol) and HATU (2.051 g, 5.39 mmol). Add tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (1.25 g, 2.57 mmol) and stir the mixture overnight at RT. Add water to the reaction mixture and separate the layers. Extract the aqueous layer twice with DCM. Dry the combined organic fractions over Na2SO4, filter, and concentrate to obtain crude tert-butyl 6-(2-(4,4-difluorocyclohexyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a yellow oil. No further purification is performed.

[0761] Step 2: To 6-(2-(4,4-difluorocyclohexyl)acetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.842 g, 5.14 mmol) in DCM (40 ml) was added trifluoroacetic acid (5.94 ml, 77 mmol). The mixture was stirred at RT for 2 h and then concentrated cold on a rotary evaporator. The crude mixture was dissolved in a few mL of DMSO and saturated aqueous Na2CO3 was added until pH > 7. The mixture was purified by RP chromatography (100 g column, gradient: 0% to 100% MeCN in 10 mM aqueous ammonium bicarbonate) to give 2-(4,4-difluorocyclohexyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethan-1-one as an off-white foam (1.08 g, 4.18 mmol, 81% yield). MS (m / e): 259.1 (MH + )

[0762] Synthesis of 4,4-difluorocyclohexyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (IB25-1)

[0763]

[0764] Step 1: To bis(4-nitrophenyl) carbonate (2.345 g, 7.71 mmol) in dry DMF (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). The mixture was stirred at RT for 1.5 h and then 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxalate (1.25 g, 2.57 mmol) in dry DMF (15 ml) and DIPEA (1.346 ml, 7.71 mmol) was added. The mixture was stirred at RT overnight. The mixture was concentrated, EtOAc, a little 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. No further purification was carried out.

[0765] 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 RT and then concentrated under cold conditions. The crude mixture was dissolved in several mL of DMSO and saturated aqueous Na2CO3 was added until pH > 7. The mixture was purified by RP chromatography (100 g column, gradient: 0% to 100% MeCN in 10 mM aqueous ammonium bicarbonate) to afford 4,4-difluorocyclohexyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as a yellow oil (873 mg, 3.35 mmol, 65.1% yield). MS (m / e): 261.2 (MH + )

[0766] The following intermediate was prepared in a similar manner to that described for IB 25-1 (using appropriate reagents and purification methods known to those skilled in the art): IB25-2

[0767]

[0768] Synthesis of N-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide (IB29-1)

[0769]

[0770] Step 1: To bis(4-nitrophenyl) carbonate (1.876 g, 6.17 mmol) in dry DMF (40 ml) was added (4-fluorophenyl)methanamine (0.752 ml, 6.58 mmol) and DIPEA (2.154 ml, 12.33 mmol). The mixture was stirred at RT for 1.5 h and then 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxalate (1 g, 2.055 mmol) was added. The mixture was stirred overnight at RT. Saturated aqueous Na2CO3 and EtOAc were added to the mixture and the layers were separated. The organic layer was washed with more saturated aqueous Na2CO3 and saturated aqueous NH4Cl. The organic fractions were combined and concentrated under reduced pressure. The crude product was purified by flash column chromatography (40 g silica gel, wet loading from DCM, heptane / EtOAc = 35:65 -> 0:1) to afford tert-butyl 6-((4-fluorobenzyl)carbamoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a white solid (1.11 g, 3.18 mmol, 77% yield). MS (m / e): 350.2 (MH + )

[0771] Step 2: To a solution of 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 overnight at RT and then concentrated in vacuo. The crude mixture was dissolved in a few mL of DMSO and saturated aqueous Na2CO3 was added until pH > 7. The mixture was purified by RP chromatography (100 g column, gradient: 0% to 100% MeCN in 10 mM aqueous ammonium bicarbonate) to afford N-(4-fluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxamide as a pale yellow oil (780 mg, 3.13 mmol, 98% yield). MS (m / e): 250.1 (MH + )

[0772] The following intermediates were prepared in a similar manner to that described for IB 29-1 (using appropriate reagents and purification methods known to those skilled in the art): IB 29-2, IB 29-3.

[0773]

[0774] Synthesis of N-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl)spiro[3.3]heptane-2,6-diamine hydrochloride (IB30-1) a) tert-Butyl 6-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-ylamino)spiro[3.3]hept-2-ylcarbamate

[0775]

[0776] b) N-(3-(4-fluorobenzyl)-1,2,4-thiadiazol-5-yl)spiro[3.3]heptane-2,6-diamine hydrochloride ​

[0777] To a solution of commercially available tert-butyl 6-aminospiro[3.3]heptan-2-ylcarbamate (1.86 g, 8.2 mmol, equivalent: 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, equivalent: 1) and DIPEA (1.6 ml, 9.18 mmol, equivalent: 1.4).

[0778] The reaction was stirred under argon at 140 °C for 30 min. The solvent was evaporated and the crude product was redissolved in EtOAc and washed with water. The aqueous layer was re-extracted with fresh EtOAc. The organic layer was dried over Na2SO4, concentrated and purified by flash chromatography (using heptane and ethyl acetate) to afford 2.39 g of the title product (87% yield). ESI [M-H] - : 417.7

[0779] ​

[0780] 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, equivalent: 1) in dioxane (22 ml) was added HCl in dioxane (4 M, 4 ml, equivalent: 7.6). After the addition of HCl, the reaction mixture changed from a light 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 another 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 with toluene twice. The product was dried under high vacuum overnight to give the title product. ESI [M+H] + : 319.1

[0781] N-(3-(4-Chlorobenzyl)-1,2,4-thiadiazol-5-yl)spiro[3.3]heptane-2,6-diamine TFA salt (IB 30-2) Synthesis

[0782]

[0783] a) tert-Butyl 6-(3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-ylamino)spiro[3.3]hept-2-ylcarbamate Ester

[0784] Commercially available tert-butyl 6-aminospiro[3.3]heptan-2-ylcarbamate (3.84 g, 17.0 mmol, equivalent: 1), commercially available 5-chloro-3-(4-chlorobenzyl)-1,2,4-thiadiazole (4.1637 g, 17.0 mmol, equivalent: 1.00) and DIPEA (4.39 g, 5.93 ml, 34.0 mmol, equivalent: 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 H2O (1x300 mL). The aqueous layer was back-extracted with EtOAc (1x100 mL). The organic layer was dried over Na2SO4, concentrated in vacuo, and the crude material was purified by flash chromatography (330 g silica gel, 0% to 50% EtOAc, on heptane) to give 5.999 g of the title compound as an off-white solid (81% yield). ESI [M+H] + : 435.3

[0785] b) N-(3-(4-Chlorobenzyl)-1,2,4-thiadiazol-5-yl)spiro[3.3]heptane-2,6-diamine TFA salt

[0786] tert-Butyl 6-(3-(4-chlorobenzyl)-1,2,4-thiadiazol-5-ylamino)spiro[3.3]heptan-2-ylcarbamate (5.999 g, 13.8 mmol, equivalent: 1.00) was combined with DCM (25 ml) to give an off-white suspension. TFA (7.86 g, 5.28 ml, 69.0 mmol, equivalent: 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 4 times to give an orange solid, which was dried at 40 °C under high vacuum to yield the title compound. ESI [M+H] + : 335.2 Synthesis of the example

[0787] According to the general protocol A, starting from intermediate 4* (e.g., IB 4-1, IB 4-2 or IB 4-3) Final compound having the formula B1A Final compound

[0788] i) Amine 4* was combined with aldehyde 5* (equivalent: 1.00) in DCM. The reaction mixture was stirred for 30 min. Sodium triacetoxyborohydride (equivalent: 1.5) was added. The reaction mixture was stirred at room temperature for 2 h. 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 and concentrated in vacuo, then separated after silica gel chromatography (using DCM / MeOH).

[0789] Or:

[0790] ii) Amine 4* was combined with aldehyde 5* (equivalent: 1.00) in EtOH, along with triethylamine (equivalent: 1.5) and acetic acid (equivalent: 2). The reaction mixture was stirred for 30 min. Sodium cyanoborohydride (equivalent: 1.2) was added. The reaction mixture was stirred at room temperature for 2 h. 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 and concentrated in vacuo, then separated by silica gel chromatography (using DCM / MeOH).

[0791] Or:

[0792] iii) To a solution of amine 4* (0.15 mmol) and triethylamine (5 equivalents) in DMF (1 mL) was added the appropriate halogenated electrophile 5*. The reaction was stirred at room temperature overnight and the resulting product was purified by preparative HPLC.

[0793] According to the general protocol B, starting from intermediate 7* (e.g., IB 7-1, IB 7-2) Final compound B1B

[0794] Combine amine 7* with aldehyde 8* (equivalent: 1.00) and TEA (equivalent: 2) in DCE. Stir the reaction mixture for 5 min. Add sodium triacetoxyborohydride (equivalent: 1.5). Stir the reaction mixture at RT for 1 h. Pour the reaction into DCM and extract with NaHCO3. Back-extract the aqueous layer with DCM, dry the organic layer over Na2SO4 and concentrate in vacuo, then separate by silica gel chromatography (using DCM / MeOH).

[0795] iv) When R in compound B1B 4b is hydrogen, a methyl group can be introduced at this position, for example, by combining compound B1B (where R 4b is hydrogen) with formaldehyde (equivalent: 1.5), TEA (equivalent: 1) and acetic acid (equivalent: 0.4) in DCE / MeOH: 4 / 1. Stir the reaction mixture for 5 min. Add sodium triacetoxyborohydride (equivalent: 2). Stir the reaction mixture at RT for 1 h. Pour the reaction into DCM and extract with NaHCO3. Back-extract the aqueous layer with DCM, dry the organic layer over Na2SO4 and concentrate in vacuo, then separate using silica gel chromatography (using heptane / ethyl acetate).

[0796] 2-(4-Fluorophenyl)-1-(6-(3-phenylpropyl)-2,6-diazaspiro[3.3]hept-2-yl)ethanone (CpdB001) Synthesis

[0797] Couple the synthetic building blocks described herein with an aldehyde according to general procedure i) for the preparation of B1A:

[0798] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0799] - Aldehyde: 3-phenylpropanal (commercially available)

[0800] ESI[M+H] + : 353.4

[0801] Synthesis of 1-(6-Benzyl-2,6-diazaspiro[3.3]hept-2-yl)-2-(4-fluorophenyl)ethanone (Cpd B002) Synthesis

[0802] Couple the synthetic building blocks described herein with an aldehyde according to general procedure i) for the preparation of B1A:

[0803] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0804] - Aldehyde: benzaldehyde (commercially available)

[0805] ESI[M+H] + : 325.2

[0806] Synthesis of 1-(6-Benzyl-2,6-diazaspiro[3.3]hept-2-yl)-2-(4-chlorophenyl)ethanone (of Cpd B003) Synthesis

[0807] Couple the synthetic building block described herein with an aldehyde according to general procedure i) for the preparation of B1A:

[0808] - Synthetic building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1)

[0809] - Aldehyde: benzaldehyde (commercially available)

[0810] ESI[M+H] + : 341.0

[0811] Synthesis of 1-(6-(4-Chlorobenzyl)-2,6-diazaspiro[3.3]hept-2-yl)-2-(4-chlorophenyl)ethanone (Cpd B004) Synthesis

[0812] Couple the synthetic building block described herein with an aldehyde according to general procedure i) for the preparation of B1A:

[0813] - Synthetic building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1)

[0814] - Aldehyde: 4-chlorobenzaldehyde (commercially available)

[0815] ESI[M+H] + : 375.0

[0816] 2-(4-Chlorophenyl)-1-(6-((2-methoxypyridin-4-yl)methyl)-2,6-diazaspiro[3.3]hept-2-yl) Ethanone (Cpd B005) Synthesis

[0817] Couple the synthetic building block described herein with an aldehyde according to general procedure i) for the preparation of B1A:

[0818] - Synthetic building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-1)

[0819] - Aldehyde: 2-methoxyisonicotinaldehyde (commercially available)

[0820] ESI[M+H] + : 372.0

[0821] Synthesis of 2-(4-Chlorophenyl)-1-(6-(2-methylbenzyl)-2,6-diazaspiro[3.3]hept-2-yl)ethanone (CpdB006) Synthesis

[0822] Couple the synthetic building block described herein with an aldehyde according to general procedure i) for the preparation of B1A:

[0823] - Synthetic building block: 2-(4-chlorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethanone (IB 4-1)

[0824] - Aldehyde: 2-methylbenzaldehyde (commercially available)

[0825] ESI[M+H]+: 355.1

[0826] Synthesis of 1-(6-Benzyl-2,6-diazaspiro[3.3]hept-2-yl)-2-(3,4-difluorophenyl)ethanone (Cpd B007) Of Synthesis

[0827] Couple the synthetic building block described herein with the aldehyde according to the general procedure ii) for preparing B1A:

[0828] - Synthetic building block: 2-(3,4-difluorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethanone (IB 4-3)

[0829] - Aldehyde: benzaldehyde (commercially available)

[0830] ESI[M+H] + : 343.2

[0831] Synthesis of 2-(4-Fluoro-phenyl)-1-[6-(3-methoxy-benzyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (Cpd B008) Synthesis

[0832] Couple the synthetic building block described herein with the halogenated electrophile according to the general procedure iii) for preparing B1A:

[0833] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethanone (IB 4-2)

[0834] - Halogenated electrophile: 1-(bromomethyl)-3-methoxybenzene (commercially available)

[0835] ESI[M+H] + : 355.3

[0836] Synthesis of 2-(4-Fluoro-phenyl)-1-[6-(4-methyl-benzyl)-2,6-diaza-spiro[3.3]hept-2-yl]-ethanone (CpdB009) Synthesis

[0837] Couple the synthetic building block described herein with the halogenated electrophile according to the general procedure iii) for preparing B1A:

[0838] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]hept-2-yl)ethanone (IB 4-2)

[0839] - Halogenated electrophile: 1-(bromomethyl)-4-methylbenzene (commercially available)

[0840] ESI[M+H] + : 339.3

[0841] Synthesis of 2-(4-Fluoro-phenyl)-1-(6-pyridin-2-ylmethyl-2,6-diaza-spiro[3.3]hept-2-yl)-ethanone (CpdB010) Synthesis

[0842] Couple the synthetic building blocks described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0843] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0844] - Halogenated electrophile: 2-(bromomethyl)pyridine (commercially available)

[0845] ESI[M+H] + : 326.3

[0846] Synthesis of 1-[6-(3-Chloro-benzyl)-2,6-diaza-spiro[3.3]hept-2-yl]-2-(4-fluoro-phenyl)-ethanone (CpdB011) Synthesis

[0847] Couple the synthetic building blocks described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0848] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0849] - Halogenated electrophile: 1-(bromomethyl)-3-chlorobenzene (commercially available)

[0850] ESI[M+H] + : 359.2

[0851] Synthesis of 3-{6-[2-(4-Fluoro-phenyl)-acetyl]-2,6-diaza-spiro[3.3]hept-2-ylmethyl}-benzamide (Cpd B012)

[0852] Couple the synthetic building blocks described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0853] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0854] - Halogenated electrophile: 3-(chloromethyl)benzamide (commercially available)

[0855] ESI[M+H] + : 368.2

[0856] Synthesis of 2-(4-Fluoro-phenyl)-1-[6-(2-trifluoromethoxy-benzyl)-2,6-diaza-spiro[3.3]hept-2-yl]-eth anone (Cpd B013) Synthesis

[0857] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0858] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0859] - Halogenated electrophile: 1-(bromomethyl)-2-(trifluoromethoxy)benzene (commercially available)

[0860] ESI[M+H] + : 409.2

[0861] Synthesis of methyl 4-{6-[2-(4-Fluoro-phenyl)-acetyl]-2,6-diaza-spiro[3.3]hept-2-ylmethyl}-benzoate Ester (Cpd B014) Synthesis

[0862] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0863] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0864] - Halogenated electrophile: Methyl 4-(bromomethyl)benzoate (commercially available)

[0865] ESI[M+H] + : 383.2

[0866] 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) Synthesis

[0867] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0868] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0869] - Halogenated electrophile: 1-(1-bromoethyl)-3-(trifluoromethyl)benzene (commercially available)

[0870] ESI[M+H]+: 407.4

[0871] 2-(4-Fluorophenyl)-1-[6-(1-phenylethyl)-2,6-diazaspiro[3.3]hept-2-yl]ethanone (CpdB016) Synthesis

[0872] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0873] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0874] - Halogenated electrophile: (1-bromoethyl)benzene (commercially available)

[0875] ESI[M+H] + : 339.1

[0876] 2-(4-Fluorophenyl)-1-[6-(6-methylpyridin-2-ylmethyl)-2,6-diazaspiro[3.3]hept-2-yl]- Ethanone (Cpd B017) Synthesis

[0877] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0878] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0879] - Halogenated electrophile: 2-(bromomethyl)-6-methylpyridine (commercially available)

[0880] ESI[M+H] + : 340.3

[0881] 1-[6-(2-Chlorobenzyl)-2,6-diazaspiro[3.3]hept-2-yl]-2-(4-fluorophenyl)ethanone (CpdB018) Synthesis

[0882] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0883] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0884] - Halogenated electrophile: 1-(bromomethyl)-2-chlorobenzene (commercially available)

[0885] ESI[M+H] + : 359.0

[0886] 2-(4-Fluorophenyl)-1-[6-(2-methylthiazol-4-ylmethyl)-2,6-diazaspiro[3.3]hept-2-yl]- Ethanone (Cpd B019) Synthesis

[0887] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0888] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0889] - Halogenated electrophile: 4-(chloromethyl)-2-methylthiazole hydrochloride (commercially available)

[0890] ESI[M+H] + : 346.0

[0891] 2-(4-Fluorophenyl)-1-[6-(1-methyl-1H-imidazol-2-ylmethyl)-2,6-diazaspiro[3.3]hept-2- yl]ethanone (Cpd B020) Synthesis

[0892] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0893] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0894] - Halogenated electrophile: 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride (commercially available)

[0895] ESI[M+H] + : 329.4

[0896] 2-(4-Fluorophenyl)-1-[6-(5-methylisoxazol-3-ylmethyl)-2,6-diazaspiro[3.3]hept-2- yl]ethanone (Cpd B021) Synthesis

[0897] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0898] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0899] - Halogenated electrophile: 3-(bromomethyl)-5-methylisoxazole (commercially available)

[0900] ESI[M+H] + : 330.0

[0901] 2-(4-Fluorophenyl)-1-(6-thiazol-4-ylmethyl-2,6-diazaspiro[3.3]hept-2-yl)ethanone (CpdB022) Synthesis

[0902] Couple the synthetic building blocks described herein with a halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0903] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0904] - Halogenated electrophile: 4-(chloromethyl)thiazole (commercially available)

[0905] ESI[M+H] + : 332.2

[0906] 2-(4-Fluorophenyl)-1-{6-[2-(3-trifluoromethylphenyl)ethyl]-2,6-diazaspiro[3.3]hept-2- yl}ethanone (Cpd B023) Synthesis

[0907] Couple the synthetic building block described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0908] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0909] - Halogenated electrophile: 1-(2-bromoethyl)-3-(trifluoromethyl)benzene (commercially available)

[0910] ESI[M+H] + : 407.4

[0911] 2-(4-Fluorophenyl)-1-{6-[2-(3-fluorophenyl)ethyl]-2,6-diazaspiro[3.3]hept-2-yl}eth anone (Cpd B024) Synthesis

[0912] Couple the synthetic building block described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0913] - Synthetic 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)

[0914] ESI[M+H] + : 357.2

[0915] 2-(4-Fluorophenyl)-1-{6-[2-(4-methoxyphenyl)ethyl]-2,6-diazaspiro[3.3]hept-2- yl}ethanone (Cpd B025) Synthesis

[0916] Couple the synthetic building block described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0917] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0918] - Halogenated electrophile: 1-(2-bromoethyl)-4-methoxybenzene (commercially available)

[0919] ESI[M+H] + : 369.2

[0920] 2-(4-Fluorophenyl)-1-[6-(2-p-tolylethyl)-2,6-diazaspiro[3.3]hept-2-yl]ethanone (Cpd B026) Synthesis

[0921] Couple the synthetic building block described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0922] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0923] Halogenated electrophile: 1-(2-bromoethyl)-4-methylbenzene (commercially available)

[0924] ESI[M+H] + : 353.3

[0925] 2-(4-Fluorophenyl)-1-{6-[2-(4-fluorophenyl)ethyl]-2,6-diazaspiro[3.3]hept-2-yl}eth anone (Cpd B027) Synthesis

[0926] Couple the synthetic building block described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0927] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0928] - Halogenated electrophile: 1-(2-bromoethyl)-4-fluorobenzene (commercially available)

[0929] ESI[M+H] + : 357.2

[0930] 2-(4-Fluorophenyl)-1-[6-(2-m-tolylethyl)-2,6-diazaspiro[3.3]hept-2-yl]ethanone (Cpd B028) Synthesis

[0931] Couple the synthetic building block described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0932] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (IB 4-2)

[0933] - Halogenated electrophile: 1-(2-bromoethyl)-3-methylbenzene (commercially available)

[0934] ESI[M+H] + : 353.3

[0935] 2-{6-[2-(4-Fluorophenyl)acetyl]-2,6-diazaspiro[3.3]hept-2-yl}-2-methyl-1-phenyl- propan-1-one (Cpd B029) Synthesis

[0936] Couple the synthetic building block described herein with the halogenated electrophile according to general procedure iii) for the preparation of B1A:

[0937] - Synthetic building block: 2-(4-fluorophenyl)-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan...

Claims

1. A compound having the formula (B1A), (B1B) or (B1C), or a salt, solvate, hydrate, polymorph, tautomer, racemate or stereoisomer thereof; or a prodrug thereof, wherein A 1a selected from the group consisting of: 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 heterocyclic group containing at least one N, O and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1a substituents, wherein each R 1a is independently selected from the group consisting of: 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, C 3-6 cycloalkyl, (R 5a )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two R 1a together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group; X 1a Selected from -CO-, -SO2-, -C(R 3a )2-, or a 5-membered heteroaryl; Y 1a Selected from -C(R 3a )2-, -NR 5a -, or -O-; or Y 1a is a single bond; Z 1a is a single bond or is selected from -C(R 3a )2-, -NR 5a -, or -O-; Each R 3a is independently selected from hydrogen, halo or C 1-6 alkyl; Each R 5a is independently selected from 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 is selected from -(C(R 4a )2) n - or -CO-; where n is an integer selected from 1 or 2; Each R 4a is independently selected from hydrogen, halo, or C 1-6 alkyl; or two Rs 4a together with the atom to which they are attached may form a C 3-6 cycloalkyl; A 2a selected from the group consisting of: C 6-10 aryl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, 5- to 10-membered saturated or partially saturated heterocyclic group, and C 3-6 cycloalkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2a substituents; wherein each R 2a is independently selected from the group consisting of: halogen, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; Provided that: A 1a Not: wherein R 1a1 and R 1a2 are each independently selected from C 1-2 alkyl, or R 1a1 and R 1a2 together with the carbon atom to which it is attached form C3-6 cycloalkyl, wherein R 1a has the same meaning as defined herein, and s is an integer selected from 0, 1 or 2; A 2a Not: wherein R 2a has the same meaning as defined herein, and s is an integer selected from 0, 1 or 2; Provided that the compound is not: 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-(toluenesulfonyl)-2,6-diazaspiro[3.3]heptane; (6-Benzyl-2,6-diazaspiro[3.3]hept-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]hept-2-yl)methanone; (6-(Cyclopropanecarbonyl)-2,6-diazaspiro[3.3]hept-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]hept-2-yl)methanone; (5-Isopropyl-1H-pyrazol-3-yl)(6-(thiophene-2-carbonyl)-2,6-diazaspiro[3.3]hept-2-yl)methanone; [2-(4-Fluoro-1-methyl-pyrazol-3-carbonyl)-2,6-diazaspiro[3.3]hept-6-yl]-(5-isopropyl-1H-pyrazol-3-yl)methanone; A 1b selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1b substituents, wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; R 3b selected from hydrogen or C 1-6 alkyl group; Y 1b Selected from -CO-, -C(R 5b )2-, or a 5-membered heteroaryl group; Z 1b is -C(R 5b )2-; R 4b selected from hydrogen, C 1-6 alkyl, or C 1-6 alkoxycarbonyl; Each R 5b is independently selected from hydrogen, halo or C 1-6 alkyl; Each R 6b is independently selected from hydrogen or C 1-6 alkyl; Y 2b is -C(R 5b )2- or a single bond; Z 2b is a single bond, or is selected from -(C(R 5b )2) m - or -CO-; where m is an integer selected from 1 or 2; A 2b selected from the group consisting of: C 6-10 aryl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, 5- to 10-membered saturated or partially saturated heterocyclic group, C 3-6 cycloalkyl, and C 1-6 alkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2b substituents, where each R 2b is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1c selected from the group consisting of: 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 heterocyclic group containing at least one N, O and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1c substituents, wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered saturated or partially saturated heterocyclic group; R 3c selected from hydrogen or C 1-6 alkyl; Y 1c is a single bond or is selected from -C(R 4c )2-, -NR 6c -, -O-, or a 5-membered heteroaryl group; Z 1c is a single bond or is selected from -C(R 4c )2- or -O-; Each R 4c is independently selected from hydrogen, halogenated or C 1-6 alkyl; Each R 6c is independently selected from 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- Z 2c is a single bond or is selected from -(C(R 5c )2) p - or -CO-; where p is an integer selected from 1 or 2; Each R 5c is independently selected from hydrogen, halo, or C 1-6 alkyl; or two Rs 5c together with the atom to which they are attached may form C 3-6 cycloalkyl; A 2c selected from the group consisting of: C 6-10 aryl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S, C 3-6 cycloalkyl, and -N(R 6c )2; wherein each in the group may be unsubstituted or substituted by one or more R 2c ; wherein each R 2c is independently selected from the group consisting of: 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group, Provided that: A 1c No A 2c No Provided that the compound is not: N-Benzyl-2-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-amine; N-(2-(2-Fluorophenyl)-2-azaspiro[3.3]hept-6-yl)-6,7-dimethoxy-2,3-dihydro-1H-cyclopenta[b]quinolin-9-amine; 6-((2-((Benzyloxy)carbonyl)-2-azaspiro[3.3]hept-6-yl)amino)-2-chloropyrimidine-4-carboxylic acid; 6-((2-Chloro-6-(methoxycarbonyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylic acid benzyl ester.

2. The compound according to claim 1, wherein A 1a selected from the group consisting of: C 6-10 aryl, C 4-6 cycloalkyl, 5- to 9-membered heteroaryl containing at least one N, O, and / or S, and 5- to 9-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1a substituents, wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; X 1a Selected from -CO-, -SO2-, -C(R 3a )2-, or a 5-membered heteroaryl group; Y 1a is a single bond or is selected from -C(R 3a )2-, -NR 5a -, or -O-; Z 1a is a single bond or is selected from -C(R 3a )2-, -NR 5a -, or -O-; Each R 3a is independently selected from hydrogen, halogenated or C 1-6 alkyl; Each R 5a is independently selected from 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- Z 2a is a single bond or is selected from –(C(R 4a )2) n – or –CO–; where n is an integer selected from 1 or 2; Each R 4a is independently selected from hydrogen, halo, or C 1-6 alkyl; or two Rs 4a together with the atom to which they are attached can form a C 3-6 cycloalkyl; A 2a selected from the group consisting of: C 6-10 aryl, 5- to 9-membered heteroaryl containing at least one N, O, and / or S, and C 3-6 cycloalkyl; wherein each in said group may be unsubstituted or substituted by one or more R 2a ; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1b selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1b substituents, wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; R 3b selected from hydrogen or C 1-6 alkyl; Y 1b Selected from -CO-, -C(R 5b )2-, or a 5-membered heteroaryl group; Z 1b is -C(R 5b )2-; R 4b selected from hydrogen, C 1-6 alkyl, or C 1-6 alkoxycarbonyl; Each R 5b is independently selected from hydrogen, halo, or C 1-6 alkyl; Each R 6b is independently selected from hydrogen or C 1-6 alkyl; Y 2b is -C(R 5b )2- or a single bond; Z 2b is a single bond or is selected from –(C(R 5b )2) m – or –CO–; where m is an integer selected from 1 or 2; A 2b selected from the group consisting of: C 6-10 aryl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, 5- to 10-membered saturated or partially saturated heterocyclic group, C 3-6 cycloalkyl, and C 1-6 alkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2b substituents, where each R 2b is independently selected from the group consisting of: 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1c selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, and 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1c substituents, wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; R 3c selected from hydrogen or C 1-6 alkyl; Y 1c is a single bond, or is selected from -C(R 4c )2-, -NR 6c -, -O-, or a 5-membered heteroaryl group; Z 1c is a single bond or selected from -C(R 4c )2- or -O-; Each R 4c is independently selected from hydrogen, halo or C 1-6 alkyl; Each R 6c is independently selected from 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- Z 2c is a single bond or is selected from –(C(R 5c )2) p – or –CO–; where p is an integer selected from 1 or 2; Each R 5c is independently selected from hydrogen, halogenated or C 1-6 alkyl; or two Rs 5c together with the atom to which they are attached can form C 3-6 cycloalkyl; A 2c Selected from the group consisting of: C 6-10 aryl, 5- to 10-membered heteroaryl containing at least one N, O, and / or S, 5- to 10-membered saturated or partially saturated heterocyclic group containing at least one N, O, and / or S, C 3-6 cycloalkyl, and -N(R 6c )2; wherein each in said group may be unsubstituted or substituted by one or more R 2c ; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, 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, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

3. The compound according to any one of claims 1-2, wherein A 1a selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; each in the group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, 3, or 4 R 1a , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; X 1a Selected from -CO-, -SO2-, -C(R 3a )2-, or 1,2,4-thiadiazolyl; preferably X 1a Selected from -CO-, -SO2-, or -C(R 3a )2-; Y 1a is a single bond or is selected from -C(R 3a )2-, -NR 5a -, or -O-; Z 1a is a single bond or is selected from -C(R 3a )2-, -NR 5a -, or -O-; Each R 3a is hydrogen, halogenated or C 1-4 alkyl; Each R 5a is hydrogen or a C 1-4 alkyl group; X 2a is a single bond or -CO-; Y 2a is a single bond or -C(R 4a )2- Z 2a is a single bond or is selected from –(C(R 4a )2) n – or –CO–; where n is an integer selected from 1 or 2; Each R 4a is independently selected from hydrogen, halo, or C 1-4 alkyl; or two Rs 4a together with the atom to which they are attached may form a C 3-5 cycloalkyl; A 2a selected from the group consisting of: C 6-10 aryl, 5- or 6-membered heteroaryl containing at least one N, O and / or S, and C 4-6 cycloalkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, 3 or 4 R 2a ; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1b selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2, 3, or 4 R 1b , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; Each R 3b is hydrogen or C 1-4 alkyl; Y 1b Selected from -CO-, -C(R 5b )2-, or 1,2,4-thiadiazolyl; Z 1b is -C(R 5b )2-; R 4b selected from hydrogen, C 1-4 alkyl, or C 1-4 alkoxycarbonyl; Each R 5b is independently selected from hydrogen, halo or C 1-4 alkyl; Each R 6b is independently selected from hydrogen or C 1-4 alkyl; Y 2b is -C(R 5b )2- or a single bond; Z 2b is a single bond, or is selected from –(C(R 5b )2) m – or –CO–; where m is an integer selected from 1 or 2; A 2b selected from the group consisting of: C 6-10 aryl, 5- to 9-membered heteroaryl containing at least one N, O, and / or S, C 3-6 cycloalkyl, and C 1-4 alkyl; wherein each in said group may be unsubstituted or substituted by one or more R 2b , for example 1, 2, 3, or 4 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1c selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, 3, or 4 R 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; Each R 3c is hydrogen or C 1-4 alkyl; Y 1c is a single bond, or is selected from -C(R 4c )2-, -NR 6c -, -O-, or 1,2,4-thiadiazolyl; Z 1c is a single bond, or is selected from -C(R 4c )2- or -O-; Each R 4c is hydrogen, halogenated or C 1-4 alkyl; Each R 6c is hydrogen or C 1-4 alkyl; X 2c is a single bond or -CO-; Y 2c is a single bond or -C(R 5c )2- Z 2c is a single bond or is selected from –(C(R 5c )2) p – or –CO–; where p is an integer selected from 1 or 2; Each R 5c is independently selected from hydrogen, halogenated or C 1-4 alkyl; or two Rs 5c together with the atom to which they are attached can form a C 3-5 cycloalkyl; A 2c selected from the group consisting of: C 6-10 aryl, 5- to 9-membered heteroaryl containing at least one N, O, and / or S, and C 3-6 cycloalkyl; wherein each in said group may be unsubstituted or substituted by one or more R 2c , for example 1, 2, 3, or 4 R 2c ; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

4. The compound according to any one of claims 1-3, wherein A 1a selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; each in the group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, 3, or 4 R 1a , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; A 2a selected from the group consisting of: C 6-10 aryl, 5- or 6-membered heteroaryl containing at least one N, O and / or S, and C 4-6 cycloalkyl; wherein each in said group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, 3 or 4 R 2a ; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1b selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2, 3, or 4 R 1b , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; A 2b selected from the group consisting of: C 6-10 aryl, 5- to 9-membered heteroaryl containing at least one N, O, and / or S, C 3-6 cycloalkyl, and C 1-4 alkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2b , for example 1, 2, 3, or 4 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1c selected from the group consisting of: C 6-10 aryl, C 3-6 cycloalkyl, a 5-9 membered heteroaryl containing at least one N, O and / or S, and a 5-9 membered saturated or partially saturated heterocyclic group containing at least one N, O and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, 3, or 4 R 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form a C 6-10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered saturated or partially saturated heterocyclic group; A 2c selected from the group consisting of: C 6-10 aryl, 5- to 9-membered heteroaryl containing at least one N, O, and / or S, and C 3-6 cycloalkyl; wherein each in said group may be unsubstituted or substituted by one or more R 2c , for example 1, 2, 3, or 4 R 2c ; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

5. The compound according to any one of claims 1-4, which has the structural formula (B1A1), (B1A2), (B1A3), (B1A4), (B1A5), (B1A6), (B1B1), (B1B2), where A 1a 、Y 1a 、Z 1a 、R 2a 、R 3a 、R 4a 、Y 2a 、Z 2a 、A 2a 、A 1b 、Y 1b 、Z 1b 、R 2b 、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 have the same meanings as defined in any one of claims 1-4, 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.

6. The compound according to any one of claims 1-5, wherein A 1a selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S; each in the group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two R 1a together with the atom to which it is attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; A 2a selected from the group consisting of: C 6-10 aryl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, or 3 R 2a ; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1b selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2, or 3 R 1b , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two R 1b together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; A 2b selected from the group consisting of: C 6-10 aryl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 cycloalkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2b , for example 1, 2, or 3 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1c selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, or 3 R 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, and C 3-6 cycloalkyl; and / or two R 1c together with the atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 2c selected from the group consisting of: C 6-10 aryl, 5- or 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 cycloalkyl; wherein each in said group may be unsubstituted or substituted by one or more R 2c , for example 1, 2, or 3 R 2c ; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 6c )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two R 2c together with the atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

7. A compound according to any one of claims 1-6, the compound having structural formulas (B1A8), (B1A9), (B1A10), (B1A11), (B1A12), (B1A13), Wherein A 1a , Y 1a , Z 1a , and A 2a have the same meanings as defined in any one of claims 1-6.

8. A compound according to any one of claims 1-7, the compound having structural formulas (B1A14), (B1A15), (B1A16), (B1A17), (B1A18), (B1A19), (B1A20), (B1A21), (B1A22), (B1A23), (B1A24), Where A 1a and A 2a have the same meaning as defined in any one of claims 1-6.

9. A compound according to any one of claims 1-8, wherein A 1a selected from the group consisting of: C 6-10 aryl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S; each in the group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, and C 3-6 cycloalkyl; and / or two R 1a together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; A 2a selected from the group consisting of: C 6-10 aryl, 5- or 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, or 3 R 2a ; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1b selected from the group consisting of: C 6-10 aryl, C 4-6 cycloalkyl, 5-6 membered heteroaryl containing at least one N, O and / or S, and 5-6 membered saturated or partially saturated heterocyclic group containing at least one N, O and / or S; each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2 or 3 R 1b , wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1b together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5-9 membered heteroaryl, or 5-9 membered saturated or partially saturated heterocyclic group; A 2b selected from the group consisting of: C 6-10 aryl, 5- or 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 cycloalkyl; wherein each in said group may be unsubstituted or substituted by one or more R 2b , for example 1, 2, or 3 R 2b , wherein each R 2b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1c selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, or 3 R 1c , wherein each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxyl, and C 3-6 cycloalkyl; and / or two R 1c together with the atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 2c selected from the group consisting of: C 6-10 aryl, 5- or 6-membered heteroaryl containing at least one N, O, and / or S, and C 4-6 cycloalkyl; wherein each in said group may be unsubstituted or substituted by one or more R 2c , for example 1, 2, or 3 R 2c ; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 6c )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two R 2c together with the atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

10. A compound according to any one of claims 1-9, wherein A 1a selected from the group consisting of: phenyl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N; each in the group may be unsubstituted or substituted by one or more R 1a , for example 1, 2, or 3 R 1a , wherein each R 1a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1a together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; A 2a selected from the group consisting of: phenyl, 5- or 6-membered heteroaryl containing at least one N, O and / or S, and C 5-6 cycloalkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2a , for example 1, 2, or 3 R 2a ; wherein each R 2a is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1b selected from the group consisting of: phenyl, C 5-6 cycloalkyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S; each in the group may be unsubstituted or substituted by one or more R 1b , for example 1, 2, or 3 R 1b , wherein each R 1b is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, and hydroxy; and / or two R 1b together with the atom to which they are attached may form C 6-10 aryl, C 3-6 cycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered saturated or partially saturated heterocyclic group; A 2b selected from the group consisting of phenyl, 5- to 6-membered heteroaryl containing at least one N, O, and / or S, and C 5-6 cycloalkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2b , for example 1, 2, or 3 R 2b , wherein each R 2b is independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, 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 atom to which they are attached may form a C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 1c selected from the group consisting of: 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 heterocyclic group containing at least one N, O, and / or S; wherein each in the group may be unsubstituted or substituted by one or more R 1c , for example 1, 2, or 3 R 1c substituents, where each R 1c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, and C 3-6 cycloalkyl; and / or two R 1c together with the atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group; A 2c selected from the group consisting of: phenyl, 5- or 6-membered heteroaryl containing at least one N, O and / or S, and C 4-6 cycloalkyl; wherein each in the group may be unsubstituted or substituted by one or more R 2c , for example 1, 2, or 3 R 2c ; wherein each R 2c is independently selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, cyano, hydroxy, carboxy, C 1-6 alkoxycarbonyl, (R 6c )2N-carbonyl, and C 1-6 alkylcarbonylamino; and / or two R 2c together with the atom to which they are attached may form C 6-10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered saturated or partially saturated heterocyclic group.

11. A compound according to any one of claims 1-10, the compound having 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), wherein R 1a , Y 1a , Z 1a , X 2a , X 1a , Y 2a , Z 2a and A 2a have the same meanings as defined in any one of claims 1 - 10, 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, D 1a is selected from CH2, O or NH, and E 1a is selected from CH, N, O or S.

12. A compound according to any one of claims 1-11, the compound having structural formulas (B1A77), (B1A78), wherein R 1a and A 2a have the same meanings as defined in any one of claims 1-10, and ma is an integer selected from 1, 2, 3 or 4.

13. A compound according to any one of claims 1-12, the compound having structural formulas (B1A79), (B1A80), wherein R 1a , R 2a and A 2a have the same meanings as defined in any one of claims 1-10, 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.

14. A compound according to any one of claims 1-13, wherein the compound is selected from the group consisting of the compounds listed in Table 1B.

15. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and at least one pharmaceutically acceptable carrier.

16. A compound according to any one of claims 1-14 or a pharmaceutical composition according to claim 15 for use as a medicament.

17. The compound according to any one of claims 1-14 or the pharmaceutical composition according to claim 15 for use in the prevention and / or treatment of neurodegenerative disorders.

18. The compound according to any one of claims 1-14 or the pharmaceutical composition according to claim 15 for preventing and / or treating 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, Hallervorden-Spatz disease, 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, preferably the neurodegenerative disorder is Alzheimer's disease.

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