CN118591375A - Compounds as HDAC6 inhibitors and their uses - Google Patents

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, wherein Y ¹ is a 9- or 10-membered bicyclic heteroaryl, Y ² is a 5-membered heteroaryl, Z ¹ is selected from (C=O)-R ⁹ , S(O)-R ⁹ and S(O ₂ )-R ⁹ , L is a linker based on alkyl-, cycloalkyl- or heterocycloalkyl-, and R ¹ and R ⁹ can be a variety of groups. The present invention also relates to a compound of formula (I) as an HDAC6 inhibitor, which is generally used to treat and/or prevent HDAC6-related diseases, such as cancer, neurodegenerative diseases, neuropathy or cardiovascular disease.

Description

Compounds as HDAC6 inhibitors and their uses

Field of the Invention

The present invention relates to compounds useful as histone deacetylase isoform 6 (HDAC6) inhibitors. In particular, the present invention relates to compounds useful for treating and/or preventing proliferative diseases such as cancer, neurodegenerative diseases, neurological diseases or cardiovascular diseases.

Background of the Invention

Inhibition of HDAC enzymes, particularly HDAC6 enzymes, plays a key role in human gene expression. Therefore, the development of effective HDAC inhibitors has the most important clinical importance in serious medical conditions (including major and rare diseases) (Seidel C et al.: "Histone deacetylase 6 in health and disease." Epigenomics. 2015, Vol. 7, No. 1, pp. 103-18). It is expected that HDAC6 inhibitors can be used for example in oncology, neurology, neuropsychiatry, neurodegeneration, inflammation (such as neuroinflammation), nephropathy, neuropathy and pain. The meaningful example of HDAC6 inhibitors with potential medical applications in the treatment of proliferative diseases is hydroxamic acid drugs (hydroxamic acid and its salt), which include vorinostat (or "SAHA", trade name ), trichostatin A (TSA), belinostat (trade name ), Panobinostat Romidepsin

However, many HDAC6 inhibitors identified so far are not highly selective, so that they may cause significant side effects. Poor pharmacokinetics and low bioavailability also limit the efficacy of some HDAC6 inhibitors. Therefore, most HDAC6 inhibitors have poor developability characteristics, even for life-threatening applications in oncology. For example, high doses of non-selective HDAC inhibitors cause fatigue and nausea. Side effects may be caused in particular by the inhibition of class I HDAC. In addition, mutagenicity issues related to the function of hydroxamates in approved HDAC inhibitors have been reported (Shen S. and Kozikowski A.P. ChemMedChem 2016, No.11, pp.15-21).

Therefore, there is an urgent need to develop highly selective HDAC6 inhibitors to overcome the limitations of some prior art HDCA6 inhibitors (e.g., hydroxamic acid-based HDCA6 inhibitors). Isoform-selective inhibitors are potentially advantageous over pan-HDACs in terms of therapeutic efficacy and toxicity. In particular, selective inhibition of cytoplasmic HDAC6 can avoid toxicity caused by inhibition of other HDACs.

The applicant surprisingly found that the compounds of formula (I) described herein are highly selective HDAC6 inhibitors. The use of these compounds can also show significant improvements in bioavailability, side effects, pharmacokinetics and/or water solubility relative to prior art drugs such as hydroxamates.

Overview

The present invention relates to compounds for treating and/or preventing HDAC6-related diseases; wherein the compounds are compounds of formula (I)

or a pharmaceutically acceptable salt and/or solvate thereof; wherein Y ¹ , Y ² , L, R ¹ and Z ¹ are as described in the claims or detailed description.

The present invention also relates to a pharmaceutical composition for treating and/or preventing HDAC6-related diseases, wherein the pharmaceutical composition comprises a compound of the present invention and at least one pharmaceutically acceptable carrier.

According to one embodiment, HDAC6-related diseases are selected from inflammatory diseases, autoimmune diseases, proliferative diseases such as cancer, neurodegenerative diseases, pain, neuropathies, mental illnesses, neurodevelopmental disorders, sleep disorders and cardiovascular diseases. In one embodiment, HDAC6-related diseases are cancers selected from malignant melanoma, multiple myeloma, leukemia, lymphoma, breast cancer and Hodgkin's disease. In one embodiment, HDAC6-related diseases are neurodegenerative diseases selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Pick's disease, Nieto-Pitt syndrome, Down's disease, Lewy body dementia, HIV dementia, amyotrophic lateral sclerosis (ALS) and multiple sclerosis. In one embodiment, HDAC6-related diseases are neuropathy selected from Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy, familial amyloid polyneuropathy, chemotherapy-induced peripheral neuropathy (CIPN) using chemotherapeutic anticancer agents, diabetic peripheral neuropathy (DPN), neuralgia, pain and/or neuropathic pain. In one embodiment, HDAC6-related diseases are cardiovascular diseases selected from heart failure, cardiomyopathy and/or myocarditis.

According to one embodiment, the compound is selected from the compounds listed in Table 2 herein and pharmaceutically acceptable salts and/or solvates thereof.

The present invention also relates to compounds of formula (I)

or a pharmaceutically acceptable salt and/or solvate thereof; wherein Y ¹ , Y ² , L, R ¹ and Z ¹ are as described in the claims or detailed description.

According to one embodiment, the compound is selected from the compounds listed in Table 1 herein and pharmaceutically acceptable salts and/or solvates thereof.

The present invention also relates to a process for preparing the compounds of the present invention, wherein the process comprises the steps of: (i) reacting a linear or cyclic amine with an acid chloride, a carboxylic acid or a sulfonyl chloride; or (ii) reacting a halo-ketone with a thiol.

The present invention also relates to pharmaceutical compositions comprising a compound of the present invention and at least one pharmaceutically acceptable carrier.

The present invention also relates to a compound of the present invention or a pharmaceutical composition of the present invention for use as a medicament. According to one embodiment, the compound or pharmaceutical composition is used to treat and/or prevent HDAC6-related diseases. In one embodiment, HDAC6-related diseases are selected from inflammatory diseases, autoimmune diseases, proliferative diseases such as cancer, neurodegenerative diseases, pain, neuropathy, mental illness, neurodevelopmental disorders, sleep disorders and cardiovascular diseases.

definition

In the present invention, unless otherwise specified, the following terms have the following meanings.

Chemical Definition

When referring to a combination of groups, such as "alkylene-heteroaryl", the point of attachment to the main structure is on the group referenced to the left. Thus, the term "alkylene-cyclic group" and variations thereof (such as "alkylene-heteroaryl", "alkylene-heterocycle", "alkylene-cycloalkyl", "alkylene-aryl", "alkylene-heteroaryl", "alkylene-heterocycle", and "alkylene-cycloalkyl") refer to a cyclic group that is attached to the main structure via the alkyl portion. In other words, the point of attachment is the alkylene group, not the cyclic group.

"Alkenyl" or "alkenyl" refers to a straight or branched hydrocarbon chain containing at least one double bond and generally 2 to 12 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of alkenyl include ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, and 2,4-pentadienyl.

"Alkyl" refers to a saturated straight or branched hydrocarbon chain, typically containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms. In the present invention, an alkyl group can be monovalent or polyvalent (i.e., "alkylene" as defined herein is included in the definition of "alkyl"), but an alkyl group is typically monovalent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl and isomers thereof (e.g., n-pentyl, isopentyl) and hexyl and isomers thereof (e.g., n-hexyl, isohexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.

"Alkylene" refers to a divalent alkyl group. Non-limiting examples of alkylene groups include methylene, ethylene, n-propylene, isopropylene, divalent butyl, divalent pentyl, and divalent hexyl. Preferred alkylene groups include methylene, ethylene, n-propylene, n-butylene, and n-butylene.

"Alkyne" or "alkynyl" refers to a straight or branched hydrocarbon chain containing at least one triple bond and typically 2 to 12 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of alkynyl include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and isomers thereof, and 2-hexynyl and isomers thereof.

"Amine" refers to a derivative of ammonia ( _NH3 ) in which one or more hydrogen atoms are replaced with a substituent such as an alkyl or aryl group.

"Amino" refers to a _-NH2 group.

"Aryl" refers to a cyclic polyunsaturated aromatic hydrocarbon group containing at least one aromatic ring. Aryl can have a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or covalently linked. Typically, aryl has 5-12 carbon atoms, preferably 6-10 carbon atoms. The aromatic ring may optionally contain one to two additional rings (cycloalkyl, heterocycloalkyl, or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic ring systems listed herein, as long as at least one ring is aromatic. Non-limiting examples of aryl include phenyl, biphenyl, biphenylene, 5- or 6-tetrahydronaphthyl, naphthalene-1- or -2-yl, 4-, 5-, 6- or 7-indenyl, 1-, 2-, 3-, 4- or 5-acenaphthenyl, 3-, 4- or 5-dihydroacenaphthenyl, 1- or 2-cyclopentadienyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or 5-pyrenyl. Preferred aryl is phenyl.

"Bicyclic", when referring to a cyclic group, means that the cyclic group consists of exactly two fused rings. In a monovalent bicyclic group, the notation "[x,y]" (wherein x and y are integers) is used herein to indicate that one ring is x-membered and the other ring is y-membered, and the point of attachment to the main structure is on the x-membered ring. "Tricyclic" and the like should be interpreted accordingly.

"Cyano" refers to a -CN group.

"Cyclic groups" are collectively defined as "cycloalkyl", "heterocycloalkyl", "aryl" and "heteroaryl" as defined herein.

"Cycloalkyl" refers to a cyclic monovalent alkyl group, typically containing 3 to 11 carbon atoms, preferably 4 to 9 carbon atoms, more preferably 5 to 7 carbon atoms. This definition encompasses multicyclic cycloalkyl (eg, bicyclic) and bridged cycloalkyl structures.

"(C _x -C _y )" preceding a radical name means that the radical contains xy carbon atoms according to common terminology in the chemical art.

"Difluoromethyl" refers to a _-CHF2 radical.

"Halide," "halo," or "halogen" refers to a fluorine, chlorine, bromine, or iodine atom, typically a chlorine or bromine atom.

"Heteroalkyl" refers to an alkyl as defined above, wherein one or more carbon atoms are substituted by heteroatoms selected from oxygen, nitrogen and sulfur. In heteroalkyl, heteroatoms are only combined with carbon atoms along the alkyl chain, i.e., each heteroatom is separated from any other heteroatom by at least one carbon atom. Nitrogen and sulfur heteroatoms can be optionally oxidized, and nitrogen heteroatoms can be optionally quaternized. Heteroalkyl may further include one or more oxo (=O) groups. Heteroalkyl is only combined with another group or molecule by carbon atoms, i.e., the combined atom is not selected from the heteroatoms included in the heteroalkyl. When substituted by one or more other groups, heteroalkyl can be substituted by carbon atoms or by heteroatoms (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heteroalkyl include alkoxy, ethers and polyethers, secondary amines, tertiary amines and thioethers.

"Heteroaryl" refers to an aromatic ring or aromatic ring system containing 5-12 carbon atoms, preferably 6-10 carbon atoms, having one or two rings fused together or covalently linked, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings are replaced by oxygen, nitrogen and/or sulfur atoms. "Heteroaryl" may also be considered as "aryl" as defined herein, wherein at least one carbon atom in the aryl is replaced by a heteroatom, and wherein the resulting molecule is chemically stable. Nitrogen and sulfur heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be quaternized. Non-limiting examples of heteroaryl groups include furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thienyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazo[1,5-a]pyridyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, benzimidazolyl, 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, 1,2,3-Benzothiadiazolyl, 2,1,3-Benzothiadiazolyl, Thienopyridinyl , purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1-(6H)-yl, 2-oxopyridin-1-(2H)-yl, 6-oxo-pyridazin-1-(6H)-yl, 2-oxopyridin-1-(2H)-yl, 1,3-benzodioxolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl and phthalazinyl.

"Heterocycloalkyl" refers to a cyclic monovalent heteroalkyl group, typically containing 2-7 carbon atoms, preferably 3-6 carbon atoms, more preferably 4-5 carbon atoms. This definition covers polycyclic heterocycloalkyl (e.g., bicyclic) and bridged heterocycloalkyl structures, including rings that are bound together by one atom ("spiro") or by two atoms. In one embodiment, heterocycloalkyl is bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected from the heteroatom included therein. In one embodiment, heterocycloalkyl is bound to another group or molecule through one of the heteroatoms included therein. When substituted by one or more other groups, heterocycloalkyl may be substituted by a carbon atom or by a heteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heterocycloalkyl groups include aziridine, pyrrolidine, piperidine, piperazine (also known as "hexahydropyrazine"), morpholine, thiomorpholine, azepane, azacyclooctane, octahydro-1H-isoindole, decahydroisoquinoline, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline (e.g., 1,2,3,4-tetrahydroisoquinoline), hexahydropyridazine, hexahydropyrimidine, decahydroquinoline, octahydropyrrolo[3,4-c]pyrrole, isoindoline, 1,2,3,4-tetrahydroquinoline, and oxetane.

"Hydroxy" refers to an -OH group.

"Keto" refers to a functional group having a linkage C-(C=O)-C.

"Oxo" refers to a =0 group, ie, an oxygen atom double-bonded, usually to a carbon atom.

"Trifluoromethyl" refers to a _-CF3 group.

General Definition

"About" is used herein to mean approximately, roughly, approximately, or within the range of. The term "about" before a number means plus or less than 10% of the numerical value. When the term "about" is used in conjunction with a numerical range, it modifies the range by expanding the boundaries above and below the numerical values by 10%.

"Administering" or variations thereof (eg, "administering") means providing a therapeutic agent (eg, a compound of the invention), alone or as part of a pharmaceutically acceptable composition, to a patient for the condition, symptom, or disease to be treated and/or prevented.

"Binding site" or "binding pocket" refers to a specific arrangement of amino acids on a protein (e.g., HDAC6) to which a compound (e.g., a compound of the invention) binds. Binding sites are typically composed of chemically active surface cliques of amino acids and have specific 3-D structural characteristics as well as specific charge characteristics. Similar to epitopes, binding sites can be linear or conformational, i.e., they can involve amino acid sequences that are not necessarily continuous in the primary structure of a protein.

"Comprising" or its variations (e.g., "including", "containing") are used herein in accordance with common patent application drafting terminology. Thus, "comprising" preceding an object and following a constituent element means that the constituent element (usually as a component of a composition) is required to be present in the object, but does not exclude the presence of any other constituent element in the object. In addition, any occurrence of "comprising" or its variations herein also encompasses the narrower expression "consisting essentially of" or "consisting mainly of", the further narrower expression "consisting of" and any variations thereof (e.g., "consisting of", "consisting of").

"HDAC" or "histone deacetylase" refers to a class of enzymes that can remove acetyl groups (O=C-CH ₃ ) from ε-N-acetyllysine amino acids on histones, allowing the histones to more tightly pack DNA and condense chromatin. Gene expression is regulated by histone acetylation and deacetylation, and therefore by HDAC activity. In the present invention, HDAC is generally "HDAC6" as defined herein.

"HDAC-related diseases" or "diseases associated with HDAC6 function" or variations thereof (e.g., "HDAC6-related diseases") refer to abnormal acetylation distribution of HDAC substrates (e.g., histones, tubulin, Hsp90, cortical actin) due to dysregulated activity, particularly increased activity, of at least one HDAC enzyme in an individual, or diseases caused by or characterized by it. In the present application, "HDAC-related diseases" and "diseases associated with HDAC6 function" are synonyms and can be used interchangeably. Typically, HDAC-related diseases are particularly associated with epigenetic regulation of changes in gene expression and/or cell motility. This definition encompasses diseases in which normal HDAC activity is reduced (inhibited) for treatment and/or prevention of disease. Typically, HDAC-related diseases can be prevented and/or treated by HDAC inhibition. Non-limiting examples of HDAC-related diseases include neuropathy, neurodegenerative diseases, proliferative diseases (e.g., cancer), metabolic disorders, immune disorders, and inflammatory diseases.

“HDAC6,” “HDAC6 enzyme,” or “histone deacetylase isoform 6” refers to the HDAC enzyme encoded by the human HDAC6 gene.

The "HDAC6 gene" refers to a gene encoding human HDAC6. The HDAC6 gene may also be referred to as KIAA0901 or JM21.

“Human” means any male or female individual at any stage of development, including newborns, infants, adolescents, teenagers, and adults.

"Patient" refers to an animal, typically a warm-blooded animal, preferably a mammal (e.g., mouse, rat, cat, guinea pig, dog, monkey or human), more preferably a human, who is awaiting or receiving medical care, or is/will be the subject of a medical procedure. A patient may also be an individual who is undergoing preventive care or a procedure.

"Pharmaceutically acceptable" means that the ingredients of the composition are compatible with each other and not deleterious to the patient to which it is administered.

"Pharmaceutically acceptable carrier" refers to an excipient that does not produce adverse, allergic or other untoward reactions when administered to animals, preferably humans. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. For human administration, the formulation should meet sterility, pyrogenicity, general safety and purity standards required by regulatory agencies (e.g., FDA or EMA).

"Prevent," "prevent," and "suppress" refer to delaying or preventing the onset of a condition and/or disease and/or any of its attendant symptoms, preventing a patient from acquiring a condition or disease, or reducing the risk of a patient acquiring a condition and/or disease and/or any of its attendant symptoms. The effect resulting from "preventing" a condition and/or disease is called "prophylactic."

"Prodrug" refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound of the invention), the biotransformation product of which is a therapeutic agent (active drug) in vivo. Prodrugs are generally characterized by increased bioavailability and are easily metabolized to active compounds in vivo. Non-limiting examples of prodrugs include amide prodrugs and carboxylate prodrugs, particularly alkyl esters, cycloalkyl esters, and aryl esters.

"Selected from" is used herein according to the common patent application drafting terminology to introduce a list of elements in which items are selected. Any appearance of "selected from" in this specification can be replaced with "selected from a group consisting of..." and can be replaced with each other without changing its meaning.

"Solvate" refers to a molecular complex comprising a compound and one or more molecules of one or more solvents in stoichiometric or substoichiometric amounts, typically a pharmaceutically acceptable solvent such as ethanol. The term "hydrate" refers to a solvate when the solvent is water ( _H2O ).

"Therapeutic agent," "active pharmaceutical ingredient," and "active ingredient" refer to compounds that are used for therapeutic purposes and are related to health. In particular, a therapeutic agent (e.g., a compound of the present invention) may be indicated for use in treating and/or preventing a disease, preferably an infectious disease. An active ingredient may also be indicated for use in improving the therapeutic activity of another therapeutic agent.

"Therapeutically effective amount" (abbreviated "effective amount") refers to the amount of a therapeutic agent (eg, a compound of the present invention) sufficient to achieve the desired therapeutic or preventive effect in the patient to whom it is administered.

"Treat" means to alleviate, reduce or eliminate a condition and/or disease and/or any of its attendant symptoms, such as an infectious disease.

Detailed Description

Compound

The present invention relates to compounds of formula (I)

wherein Y ¹ , Y ² , L, R ¹ and Z ¹ are as defined below in the detailed description.

In the compounds of formula (I) as described below in the detailed description, unless otherwise indicated, any alkyl (including alkylene) group may be "optionally substituted", i.e., each hydrogen atom bonded to a carbon atom in the alkyl moiety may be optionally replaced by at least one low molecular weight substituent, for example a substituent selected from halogen, cyano, hydroxy, oxo, amino, -O-(C ₁ -C ₆ )alkyl, -NH-(C ₁ -C ₆ )alkyl and -N-((C ₁ -C ₆ )alkyl) _2. Only substitutions where the resulting molecule is chemically stable are encompassed by this definition. Typically, the (C ₁ -C ₆ )alkyl group present in the substituent group is not itself further substituted. Preferred substituted alkyl groups include alkyl groups substituted by one or more fluorine atoms and/or hydroxy groups, for example trifluoromethyl.

In the compounds of formula (I) as described below in the detailed description, unless otherwise indicated, any cyclic group (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl) may be "optionally substituted", i.e., each hydrogen atom bonded to a carbon atom in the cyclic moiety may be optionally replaced by at least one low molecular weight substituent, for example a group selected from halogen, cyano, hydroxy, oxo, amino, -(C ₁ -C ₆ ) alkyl, -CH ₂ -O-(C ₁ -C ₆ ) alkyl, -CH ₂ -NH-(C ₁ -C ₆ ) alkyl, -CH ₂ -N-((C ₁ -C ₆ ) alkyl) ₂ , -O-(C ₁ -C ₆ ) alkyl, -NH-(C ₁ -C ₆ ) alkyl and -N-((C ₁ -C ₆ ) alkyl) _2. Only substitutions where the resulting molecule is chemically stable are encompassed by this definition. Typically, a (C ₁ -C ₆ ) alkyl group present in a substituent is itself not further substituted. Preferred substituted cyclic groups include cyclic groups substituted with one or more fluorine atoms and/or hydroxyl groups, such as difluorocyclopropyl.

In the formulae presented herein, the dashed line - represents the point of attachment of the depicted moiety to the main molecular structure.

Y ¹ Definition

In the above formula (I), Y ¹ is a bicyclic heteroaryl. According to one embodiment, Y ¹ is a 9- to 11-membered bicyclic heteroaryl. According to one embodiment, Y ¹ is a 9- or 10-membered bicyclic heteroaryl. According to one embodiment, Y ¹ comprises two fused rings selected from a 5-membered heteroaryl and a 6-membered heteroaryl.

According to one embodiment, Y ¹ comprises two fused rings consisting of:

- the first 5- or 6-membered heteroaryl ring is selected from:

*Formula (Y ¹ -0-1-Aa)

wherein ^GA is selected from ^CR2 and N, ^GB is selected from ^CR3 and N, and ^GC and ^GD are independently selected from ^CR2 , ^CR3 and N (wherein ^R2 and ^R3 are independently as defined below), and

*Formula (Y ¹ -0-1-Ab)

wherein ^GA and ^GB are independently selected from CR ² , CR ³ and N, and ^GE is selected from O, S and NR ⁴ , in particular O and NR ⁴ (wherein R ² , R ³ and R ⁴ are independently as defined below), and

- The second ring is selected from 5-membered heteroaryl, 6-membered heteroaryl and aryl, wherein the second ring is fused with ^GA and ^GB , ^GB and ^GC , ^GC and ^GD or ^GB and ^GE of the first ring to form a 5-membered heteroaryl, 6-membered heteroaryl or aryl.

According to one embodiment, Y ¹ is a 9- or 10-membered bicyclic heteroaryl group selected from the group consisting of the following formula (Y ¹ -I):

wherein ^A1 , ^A2 , ^A3 , ^A4 , ^A5 , ^A6 and ^A7 are each independently selected from ^CR7 and N; ^A8 , ^A9 , ^A10 and ^A11 are each independently selected from ^CR7 and N; ^G1 is selected from ^CR3 and N; ^G2 is selected from O and ^NR4 ; and B is selected from O, S and ^NR5 . "(ScX)" means "(skeleton n°X)".

According to one embodiment, Y ¹ is a 9- or 10-membered bicyclic heteroaryl group selected from the group consisting of the following formula (Y ¹ -I′):

wherein ^A1 , ^A2 , ^A3 , ^A4 , ^A5 , ^A6 and ^A7 are each independently selected from ^CR7 and N; ^A8 , ^A9 , ^A10 and ^A11 are each independently selected from ^CR7 and N; ^G1 is selected from ^CR3 and N; ^G2 is selected from O and ^NR4 ; and B is selected from O, S and ^NR5 . "(ScX)" means "(skeleton n°X)".

According to one embodiment, Y ¹ is a 9- or 10-membered bicyclic heteroaryl group selected from the group consisting of the following formula (Y ¹ -Ia):

wherein ^A1 , ^A2 , ^A3 , ^A4 , ^A5 , ^A6 and ^A7 are each independently selected from ^CR7 and N; ^A8 , ^A9 , ^A10 and ^A11 are each independently selected from ^CR7 and N; ^G1 is selected from ^CR3 and N; and B is selected from O, S and ^NR5 . "(ScX)" means "(skeleton n°X)".

In one embodiment, when ^A8 , ^A9 , ^A10 and ^A11 are present, at least one of ^A8 , ^A9 , ^A10 or ^A11 is N. In one embodiment, when ^A5 and ^A6 are present, when ^A5 and ^A6 are ^CR7 , B is not S. In one embodiment, when ^A5 , ^A6 and ^A7 are present, when ^A5 , ^A6 and ^A7 are ^CR7 , B is not S. In one embodiment, ^G1 is N.

According to one embodiment, Y ¹ is a 9- or 10-membered bicyclic heteroaryl group selected from the group consisting of the following formula (Y ¹ -I-1):

wherein A ¹ -A ⁴ , A ⁶ , A ⁷ , G ¹ and R ² are independently as defined herein.

According to one embodiment, Y ¹ is a 9-membered bicyclic heteroaryl group selected from the group consisting of the following formula (Y ¹ -I-2):

wherein A ¹ -A ⁴ , A ⁸ -A ¹¹ , G ¹ and G ² are independently as defined herein.

According to one embodiment, Y ¹ is a 9-membered bicyclic heteroaryl group of formula (Y ¹ -0-2)

wherein G ¹ is selected from CR ³ and N, B ¹ -B ⁵ are selected from O, S and any one of A ⁵ , A ⁶ or A ⁷ as defined herein; and B ¹ -B ⁵ together form a 5-membered heteroaryl, i.e. the bonds between B ¹ -B ⁵ are arranged such that the ring is aromatic and at least one of B ¹ -B ⁵ is selected from O, S and NR ⁵ .

According to one embodiment, Y ¹ is a 10-membered bicyclic heteroaryl group of formula (Y ¹ -Ia-1)

wherein A ¹ -A ⁴ , G ¹ and R ² are independently as defined herein.

In ^Y as defined herein, ^R is selected from hydrogen, halogen, cyano, amino, hydroxy, -(C ₁ -C ₆ ) alkyl, -(C ₃ -C ₇ ) cycloalkyl, -(C ₃ -C ₇ ) heterocycloalkyl, aryl, heteroaryl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C 7 ) cycloalkyl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) heterocycloalkyl, -OR ¹⁵ , -(C ₁ -C ₆ ) alkylene-OR ¹⁵ , -O-(C ₂ -C ₆ ) alkylene-OR ¹⁵ , -NR ¹⁶ (C 2 -C ₆ ) alkylene-OR ¹⁵ , -NR ¹⁷ R ¹⁸ , -(C ₁ -C ₆ ) alkylene-NR ¹⁷ R ¹⁸ , -O-(C _{2 -C 6 )} alkylene- -C ₆ )alkylene-NR ¹⁷ R ¹⁸ , -NR ¹⁶ -(C ₂ -C ₆ )alkylene-NR ¹⁷ R ¹⁸ , -(C ₁ -C ₆ )alkylene-SO ₂ -NR ¹⁷ R ¹⁸ , -NR ¹⁶ -SO ₂ -R ¹⁵ , -(C ₁ -C ₆ )alkylene-NR ¹⁶ -SO ₂ -R ¹⁵ , -O-(C ₂ -C ₆ )alkylene-NR ¹⁶ -SO ₂ -R ¹⁵ , -NR ¹⁶ -(C ₂ -C ₆ )alkylene-NR ¹⁷ -SO ₂ -R ¹⁵ , -C(O)-NR ¹⁷ R ¹⁸ , -(C ₁ -C ₆ )alkylene-C(O)-NR ¹⁷ R ¹⁸ , -O-(C ₁ -C ₆ -C(O)-R ^{15 ,} -(C ₁ -C ₆ )alkylene-NR ¹⁶ C(O)-R ¹⁵ , -O-(C ₂ -C ⁶ )alkylene-NR ¹⁶ C(O)-R ¹⁵ , -NR ¹⁶ -(C ₂ -C ₆ )alkylene-NR ¹⁶ C( ^O )-R ^{15 ,} -C(O)-R ¹⁵ , -C(O)OR ¹⁵ , -(C ₁ -C ₆ )alkylene- _C ⁽ O)OR ¹⁵ , -O- ⁽ C ₁ -C ₆ )alkylene-C(O)OR ¹⁵ , -NR ¹⁶ -(C ₁ -C ₆ )alkylene-C(O) ₁ -C ₆ )alkylene-C(O)OR ¹⁵ .

In one embodiment, ^R2 is -( _C1 - _C6 )alkyl, such as methyl, isopropyl, ethyl or alkyl, wherein the alkyl is optionally substituted with at least one fluorine atom. Preferred substituted -( _C1 - _C6 )alkyl include difluoromethyl and trifluoromethyl.

In one embodiment, ^R is hydrogen. In one embodiment, R ^is -(C ₃ -C ₇ ) cycloalkyl, for example ^cyclopropyl optionally substituted by at least one methyl, hydroxyl or fluorine atom. In one embodiment, R is -(C ₃ -C ₇ ) heterocycloalkyl, for example tetrahydrothiophene or tetrahydrofuran, which is optionally substituted by at least one methyl. In one embodiment, ^R is heteroaryl, for example thiophene or furan, which is optionally substituted by at least one methyl or ethyl. In one embodiment, R ^is -(C ₃ -C ₇ ) heterocycloalkyl, for example morpholine, which is optionally substituted by at least one methyl, hydroxyl or fluorine atom.

In ^Y1 as defined herein, ^R3 is selected from halogen, cyano, amino, hydroxy, -( _C1 - _C6 )alkyl, -( _C3 - _C7 )cycloalkyl, -( _C3 - _C7 )heterocycloalkyl, aryl, heteroaryl, -( _C1 - _C6 )alkylene-(C3- _C7 )cycloalkyl, -( _C1 -C6)alkylene-( _C3 - _C7 )heterocycloalkyl, ^-OR15 , -( _C1 - _C6 )alkylene-OR15, -O-( _C2 - _C6 )alkylene- ^OR15 , -NR16( _C2 -C6)alkylene- ^OR15 , -NR17R18, -(C1-C6)alkylene-NR17R18, -O-(C2- _C6 )alkylene- ^OR15 , ^-NR16 ( _C2 - _C6 )alkylene- ^OR15 , ^-NR17R18 , -( _C1 - _C6 )alkylene ^{-NR17R18 ,} -O-( _C2 -C6)alkylene _- (C 1 -C 6 )alkylene-NR ¹⁷ R ¹⁸ , -NR ¹⁶ -(C ₂ -C ₆ )alkylene-NR ¹⁷ R ¹⁸ , -(C ₁ -C ₆ )alkylene-SO ₂ -NR ¹⁷ R ¹⁸ , -NR ¹⁶ -SO ₂ -R ¹⁵ , -(C ₁ -C ₆ )alkylene-NR ¹⁶ -SO ₂ -R ¹⁵ , -O-(C ₂ -C ₆ )alkylene-NR ¹⁶ -SO ₂ -R ¹⁵ , -NR ¹⁶ -(C ₂ -C ₆ )alkylene-NR ¹⁷ -SO ₂ -R ¹⁵ , -C(O)-NR ¹⁷ R ¹⁸ , -(C ₁ -C ₆ )alkylene-C(O)-NR ¹⁷ R ¹⁸ , -O-(C ₁ -C ₆ -C(O)-R ^{15 ,} -(C ₁ -C ₆ )alkylene-NR ¹⁶ C(O)-R ¹⁵ , -O-(C ₂ -C ⁶ )alkylene-NR ¹⁶ C(O)-R ¹⁵ , -NR ¹⁶ -(C ₂ -C ₆ )alkylene-NR ¹⁶ C( ^O )-R ^{15 ,} -C(O)-R ¹⁵ , -C(O)OR ¹⁵ , -(C ₁ -C ₆ )alkylene- _C ⁽ O)OR ¹⁵ , -O- ⁽ C ₁ -C ₆ )alkylene-C(O)OR ¹⁵ , -NR ¹⁶ -(C ₁ -C ₆ )alkylene-C(O) ₁ -C ₆ )alkylene-C(O)OR ¹⁵ .

In ^Y1 as defined herein, ^R4 is selected from hydrogen, -( _C1 - _C6 )alkyl, -( _C3 - _C7 )cycloalkyl, -( _C1 - _C6 )alkylene-( _C3 - _C7 )cycloalkyl, -( _C1 - _C6 )alkylene-( _C3 - _C7 )heterocycloalkyl, -( _C1 - _C6 )alkylene-aryl, -( _C1 - _C6 )alkylene-heteroaryl, -( _C1 - _C6 )alkylene- ^OR15 , -( _C1 - _C6 )alkylene- ^NR17R18 , -( _C1 - _C6 )alkylene-C(O) ^{-NR17R18 ,} -( _C1 - _C6 )alkylene- ^NR16C (O) ^-R15 , -( _C1 - _C6) ^alkylene- )alkylene-C(O)OR ¹⁵ and -(C ₁ -C ₆ )alkylene-OC(O)-R ¹⁵ .

In one embodiment, ^R4 is hydrogen.

In ^Y1 as defined herein, ^R5 is selected from hydrogen, -( _C1 - _C6 )alkyl, -( _C3 - _C7 )cycloalkyl, -( _C3 - _C7 )heterocycloalkyl, aryl, heteroaryl, -( _C1 - _C6 )alkylene-( _C3 - _C7 )cycloalkyl, -( _C1 - _C6 )alkylene-( _C3 - _C7 )heterocycloalkyl, -( _C1 - _C6 )alkylene-aryl, -( _C1 - _C6 )alkylene-heteroaryl, -( _C1 - _C6 )alkylene- ^OR15 , -( _C1 - _C6 )alkylene- ^{NR17R18 ,} -( _C1 - _C6 )alkylene-C(O) ^{-NR17R18 ,} -( _C1 - _C6 )alkylene- ^NR16 C(O) ^-R15 , -( _C1 - _C6 )alkylene-C(O) ^OR15 and -( _C1 - _C6 )alkylene-OC(O) ^-R15 .

In one embodiment, R ⁵ is -(C ₁ -C ₆ )alkyl, such as methyl. In one embodiment, R ⁵ is aryl, such as phenyl optionally substituted with at least one halogen or methyl.

In the case where Y ^is as defined herein, R ^is independently selected from hydrogen, halogen, amino, hydroxy, -(C ₁ -C ₆ ) alkyl, -(C ₃ -C ₇ ) cycloalkyl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) cycloalkyl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) heterocycloalkyl, -(C ₃ -C ₇ ) heterocycloalkyl, aryl, heteroaryl, -OR ¹⁵ , -(C ₁ -C ₆ ) alkylene-OR ¹⁵ , -O-(C ₂ -C ₆ ) alkylene-OR ¹⁵ , -NR ¹⁶ (C ₂ -C ₆ ) alkylene-OR ¹⁵ , -NR ¹⁷ R ¹⁸ , -(C ₁ -C ₆ ) alkylene-NR ¹⁷ R ¹⁸ , -O-(C ₂ -C 6 ) alkylene- -NR ¹⁷ R ¹⁸ , -NR ¹⁶ -(C ₂ -C ₆ )alkylene-NR ¹⁷ R ¹⁸ , -SO-R ¹⁵ , -SO ₂ -R ¹⁵ , -SO ₂ NR ¹⁷ R ¹⁸ , -(C ₁ -C ₆ )alkylene-SO ₂ -NR ¹⁷ R ¹⁸ , -NR ¹⁶ -SO ₂ -R ¹⁵ , -(C ₁ -C ₆ )alkylene-NR 16 -SO 2 -R 15 , -O-(C 2 -C ₆ )alkylene-NR ¹⁶ -SO ₂ -R ¹⁵ , -NR 16 -(C ₂ -C ₆ )alkylene-NR ¹⁷ -SO ₂ -R ¹⁵ , -C(O)-NR ¹⁷ R ¹⁸ , -(C ₁ -C ₆ )alkylene-SO ^{2 -NR 17} R ¹⁸ , -NR 16 -SO ₂ -R ¹⁵ , -(C ₁ -C ₆ )alkylene-NR 16 -SO 2 -R )alkylene-C(O)-NR ¹⁷ R ¹⁸ , -O-(C ₁ -C ₆ )alkylene-C(O)-NR ¹⁷ R ¹⁸ , -NR ¹⁶ -(C ₁ -C ₆ )alkylene-C(O)-NR ¹⁷ R ¹⁸ , -NR ¹⁶ C(O)-R ¹⁵ , -(C ₁ -C ₆ )alkylene-NR ¹⁶ C(O)-R ¹⁵ , -O-(C ₂ -C ₆ )alkylene-NR ¹⁶ C(O)-R ¹⁵ , -NR ¹⁶ -(C ₂ -C ₆ )alkylene-NR ¹⁷ C(O)-R ¹⁵ , -C(O)-R ¹⁵ , -C(O)OR ¹⁵ , -(C ₁ -C ₆ )alkylene-C(O)OR ¹⁵ -O-(C ₁ -C ₆ )alkylene-C(O)OR ¹⁵ , -NR ¹⁶ -(C ₁ -C ₆ )alkylene-C(O)OR ¹⁵ , -OC(O)-R ¹⁵ , -(C ₁ -C ₆ )alkylene-OC(O)-R ¹⁵ , -O-(C ₂ -C ₆ )alkylene-OC(O)-R ¹⁵ , -NR ¹⁶ -(C ₂ -C ₆ )alkylene-OC(O)-R ¹⁵ , or -NR ¹⁶ -C(O)OR ¹⁵ .

In one embodiment, ^R7 is hydrogen. In one embodiment, ^R7 is -( _C1 - _C6 )alkyl, such as methyl.

In one embodiment, R ⁷ is (C ₃ -C ₇ ) heterocycloalkyl, such as optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted 1,4-oxazepanyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl or optionally substituted 2-oxa-5-azabicyclo[2.2.2]octan-5-yl. In one embodiment, (C ₃ -C ₇ ) heterocycloalkyl is substituted by one or two -(C ₁ -C ₆ ) alkyl, such as one or two methyl.

In R ² , R ³ , R ⁴ and R ⁷ as defined herein, R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently selected from hydrogen, -(C ₁ -C ₆ )haloalkyl, -(C ₁ -C ₆ )alkyl, -(C ₃ -C ₇ )cycloalkyl, -(C ₁ -C ₆ )alkylene-(C ₃ -C ₇ )cycloalkyl, -(C ₃ -C ₇ )heterocycloalkyl, aryl, heteroaryl, -(C ₁ -C ₆ )alkylene-(C ₃ -C ₇ )heterocycloalkyl, -(C ₁ -C ₆ )alkylene-heteroaryl and -(C ₁ -C ₆ )alkylene-aryl; and/or two groups selected from R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ together form a ring selected from -(C ₃ -C ₇ )cycloalkyl, -(C ₃ -C ₇ )heterocycloalkyl, aryl and heteroaryl.

In one embodiment, Y ¹ is a 10-membered [6,6] bicyclic heteroaryl.

In one embodiment, ^Y1 is selected from the group consisting of:

wherein R ² , R ³ and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is 9-membered bicyclo[6,5]heteroaryl.

In one embodiment, Y ¹ is selected from the group consisting of ^:

wherein R ² , R ³ , R ⁵ and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is selected from the group consisting of ^:

wherein R ² , R ³ , R ⁵ and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is selected from the group consisting of the following formula (Y ¹ -4):

wherein R ² , R ³ , R ⁵ and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is selected from the group consisting of the following formula (Y ¹ -5):

wherein R ² , R ³ and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is selected from the group consisting of the following formula (Y ¹ -6):

wherein R ² , R ³ and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is 9-membered bicyclo[5,6]heteroaryl.

In one embodiment, Y ¹ is selected from the group consisting of ^:

wherein R ² and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is selected from the group consisting of the following formula (Y ¹ -8):

wherein A ¹ , A ² , A ³ , A ⁴ and R ⁴ are independently as defined herein.

In one embodiment, ^Y is selected from optionally substituted naphthyridine (e.g., optionally substituted 1,7-naphthyridine, 1,6-naphthyridine, or 2,7-naphthyridine), optionally substituted 1H-pyrazolo-pyrimidine, optionally substituted 2H-pyrazolo-pyrimidine, optionally substituted benzimidazole, optionally substituted benzoxazole, optionally substituted imidazo[1,2-a]pyrazine, optionally substituted imidazo[1,5-a]pyrazine, optionally substituted imidazo[4,5-b]pyridine, optionally substituted pyrazolo[1,5-a][1,3,5]triazine. , optionally substituted pyrazolo[1,5-a]pyrazine, optionally substituted pyrido[2,3-d]pyrimidine, optionally substituted pyrido[3,2-d]pyrimidine, optionally substituted pyrido[3,4-d]pyrimidine, optionally substituted oxazolo[4,5-b]pyridine, optionally substituted oxazolo[4,5-c]pyridine, optionally substituted oxazolo[5,4-b]pyridine, substituted oxazolo[5,4-c]pyridine, optionally substituted quinazoline, optionally substituted quinoline and optionally substituted phthalazine.

In one embodiment, Y ¹ is an optionally substituted 1H-pyrazolo-pyrimidine. In one embodiment, Y ¹ is a 1H-pyrazolo-pyrimidine. In one embodiment, Y 1 is an optionally substituted 2H-pyrazolo-pyrimidine. In one embodiment, Y ¹ is a 2H-pyrazolo-pyrimidine. In one embodiment, Y ¹ is selected from optionally substituted pyrido [2,3-d] pyrimidine, optionally substituted pyrido [3,2-d] pyrimidine, and optionally substituted pyrido [3,4-d] pyrimidine. ^{Y 1 is} selected from pyrido [2,3-d] pyrimidine, pyrido [3,2-d] pyrimidine, and pyrido [3,4-d] pyrimidine. In one embodiment, Y ¹ is an optionally substituted quinazoline. In one embodiment, Y ¹ is quinazoline.

In one embodiment, Y ¹ is selected from the group consisting of ^:

wherein R ² and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is selected from the group consisting of ^:

wherein R ² , R ⁵ and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is selected from the group consisting of the following formula (Y ¹ -3a):

wherein R ² , R ⁵ and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is selected from the group consisting of ^:

wherein R ² , R ⁵ and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is selected from the group consisting of ^:

wherein R ² and R ⁷ are independently as defined herein.

In one embodiment, Y ¹ is optionally substituted phthalazine (eg, phthalazin-1-yl).

In one embodiment, the bicyclic heteroaryl in Y ¹ is substituted by one or two -(C ₁ -C ₆ )alkyl groups, such as one or two methyl groups.

^Y2 Definition

In the above formula (I), Y ² is a monocyclic heteroaryl or aryl. According to one embodiment, Y ² is a 5- or 6-membered heteroaryl. According to one embodiment, Y ² is a 5-membered heteroaryl.

According to one embodiment, Y ² is selected from the group consisting of ^:

wherein R ¹² , R ¹³ and R ¹⁴ are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -(C ₁ -C ₆ )alkyl, -CH ₂ -O-(C ₁ -C ₆ )alkyl, -CH ₂ -NH-(C ₁ -C ₆ )alkyl), -CH ₂ -N-((C ₁ -C ₆ )alkyl) ₂ , -O-(C ₁ -C ₆ )alkyl, -NH-(C ₁ -C ₆ )alkyl) and -N-((C ₁ -C ₆ )alkyl) ₂ .

According to one embodiment, Y ² is selected from the group consisting of the following formula (Y ² -I):

wherein R ¹² , R ¹³ and R ¹⁴ are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -(C ₁ -C ₆ )alkyl, -CH ₂ -O-(C ₁ -C ₆ )alkyl, -CH ₂ -NH-(C ₁ -C ₆ )alkyl), -CH ₂ -N-((C ₁ -C ₆ )alkyl) ₂ , -O-(C ₁ -C ₆ )alkyl, -NH-(C ₁ -C ₆ )alkyl) and -N-((C ₁ -C ₆ )alkyl) ₂ .

In one embodiment, Y ² is selected from the group consisting of ^:

wherein R ¹² , R ¹³ and R ¹⁴ are independently as defined herein.

In one embodiment, Y ² is selected from optionally substituted thiadiazole, optionally substituted thiazole, and optionally substituted thiophene. In one embodiment, Y ² is selected from thiophene, fluoro-thiophene, thiadiazole, and thiazole.

In one embodiment, R ¹² and R ¹³ , or R ¹² and R ¹⁴ are selected from hydrogen and (C ₁ -C ₃ )alkyl. In one embodiment, R ¹² and R ¹³ , or R ¹² and R ¹⁴ are each hydrogen, ie, Y ² is a divalent unsubstituted thiophene.

L Definition

In the above formula ( _{I), L is selected from -(CR10R11)n, -(C3-C7} ⁾ _cycloalkyl ^and _- ( _C3 - _C7 )heterocycloalkyl, wherein n is an integer of 1-10; and ^R10 and ^R11 are independently selected from hydrogen, halogen, hydroxyl, amino, -( _C1 - _C6 )alkyl, -O-( _C1 - _C6 )alkyl, -NH-( _C1 - _C6 )alkyl and -N-(( _C1 - _C6 )alkyl) ₂ .

According to one embodiment, n is an integer selected from 1, 2, 3 and 4.

According to one embodiment, R ¹⁰ and R ¹¹ are independently selected from hydrogen, halogen, hydroxy, amino, -(C ₁ -C ₃ )alkyl, -(C ₁ -C ₂ )haloalkyl, -(C ₁ -C ₂ )hydroxyalkyl, -(C ₁ -C ₂ )aminoalkyl, -O-(C ₁ -C ₄ )alkyl, -NH-(C ₁ -C ₃ )alkyl and -N-((C ₁ -C ₃ )alkyl) ₂ .

In one embodiment, L is selected from -(C ₄ -C ₇ )cycloalkyl and -(C ₄ -C ₇ )heterocycloalkyl. In a particular embodiment, L is selected from -(C ₅ -C ₆ )cycloalkyl and -(C ₅ -C ₆ )heterocycloalkyl.

In one embodiment, n is an integer selected from 1, 2, and 3. In one embodiment, n is an integer selected from 1 and 2. In one embodiment, n is 1. In one embodiment, n is 2.

In one embodiment, R ¹⁰ and R ¹¹ are each independently selected from hydrogen and (C ₁ -C ₃ )alkyl. In one embodiment, R ¹⁰ and R ¹¹ are each hydrogen.

Z ¹ Definition

In the above formula (I), Z ¹ is selected from (C=O)-R ⁹ , S(O)-R ⁹ and S(O ₂ )-R ⁹ . According to one embodiment, Z ¹ is selected from (C=O)-R ⁹ and S(O ₂ )-R ⁹ .

In ^Z as defined herein, R ^is selected from amino, -(C ₁ -C ₆ ) alkyl, -(C ₃ -C ₇ ) cycloalkyl, -(C ₃ -C ₇ ) heterocycloalkyl, aryl, heteroaryl, -(C ₁ -C 6 ) alkylene-(C 3 -C ₇ ) cycloalkyl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) heterocycloalkyl, -(C ₁ -C ₆ ) alkylene-aryl, -(C ₁ -C ₆ ) alkylene-heteroaryl, -(C ₁ -C ₆ ) alkylene-OR ²¹ , -(C ₁ -C ₆ ) alkylene-NR 23 R 24 , -(C ₁ -C ₆ ) alkylene-C(O)-NR ²³ R ²⁴ , -(C ₁ -C ₆ ) alkylene-C(O)-NR ²³ R ²⁴ , -(C ₁ -C ₆ -(C ₁ -C ₆ )alkylene-NR ²² -C(O)-R ²¹ , -(C ₁ -C ₆ )alkylene-C(O)OR ²¹ , -OR ²¹ , -NR ²³ R ²⁴ , -NR ²² -(C ₂ -C ₆ ^{)alkylene-OR 21 , -NR 22 -(C 2 -C 6 )alkylene-NR 23 R 24 , -NR} _{22 -} ^{( C 1} _{-C 6} )alkylene-C(O)OR ^{21 .}

In R ⁹ as defined herein, R ²¹ , R ²² , R ²³ and R ²⁴ are each independently selected from hydrogen, -(C ₁ -C ₆ ) alkyl, -(C ₃ -C ₇ ) cycloalkyl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) cycloalkyl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) halocycloalkyl, -(C ₃ -C ₇ ) heterocycloalkyl, aryl, heteroaryl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) heterocycloalkyl, -(C ₁ -C ₆ ) alkylene-heteroaryl and -(C ₁ -C ₆ ) alkylene-aryl; and/or two groups selected from R ²¹ , R ²² , R ²³ and R ²⁴ together form a ring selected from -(C ₃ -C ₇ )cycloalkyl, -(C ₃ -C ₇ )heterocycloalkyl, aryl and heteroaryl.

In one embodiment, R ^is selected from methyl, tert-butyl, cyclopropyl, O-tert-butyl, hydroxymethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxypropan-2-yl, 1-hydroxycyclopropyl, methoxymethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, phenylmethyl, phenyl, 2,2-difluorocyclopropyl, 2,2,3,3,3-pentafluoro-propyl, _H2 , N-methyl, N-methyl-NH-methyl, methylazetidinyl, 1-hydroxyethyl (e.g., (S)-1-hydroxyethyl or (R)-1-hydroxyethyl) and pyrrolidinyl. In one embodiment, R ⁹ is selected from cyclopropyl, hydroxymethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxypropan-2-yl, 1-hydroxycyclopropyl, 2,2-difluorocyclopropyl and 2,2,3,3,3-pentafluoro-propyl.

R ¹ Definition

In the above formula (I), R ¹ is any single non-cyclic moiety, or R ¹ is combined with another moiety in formula (I) to form a heterocycloalkyl group containing at least one nitrogen atom.

According to a first embodiment of the present invention, R ¹ is selected from hydrogen, -(C ₁ -C ₆ ) alkyl, -(C ₃ -C ₇ ) cycloalkyl, -(C ₃ -C ₇ ) heterocycloalkyl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) cycloalkyl, -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) heterocycloalkyl, -(C ₁ -C ₆ ) alkylene-OR ¹⁹ and -(C ₁ -C ₆ ) alkylene-NR ¹⁹ R ²⁰ , wherein R ¹⁹ and R ²⁰ are each independently selected from hydrogen, -(C ₁ -C ₆ ) alkyl and -(C ₃ -C ₇ ) cycloalkyl; or R ¹⁹ and R ²⁰ together form a ring selected from -(C ₃ -C ₇ ) cycloalkyl and -(C ₃ -C ₇ ) heterocycloalkyl.

According to a second embodiment of the invention, R ¹ together with one of R ¹⁰ or R ¹¹ forms a (C ₃ -C ₇ )heterocycloalkyl group containing at least one nitrogen atom.

According to a third embodiment of the invention, R ¹ and R ⁹ (as defined herein in the definition of R ⁹ ) together form a (C ₃ -C ₇ )heterocycloalkyl group comprising at least one nitrogen atom.

In one embodiment, R ¹ is selected from hydrogen and (C ₁ -C ₃ ) alkyl, preferably R ¹ is hydrogen or methyl. In one embodiment, R ¹ is hydrogen. In one embodiment, R ¹ is taken together with one of R ¹⁰ or R ¹¹ to form a 5- or 6-membered heterocycloalkyl containing one nitrogen atom. In one embodiment, R ¹ is taken together with one of R ¹⁰ or R ¹¹ to form pyrrolidine. In one embodiment, R ¹ and R ⁹ are taken together to form a 5- or 6-membered heterocycloalkyl containing one nitrogen atom. In one embodiment, R ¹ and R ⁹ are taken together to form a pyrrolidone or morpholin-3-one.

Specific compounds

According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 below.

Table 1

According to one embodiment, the compound of formula (I) is selected from the compounds of Table 2 below.

Table 2

use The compounds in Table 1 and Table 2 were named using PerkinElmer Professional 15.0 (PerkinElmer).

According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 or Table 2 herein.

Optional compounds

All references to compounds of the invention (e.g., "compounds of formula (I)") herein include references to their salts, preferably pharmaceutically acceptable salts, solvates, multi-component complexes, and liquid crystals. All references to compounds of the invention herein include references to their polymorphs and crystal habits. All references to compounds of the invention include references to their pharmaceutically acceptable prodrugs. All references to compounds of the invention include references to isotopically labeled compounds, including deuterated compounds.

The compounds of the invention (e.g., "compounds of formula (I)") and their subformulae may contain at least one asymmetric center and may therefore exist in different stereoisomeric forms. Therefore, all references to the compounds of the invention include references to all possible stereoisomers and include not only racemic compounds but also individual enantiomers and non-racemic mixtures thereof. When a compound is desired as a single enantiomer, such a single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods known in the art. Resolution of the final product, intermediate or starting material may be carried out by any suitable method known in the art.

The compounds of the present invention (e.g., "compounds of formula (I)") may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts include acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases that form nontoxic salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, 2-(diethylamino)ethanol salts, diethanolamine salts, ethanolamine salts, glycine salts, 4-(2-hydroxyethyl)-morpholine salts, lysine salts, magnesium salts, meglumine salts, morpholine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts and zinc salts. Hemi-salts of acids and bases, such as hemisulphates and hemicalcium salts, can also be formed. When a compound contains an acidic group as well as a basic group, the compound can also form an inner salt, and such compounds are within the scope of the present invention. When a compound contains a hydrogen-donating heteroatom (e.g. NH), the present invention also encompasses salts and/or isomers formed by transferring the hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the compounds of the invention may be prepared by one or more of these methods: (i) by reacting the compound with a desired acid; (ii) by reacting the compound with a desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound, or by opening a suitable cyclic precursor (e.g., lactone or lactam) with a desired acid; and/or (iv) by converting one salt of the compound into another salt by reaction with a suitable acid or by passing through a suitable ion exchange column. All of these reactions are typically carried out in solution. The salt may be precipitated from solution and collected by filtration, or may be recovered by evaporating the solvent. The degree of ionization in the salt may vary from fully ionized to almost non-ionized.

Other compound definitions

According to one embodiment, the compound of formula (I) is not CAS#1287068-38-5: N-((5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide) or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#2182075-55-2: N-((5-(2-((2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1147354-39-9: N-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1010596-74-3: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#871674-28-1: N-((5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1147537-22-1: N-((5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1009199-55-6: N-(2-(5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1010596-81-2: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1089547-51-2: N-(2-(5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1321173-73-2: N-((5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1320446-60-3: N-(2-(5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the compound of formula (I) is not selected from:

CAS#2182075-55-2: N-((5-(2-((2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide,

CAS#1010596-74-3: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide,

CAS#871674-28-1: N-((5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide,

CAS#1147537-22-1: N-((5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide,

CAS#1009199-55-6: N-(2-(5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide,

CAS#1089547-51-2: N-(2-(5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide,

CAS#1321173-73-2: N-((5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide,

CAS#1320446-60-3: N-(2-(5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, and

Pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the compound of formula (I) is not selected from:

CAS#1287068-38-5: N-((5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#2182075-55-2: N-((5-(2-((2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#1147354-39-9: N-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#1010596-74-3: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide

CAS#871674-28-1: N-((5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#1147537-22-1: N-((5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#1009199-55-6: N-(2-(5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide

CAS#1010596-81-2: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#1089547-51-2: N-(2-(5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#1321173-73-2: N-((5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#1320446-60-3: N-(2-(5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, and

Pharmaceutically acceptable salts and solvates thereof.

According to one embodiment, when Y ¹ is an optionally substituted quinazolinyl (e.g., quinazolin-4-yl), R ² is not an optionally substituted (C ₁ -C ₆ ) alkyl, such as methyl or trifluoromethyl. In one embodiment, when Y ¹ is an optionally substituted quinazolinyl (e.g., quinazolin-4-yl), R ² is not an optionally substituted (C ₃ -C ₇ ) cycloalkyl, such as cyclopropyl. In one embodiment, when Y ¹ is an optionally substituted quinazolinyl (e.g., quinazolin-4-yl), R ² is not an optionally substituted heteroaryl, such as furanyl or thienyl. In one embodiment, when Y ¹ is an optionally substituted quinazolinyl, such as quinazolin-4-yl, R ² is not an optionally substituted -(C ₁ -C ₆ ) alkylene-(C ₃ -C ₇ ) heterocycloalkyl, such as -CH ₂ -morpholinyl.

In one embodiment, Y ¹ is not optionally substituted quinazolin-4-yl. In a particular embodiment, Y ¹ is not optionally substituted quinazolinyl.

According to one embodiment, when Y ¹ is optionally substituted quinazolinyl (eg quinazolin-4-yl) and R ¹ is hydrogen, Z ¹ is not optionally substituted -C(O)-(C ₁ -C ₆ )alkyl, such as -C(O)-methyl.

According to one embodiment, when Y ¹ is optionally substituted quinazolinyl (eg quinazolin-4-yl) and R ¹ is hydrogen, Z ¹ is not optionally substituted -S(O) ₂ -(C ₁ -C ₆ )alkyl, such as -S(O) ₂ -methyl.

According to one embodiment, the compound of formula (I) is not CAS# 1210761-93-5: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1011056-89-5: N-(2-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1060780-01-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide [CAS#1326255-51-9] or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#920953-29-3: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1324562-11-9: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1011002-97-3: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1030737-65-5: N-((5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the compound of formula (I) is not selected from:

CAS#1011056-89-5: N-(2-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide,

CAS#1060780-01-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide,

CAS#1326255-51-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide,

CAS#920953-29-3: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide,

CAS#1324562-11-9; N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide,

CAS#1030737-65-5: N-((5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, and

Pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the compound of formula (I) is not selected from:

CAS#1210761-93-5: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

CAS#1011056-89-5: N-(2-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#1060780-01-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#1326255-51-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide

CAS#920953-29-3: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#1324562-11-9: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide

CAS#1011002-97-3: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#1030737-65-5: N-((5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, and

Pharmaceutically acceptable salts and solvates thereof.

According to one embodiment, when Y ¹ is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g. 1H-pyrazolo[3,4-d]pyrimidin-4-yl), R ⁵ is not optionally substituted (C ₁ -C ₆ )alkyl, such as methyl. In one embodiment, when Y ¹ is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g. 1H-pyrazolo[3,4-d]pyrimidin-4-yl), R ⁵ is not optionally substituted aryl, such as phenyl or fluorophenyl (e.g. 4-fluorophenyl).

In one embodiment, Y ¹ is not optionally substituted 1H-pyrazolo[3,4-d]pyrimidin-4-yl. In a particular embodiment, Y ¹ is not optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl.

According to one embodiment, when Y ¹ is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g. 1H-pyrazolo[3,4-d]pyrimidin-4-yl) and R ¹ is hydrogen, Z ¹ is not optionally substituted -C(O)-(C ₁ -C ₆ )alkyl, such as -C(O)-methyl and -C(O)-tert-butyl.

According to one embodiment, when Y ¹ is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (eg 1H-pyrazolo[3,4-d]pyrimidin-4-yl) and R ¹ is hydrogen, Z ¹ is not optionally substituted -S(O) ₂ -(C ₁ -C ₆ )alkyl, eg -SO ₂ -methyl.

According to one embodiment, the compound of formula (I) is not CAS#1325066-46-3: N-((5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1324658-47-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1325082-97-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#949826-51-1: 2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1099735-84-8: N-((5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1009471-75-3: N-(2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1118826-22-4: N-(2-(5-(2-((6,8-dichloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1299961-73-1: N-((5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1302276-01-2: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1293687-72-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 878598-17-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 2184821-90-5: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS# 1297565-13-9: N-(2-(5-(2-((6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#919869-52-6: N-(2-(5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1001791-67-8: 2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-1-(5-(2-morpholino-2-oxoethyl)thiophen-2-yl)ethan-1-one or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#874609-73-1: N-((5-(2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)pivalamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS#1010352-07-4: N-(2-(5-(2-((6-(N,N-diethylsulfamoyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the compound of formula (I) is not selected from:

CAS#1325066-46-3: N-((5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#1324658-47-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide

CAS#1325082-97-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#949826-51-1: 2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)acetamide

CAS#1099735-84-8: N-((5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#1009471-75-3: N-(2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#1118826-22-4: N-(2-(5-(2-((6,8-dichloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide

CAS#1299961-73-1: N-((5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#1302276-01-2: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide

CAS#1293687-72-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#878598-17-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

CAS#2184821-90-5: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#1297565-13-9: N-(2-(5-(2-((6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#919869-52-6: N-(2-(5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

CAS#1001791-67-8: 2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-1-(5-(2-morpholino-2-oxoethyl)thiophen-2-yl)ethan-1-one

CAS#874609-73-1: N-((5-(2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)pivalamide

CAS#1010352-07-4: N-(2-(5-(2-((6-(N,N-diethylsulfamoyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, and

Pharmaceutically acceptable salts and solvates thereof.

In one embodiment, Y ¹ is not optionally substituted imidazo[1,5-a]pyridin-3-yl. In a particular embodiment, Y ¹ is not optionally substituted imidazo[1,5-a]pyridin-3-yl. In one embodiment, Y ^{1 is not optionally substituted imidazo[1,5-b]pyridazin-7-yl. In a particular embodiment, Y 1} is not optionally substituted imidazo[1,5-b]pyridazin-7-yl. In a particular embodiment, Y ¹ is not optionally substituted imidazo[1,5-b]pyridazin-7-yl. In one embodiment, Y ¹ is not optionally substituted [1,2,4]triazolo[4,3-a]pyridin-3-yl. In a particular embodiment, Y ¹ is not optionally substituted [1,2,4]triazolo[4,3-a]pyridin-3-yl. In one embodiment, Y ¹ is not optionally substituted [1,2,4]triazolo[4,3-a]pyridin-3-yl. In a particular embodiment, Y ¹ is not optionally substituted [1,2,4]triazolo[4,3-a]pyrimidinyl. In one embodiment, Y ¹ is not optionally substituted [1,2,4]triazolo[4,3-a]pyridin-3-yl. In a particular embodiment, Y ¹ is not optionally substituted [1,2,4]triazolo[4,3-a]pyridinyl.

In a particular embodiment, Y ¹ is not a group of formula (Sc7)

wherein A ¹ -A ⁴ and G ¹ are independently as defined above.

According to one embodiment, the compound of formula (I) is not CAS# 2419446-18-5: N-(2-(5-(2-((5-methyloxazolo[4,5-b]pyridin-2-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide [using Professional 15.0 (PerkinElmer)]

Nor are pharmaceutically acceptable salts and/or solvates thereof.

According to one embodiment, Y ¹ is not optionally substituted oxazolo[4,5-b]pyridin-2-yl, such as 5-methyloxazolo[4,5-b]pyridin-2-yl. In a particular embodiment, Y ¹ is not optionally substituted oxazolo[4,5-b]pyridinyl, such as 5-methyloxazolo[4,5-b]pyridin-2-yl.

According to one embodiment, when Y ¹ is optionally substituted oxazolo[4,5-b]pyridin-2-yl (e.g. 5-methyloxazolo[4,5-b]pyridin-2-yl) and R ¹ is hydrogen, Z ¹ is not optionally substituted -C(O)-(C ₁ -C ₆ )alkyl, such as -C(O)-methyl and -C(O)-tert-butyl.

Preparation method

The present invention also relates to a process for preparing the compounds of the present invention as described herein. According to one embodiment, the process comprises the steps of: (i) reacting a linear or cyclic amine with an acyl chloride, a carboxylic acid or a sulfonyl chloride; or (ii) reacting a halo-ketone with a thiol.

Pharmaceutical composition

The present invention also relates to pharmaceutical compositions comprising a compound of the invention as described herein and at least one pharmaceutically acceptable carrier.

According to one embodiment, the pharmaceutical composition does not include any therapeutic agent other than the compounds of the present invention. According to another embodiment, the pharmaceutical composition further comprises at least one other therapeutic agent. In one embodiment, the at least one other therapeutic agent is selected from therapeutic agents known in the art for treating inflammatory diseases, autoimmune diseases, proliferative diseases (e.g., cancer), neurodegenerative diseases, pain, neuropathy, mental illness, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, pulmonary diseases, metabolic or hormonal disorders, immune disorders, age-related diseases and/or idiopathic diseases.

The compounds of the present invention may be formulated alone or together into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each administration route.

Medical uses and treatments

The present invention also relates to a compound of the invention as described herein or a pharmaceutical composition of the invention as described herein for use as a medicament.

According to a particular embodiment, the compounds or pharmaceutical compositions of the invention are used for the treatment and/or prevention of an HDAC6-associated disease as defined herein.

The present invention also relates to methods for inhibiting HDAC6 enzymes. According to one embodiment, inhibition of HDAC6 enzymes treats and/or prevents HDAC6-related diseases. According to one embodiment, the method includes administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention as described herein or a pharmaceutical composition of the present invention as described herein.

The present invention also relates to a method for treating and/or preventing HDAC6-related diseases, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention as described herein or a pharmaceutical composition of the present invention as described herein. The present invention also relates to the use of a compound of the present invention as described herein or a pharmaceutical composition of the present invention as described herein in the preparation of a medicament for treating and/or preventing HDAC6-related diseases. The present invention also relates to the use of a compound of the present invention as described herein or a pharmaceutical composition of the present invention as described herein in the treatment and/or prevention of HDAC6-related diseases.

Advantageously, compared with the prior art compounds for treating and/or preventing HDAC-related diseases, the compounds of the present invention show excellent inhibitory activity on HDAC enzymes (e.g., Class II HDAC enzymes, preferably HDAC6 enzymes). Advantageously, compared with the compounds of the prior art for treating and/or preventing HDAC-related diseases, the compounds of the present invention show low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, hematotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) on HDAC enzymes (e.g., Class II HDAC enzymes, preferably HDAC6 enzymes). In particular, the compounds of the present invention show low genotoxicity.

According to one embodiment, HDAC6-related diseases are selected from the group comprising or consisting of: inflammatory diseases, autoimmune diseases, proliferative diseases (e.g., cancer), neurodegenerative diseases, pain, neuropathy, psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, pulmonary diseases, metabolic or hormonal disorders, immune disorders, age-related diseases, and idiopathic diseases. According to one embodiment, HDAC6-related diseases are selected from the group comprising or consisting of: inflammatory diseases, autoimmune diseases, proliferative diseases (e.g., cancer), neurodegenerative diseases, pain, neuropathy, psychiatric diseases, neurodevelopmental disorders, sleep disorders, and cardiovascular diseases. According to one embodiment, HDAC6-related diseases are selected from the group comprising or consisting of: proliferative diseases (e.g., cancer), neurodegenerative diseases, neuropathy, and cardiovascular diseases.

A selection of references demonstrating that inhibition of HDAC6 has the effect of treating and/or preventing a given class of diseases is listed in Table 3 below.

Table 3

According to one embodiment, the HDAC6-related disease is an inflammatory disease, such as acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, suppurative hidradenitis, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, etc. In one embodiment, the inflammatory disease is selected from the group comprising or consisting of acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or post-traumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, suppurative hidradenitis, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis and Crohn's disease.

According to one embodiment, the HDAC6-related disease is an autoimmune disease, such as arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (such as Crohn's disease or ulcerative colitis), Sjögren's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman's disease, ankylosing spondylarthritis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, dermatitis, radiation dermatitis, primary biliary cirrhosis, etc. In one embodiment, the autoimmune disease is selected from the group comprising or consisting of arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), Sjögren's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman's disease, ankylosing spondylarthritis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, deep lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft-versus-host disease, dermatitis, radiation dermatitis, and primary biliary cirrhosis.

According to one embodiment, the HDAC6-related disease is a proliferative disease, such as a cancer, such as a malignant tumor, angiogenic glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, angiogenesis, cachexia, breast cancer metastasis, colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, or gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, or adenocarcinoma), squamous cell carcinoma), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, or inflammatory breast cancer), ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, or ovarian tumor of low malignant potential), prostate cancer (e.g., hormone-dependent prostate cancer or hormone-independent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma in the kidney, or transitional cell carcinoma in the urinary tract), uterine cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, astrocytoma, diffuse astrocytoma or anaplastic astrocytoma), melanoma, sarcoma, bladder cancer, blood cancer, etc., including multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinoblastoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumors, bile duct cancer, gallbladder cancer, penile cancer, urinary tract cancer, testicular tumors, vulvar cancer, cervical cancer, endometrial cancer, uterine sarcoma, choriocarcinoma, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumors, soft tissue Sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, adult T-cell leukemia, chronic myeloproliferative disease, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, carcinoma of unknown primary, leukemia (e.g., acute leukemia (e.g., acute lymphocytic leukemia or acute myeloid leukemia), chronic leukemia (e.g., chronic lymphocytic leukemia or chronic myeloid leukemia), myelodysplastic syndrome, uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma or endometrial stromal tumor), myelofibrosis, etc. In one embodiment, the proliferative disease (e.g., cancer) is selected from the group comprising or consisting of: malignant tumor, angiogenic glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastatic melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, breast cancer metastasis, colorectal cancer (e.g., familial colorectal cancer, hereditary non-polyposis colorectal cancer, or gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma), or adenosquamous carcinoma), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, or inflammatory breast cancer), ovarian cancer (e.g., epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, or ovarian tumor of low malignant potential), prostate cancer (e.g., hormone-dependent prostate cancer or hormone-independent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid cancer), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma in the kidney, or transitional cell carcinoma in the urinary tract), uterine cancer, brain tumors (e.g., pineal astrocytoma, hair cell astrocytoma, diffuse astrocytoma or anaplastic astrocytoma), melanoma, sarcoma, bladder cancer, blood cancer, etc., including multiple myeloma, pituitary adenoma, glioma, acoustic neuroma, retinoblastoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophageal cancer, duodenal cancer, colorectal cancer, rectal cancer, liver cancer, pancreatic endocrine tumors, bile duct cancer, gallbladder cancer, penile cancer, urinary tract cancer, testicular tumors, vulvar cancer, cervical cancer, endometrial cancer, uterine sarcoma, choriocarcinoma, vaginal cancer, skin cancer, mycosis fungoides, basal cell tumors, soft tissue Sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, adult T-cell leukemia, chronic myeloproliferative disease, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, carcinoma of unknown primary, leukemia (e.g., acute leukemia (e.g., acute lymphocytic leukemia or acute myeloid leukemia), chronic leukemia (e.g., chronic lymphocytic leukemia or chronic myeloid leukemia)), myelodysplastic syndrome, uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma or endometrial stromal tumor) and myelofibrosis. In a particular embodiment, the proliferative disease is cancer. In one embodiment, the cancer is selected from the group comprising or consisting of malignant melanoma, multiple myeloma, leukemia, lymphoma, breast cancer and Hodgkin's disease.

According to one embodiment, the HDAC6-related disease is a neurodegenerative disease, such as Alzheimer's disease, Alzheimer's dementia, Alzheimer's senile dementia, Parkinson's disease, muscular dystrophy, Parkinson's disease associated with dementia, senile dementia, age-related cognitive memory disorders, Huntington's disease, multi-infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick's disease, Parkinson's dementia, Nieto-Pitt syndrome, Down's disease, vascular dementia, post-encephalitic Parkinson's syndrome, Lewy body dementia, Rutgers syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND), Krashen disease, etc. In one embodiment, the neurodegenerative disease is selected from the group comprising or consisting of Alzheimer's disease, Alzheimer's dementia, senile dementia of the Alzheimer's type, Parkinson's disease, muscular dystrophy, Parkinson's disease associated with dementia, senile dementia, age-related cognitive memory disorders, Huntington's disease, multi-infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick's disease, Parkinson's type dementia, Nieto-Pitt syndrome, Down's disease, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, Rutgers syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND) and Krasnoyarskoglu disease. In a particular embodiment, the neurodegenerative disease is selected from the group comprising or consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Pick's disease, Nieto-Pitt syndrome, Down's disease, dementia with Lewy bodies, HIV dementia, amyotrophic lateral sclerosis (ALS) and multiple sclerosis.

According to one embodiment, the HDAC6-related disease is pain (including central or peripheral pain), such as pain, cancer pain, acute pain caused by inflammation, pain associated with chronic inflammation, postoperative pain (such as incisional pain, deep pain, visceral pain or chronic pain after surgery), muscle pain (such as muscle pain associated with chronic pain disease or shoulder stiffness), joint pain, toothache, temporomandibular joint pain, headache (such as migraine, tension headache, headache associated with fever or headache associated with hypertension), visceral pain (such as cardiac pain, angina, abdominal pain, kidney pain, urinary tract pain or bladder pain), obstetric and gynecological pain (intermenstrual pain, dysmenorrhea, labor pain), neuropathic pain (such as intervertebral disc herniation, radicular pain, postherpetic neuralgia, trigeminal neuralgia or low back pain), migraine, stress headache, tension headache, muscle spasm, irritable bowel syndrome, etc. In one embodiment, the pain is selected from the group comprising or consisting of pain, cancer pain, acute pain caused by inflammation, pain associated with chronic inflammation, postoperative pain (e.g. incisional pain, deep pain, visceral pain, or chronic pain after surgery), muscle pain (e.g. muscle pain associated with chronic pain disorders or stiff shoulders), joint pain, dental pain, temporomandibular joint pain, headache (e.g. migraine, tension headache, headache associated with fever, or headache associated with hypertension), visceral pain (e.g. cardiac pain, angina, abdominal pain, kidney pain, urinary tract pain, or bladder pain), obstetric and gynecological pain (e.g. intermenstrual pain, dysmenorrhea, or labor pain), neuropathic pain (e.g. disc herniation, radicular pain, postherpetic neuralgia, trigeminal neuralgia, or low back pain), migraine, stress headache, tension headache, muscle spasm, and irritable bowel syndrome.

According to one embodiment, HDAC6-related diseases are neuropathy (including central or peripheral neuropathy), such as demyelinating diseases and neuropathy (such as multiple sclerosis, Guillain-Barre syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy or familial amyloid polyneuropathy), peripheral neuropathy (CIPN) derived from anticancer drugs and neurological symptoms associated therewith (such as chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic neuropathy (CINP)), diabetic neuropathy (CIPN), autonomic ataxia, injury-related neuropathy (such as traumatic brain injury or stroke), etc. Anticancer drugs that are prone to cause neuropathy include taxanes (such as paclitaxel (Taxol)), vinca alkaloids (such as vincristine), platinum-based active agents (such as cisplatin, carboplatin or oxaliplatin) or other molecular targeted drugs (such as bortezomib). In one embodiment, the neuropathy is selected from the group comprising or consisting of demyelinating diseases and neuropathies (e.g., multiple sclerosis, Guillain-Barre syndrome, Fisher's syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy or familial amyloid polyneuropathy), peripheral neuropathy (CIPN) derived from anticancer drugs and neurological symptoms associated therewith (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic ataxia and injury-related neuropathy (e.g., traumatic brain injury or stroke).

In a particular embodiment, the neuropathy is selected from the group comprising or consisting of Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy, familial amyloid polyneuropathy, chemotherapy-induced peripheral neuropathy (CIPN) using chemotherapeutic anticancer agents, diabetic peripheral neuropathy (DPN), neuralgia, pain and neuropathic pain.

According to one embodiment, the HDAC6-related disease is a psychiatric disorder, such as depression, major depression, bipolar depression, psychotic major depression, refractory major depression, treatment-resistant depression, depressive symptoms, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptoms, negative symptoms or cognitive symptoms), cognitive dysfunction associated with schizophrenia, stress disorder, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, dysthymic disorder, mood disorders (e.g., seasonal affective disorder), phobia, social phobia, neurosis, chronic fatigue syndrome, epilepsy, cyclothymia, addiction, anorexia nervosa, eating disorders, anorexia nervosa, bulimia or other eating disorders, drug addiction, pharmacophobia and drug addiction, etc. In one embodiment, the psychiatric disorder is selected from the group comprising or consisting of depression, major depression, bipolar depression, psychotic major depression, refractory major depression, treatment-resistant depression, depressive symptoms, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptoms, negative symptoms, or cognitive symptoms), cognitive dysfunction associated with schizophrenia, stress disorders, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, dysthymic disorder, mood disorders (e.g., seasonal affective disorder), phobia, social phobia, neurosis, chronic fatigue syndrome, epilepsy, cyclothymia, addiction, anorexia nervosa, eating disorders, anorexia nervosa, bulimia or other eating disorders, drug addiction, pharmacophobia, and drug addiction.

According to one embodiment, the HDAC6-related disease is a neurodevelopmental disorder, such as Tourette syndrome, autism, autism spectrum syndrome, fragile X syndrome, Rett syndrome, attention deficit hyperactivity disorder (ADHD), etc. In one embodiment, the neurodevelopmental disorder is selected from the group comprising or consisting of Tourette syndrome, autism, autism spectrum syndrome, fragile X syndrome, Rett syndrome and attention deficit hyperactivity disorder (ADHD).

According to one embodiment, the HDAC6-related disease is a sleep disorder, for example, an endogenous sleep disorder (e.g., psychophysiological insomnia), an exogenous sleep disorder, a circadian rhythm disorder (e.g., time zone change syndrome (jet lag syndrome), shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome or non-24-hour sleep-wake), a parasomnia, a sleep disorder associated with an intrinsic medical or mental disorder (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression or anxiety neurosis), stress, insomnia, insomnia neurosis, sleep apnea syndrome, etc. In one embodiment, the sleep disorder is selected from the group comprising or consisting of an endogenous sleep disorder (e.g., psychophysiological insomnia), an exogenous sleep disorder, a circadian rhythm disorder (e.g., time zone change syndrome (jet lag syndrome), shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, or non-24-hour sleep-wake), a parasomnia, a sleep disorder associated with an intrinsic medical or psychiatric disorder (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression or anxiety neurosis), stress, insomnia, insomnia, insomnia neurosis, and sleep apnea syndrome.

According to one embodiment, HDAC6-related diseases are cardiovascular diseases, such as chronic heart failure or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, hypertension, heart disease, tachycardia, congestive heart failure, etc. In one embodiment, cardiovascular diseases are selected from the group consisting of chronic heart failure or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, hypertension, heart disease, tachycardia and congestive heart failure. In a particular embodiment, heart-related diseases are selected from the group consisting of heart failure, cardiomyopathy and myocarditis.

According to one embodiment, the HDAC6-related disease is an addiction-related disorder, such as alcohol dependence, alcohol abuse, alcoholic amnesia, alcoholic paranoia, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcohol intoxication, alcoholic jealousy, alcoholic mania, alcohol-dependent psychiatric disorder, alcoholic psychosis, drug withdrawal, etc. In one embodiment, the addiction-related disorder is selected from the group comprising or consisting of alcohol dependence, alcohol abuse, alcoholic amnesia, alcoholic paranoia, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcohol intoxication, alcoholic jealousy, alcoholic mania, alcohol-dependent psychiatric disorder, alcoholic psychosis, and drug withdrawal.

According to one embodiment, the HDAC6-related disease is a gastrointestinal disease, such as peptic ulcer, irritable gastrointestinal disorder, stress vomiting, peptic ulcer, diarrhea, constipation or postoperative ileus, etc. In one embodiment, the gastrointestinal disease is selected from the group comprising or consisting of peptic ulcer, irritable gastrointestinal disorder, stress vomiting, peptic ulcer, diarrhea, constipation ileus and postoperative ileus.

According to one embodiment, the HDAC6-related disease is a pulmonary disease, such as hyperventilation, bronchial asthma, apnea, etc. In one embodiment, the pulmonary disease is selected from the group comprising or consisting of hyperventilation, bronchial asthma and apnea.

According to one embodiment, the HDAC6-related disease is a metabolic or hormonal disorder, such as obesity, diabetes, acromegaly, infertility, metabolic syndrome, etc. In one embodiment, the metabolic or hormonal disorder is selected from the group comprising or consisting of obesity, diabetes, acromegaly, infertility and metabolic syndrome.

According to one embodiment, the HDAC6-related disease is an immune disorder, such as an allergic disease, an immunodeficiency syndrome caused by HIV infection, an immunodeficiency syndrome caused by stress, etc. In one embodiment, the immune disorder is selected from the group comprising or consisting of an immunodeficiency syndrome caused by HIV infection and an immunodeficiency syndrome caused by stress.

According to one embodiment, the HDAC6-related disease is an age-related disease, such as alopecia, glaucoma, impotence, menopausal disorders, incontinence, osteoporosis, etc. In one embodiment, the age-related disease is selected from the group comprising or consisting of alopecia, glaucoma, impotence, menopausal disorders, incontinence and osteoporosis.

According to one embodiment, the HDAC6-related disease is an idiopathic disease, such as Meniere's disease, sudden infant death syndrome, etc. In one embodiment, the idiopathic disease is Meniere's disease or sudden infant death syndrome.

The compounds of the present invention or pharmaceutical compositions can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular (ICV), intracisternal injection or infusion, subcutaneous injection or implantation), inhalation spray, nasal, vaginal, rectal, sublingual or topical administration. In the treatment and/or prevention of infectious diseases, suitable dosage levels can be about 0.01-500 mg/kg patient body weight/day (mg/kg/day), which can be administered in single or multiple doses. Typically, the dosage level will be about 0.1-about 250 mg/kg/day, preferably about 0.5-about 100 mg/kg/day, more preferably about 2.5-about 20 mg/kg/day. The compound can be administered 1 to 4 times a day, preferably once or twice a day. However, it is to be understood that the specific dosage level and dosage frequency for any particular patient may vary and depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and duration of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular disease and the host being treated.

Advantageously, the compounds of the present invention are selective for at least one HDAC other than HDAC6, preferably selective for at least one class II HDAC other than HDAC6, more preferably selective for any class II HDAC other than HDAC6, and further preferably selective for HDACs other than HDAC6. Particularly advantageously, the compounds of the present invention are selective for HDAC1. Particularly advantageously, the compounds of the present invention are selective for HDAC10. Selectivity is closely related to avoiding the side effects of HDAC inhibitors.

Pill Box

The present invention also relates to a kit comprising a compound of the invention as described herein or a pharmaceutical composition of the invention as described herein and a means for administering said compound or pharmaceutical composition.

Means for administering compounds or pharmaceutical compositions are well known in the art and can be identified by one skilled in the art depending on the desired route of administration.

Example

The present invention is further illustrated by the following examples.

Example 1: Synthesis of compounds

Compounds (1)-(196) of formula (I) shown in Table 1 and/or Table 2 above were prepared as described below. Compounds 99 (CAS1287068-38-5), 100 (CAS1147354-39-9), 102 (CAS1210761-93-5) and 104 (CAS2419446-18-5) are commercially available. However, they can be prepared by using similar methods.

General synthetic method

The compounds of the present invention, particularly compounds of formula (I), can be prepared by methods known to those skilled in the art of organic synthesis or by using the following synthesis schemes. In all schemes described below, it should be understood that, according to the general principles of organic chemistry, the protecting groups of sensitive or reactive groups are used when necessary. Protecting groups are operated according to standard methods (TW Green and PGM Wuts, Protecting Groups in Organic Synthesis, 1991, John Wiley & Sons, Inc.). These groups are then removed at a convenient stage of synthesis using methods apparent to those skilled in the art. Many heterocyclic compounds of formula (I), wherein Y ¹ or Y ² are heteroaryl, can be prepared using synthetic routes well known in the art (AR Katrizky and C W Rees, 1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

The synthesis of the HDAC6 inhibitor disclosed in the present invention has been prepared using the following synthesis scheme. The specific implementation conditions of these reactions are provided in the detailed examples. The synthesis schemes described below show exemplary methods of the compounds of the present invention, but these routes should not be regarded as the only possible synthesis routes of the compounds of the present invention.

The compound of formula (I) can be obtained according to the following scheme 1:

Solution 1/Method 1

Amines T-1 are commercially available or can be synthesized by those skilled in the art of organic chemistry using a variety of methods described in the literature. Intermediate T-2 is prepared by protecting the amine group of T-1, for example using Boc ₂ O in the presence of a base (e.g., Et ₃ N or NaHCO ₃ ) and in a solvent (e.g., DCM or THF) at a suitable temperature (step 1). The protected amine intermediate T-2 can be subjected to a halogenation step using, for example, NBS or Br ₂ in a solvent (e.g., DCM) at a suitable temperature to give T-3, wherein X is a halogen, such as bromine (Br) (step 2). Next, the halide T-3 can be converted to the corresponding ketone T-4 in a single or multi-step-sequence, for example: (Option 1) a 2-step sequence, for example (i) a metal-catalyzed cross-coupling sequence, using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst/ligand system (e.g., Pd( _PPh3 ) ₄ , a base (e.g., t-BuOK), in a solvent (e.g., dioxane)), at a suitable temperature to give an enol ether intermediate, which is then converted to the desired ketone T-4 using an acid medium, such as HCl or aqueous formic acid at a suitable temperature (step 3); or (Option 2) in a 3-step sequence, for example (i) a metal-halide exchange, using, for example, n-BuLi, in an inert atmosphere such as nitrogen, at a controlled temperature such as -78°C, in an aprotic solvent such as dry THF, followed by introduction of dimethylformaldehyde or an equivalent reagent, to give the corresponding aldehyde intermediate T-5 (step 4). Intermediate T-5 can be treated with a methylating agent such as MeMgBr in an aprotic solvent such as THF at a suitable temperature to give the resulting alcohol T-6 (step 5). Alcohol T-6 can be converted to the corresponding ketone T-4 by using an oxidizing agent such as DMP or PCC in a solvent such as DCM at a suitable temperature (step 6). Ketone T-4 can be further halogenated using, for example, NBS or phenyltrimethylammonium tribromide in a solvent such as DCM or THF at a suitable temperature to give halo-ketone T-7 (step 7). Halo-ketone T-7 is then reacted with a thiol heteroaryl derivative of formula Y ¹ -SH in the presence of a base such as MeONa or K ₂ CO ₃ in a solvent such as DMF or ACN at a suitable temperature to give heteroaryl intermediate T-8 (step 8). Heteroaryl Y ¹ -SH is commercially available or can be prepared by methods known to those skilled in the art, for example from the corresponding heteroaryl Y ¹ -OH derivatives using Lawesson's reagent or P ₂ S ₅ reagent in a solvent such as toluene at a suitable temperature. Heteroaryl Y ¹ -OH is commercially available or can be prepared by methods known to those skilled in the art. The protected amine T-8 can then be deprotected in an acidic or basic medium, depending on the choice of the protecting group, for example in an acidic medium such as formic acid or aqueous HCl to remove the BoC-protecting group, or in hydrogenolysis using H ₂ in the presence of a catalyst such as Pd(OH) ₂ in a protic solvent such as MeOH to remove the benzyl-type protecting group, such as Cbz, to finally give the corresponding amine intermediate T-9 (step 9).

The final compound of formula (I), wherein Z ¹ is CO-R ⁹ , can be obtained by reacting amine T-9 with an acid chloride of formula R ⁹ -COCl in the presence of a base (such as Et ₃ N), a suitable solvent (such as DCM or THF), and at a suitable temperature (step 10a). Alternatively, the final compound of formula (I), wherein Z ¹ is CO-R ⁹ , can be obtained by reacting amine T-9 or with a carboxylic acid of formula R ⁹ -CO ₂ H acid in the presence of a coupling agent (such as HOBt or HATU), a base (such as Et ₃ N), in a solvent (such as DMF), and at a suitable temperature (step 10b). The final compound of formula (I), wherein Z ¹ is CO-R ⁹ and R ⁹ is -CH ₂ -OH, can be obtained by reacting amine T-9 with a carboxylic acid of formula HO ₂ C-CH ₂ -OSiR ₃ in the presence of a coupling agent (e.g. EDCI/HOBt or HATU), a base (e.g. Et ₃ N) in a solvent (e.g. DMF) at a suitable temperature, followed by deprotection of the silyl ether function -OSiR ₃ using a fluoride-based reagent (e.g. TBAF) in an aprotic solvent (e.g. THF) at a suitable temperature (step 10c), wherein SiR ₃ is, for example, tert-butyldiphenylsilyl (TBDPS-). Final compounds of formula (I), wherein Z ¹ is SO ₂ —R ⁹ , are obtained by reacting amine T-9 with a sulfonyl chloride of formula R ⁹ —SO ₂ Cl in the presence of a base such as Et ₃ N, a solvent such as DCM or THF, at a suitable temperature (step 10b).

The compound of formula (I) can also be obtained according to the following scheme 2 (method 2):

Solution 2/Method 2

Amine T-10 is commercially available or can be synthesized by one skilled in the art of organic chemistry using a variety of methods described in the literature. Intermediate compound T-11, wherein Z ¹ is CO-R ⁹ , can be prepared by reacting amine T-10 with an acid chloride of formula R ⁹ -COCl in the presence of a base (e.g., Et ₃ N) in a solvent (e.g., DCM or THF) at a suitable temperature; or with a carboxylic acid of formula R ⁹ -CO ₂ H acid in the presence of a coupling agent (e.g., EDCI/HOBt or HATU), a base (e.g., Et ₃ N) in a solvent (e.g., DMF) at a suitable temperature (step 1a). Intermediate compound T-11, wherein Z ¹ is SO ₂ -R ⁹ , can be obtained by reacting amine T-10 with a sulfonyl chloride of formula R ⁹ -SO ₂ Cl in the presence of a base (e.g., Et ₃ N) in a solvent (e.g., DCM or THF) at a suitable temperature (step 1b). The heteroaryl intermediate T-11 is then reacted with an acylating agent such as acetyl chloride in the presence of a suitable catalyst such as AlCl ₃ in a suitable solvent such as DCM at a suitable temperature to give the intermediate ketone T-12 (step 2). An alternative method for preparing ketone T-12 may be used, such as the method described in Scheme 1 (Method 1), using the reaction synthesis sequence of steps 2 and 3 or steps 2 to 6 from Scheme 1. Ketone T-12 may be subjected to a halogenation reaction using, for example, NBS or phenyltrimethylammonium tribromide in a solvent such as DCM or THF at a suitable temperature to give halo-ketone T-13 (step 3). Halo-ketone T-13 may be reacted with a heteroaryl thiol derivative of formula Y ¹ -SH in the presence of a base such as MeONa or K ₂ CO ₃ in a solvent such as DMF or ACN at a suitable temperature to give compounds of formula (I) (step 4).

In some cases, Z ¹ may carry a protecting group, such as tert-butyldiphenylsilyl (TBDPS). The protecting group may be removed during one of the reaction steps, such as step 3. Alternatively, the protecting group may be removed in a separate deprotection step using a suitable deprotecting agent, such as pyridinium fluoride (HF.Py), in a suitable solvent such as ACN at a suitable temperature, such as 30°C.

The compound of formula (I) can also be obtained according to the following Scheme 3 (Method 3), wherein L and R ¹ are linked together to form a cyclic amine:

Solution 3/Method 3

Protected cyclic amines T-14 are commercially available or can be synthesized by one skilled in the art of organic chemistry using a variety of methods described in the literature, for example, using Step 1 as described in Scheme 1, Method 1, from the corresponding free cyclic amine. Compound T-14 can be reacted with phenyltrifluorocarboximide, N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-trifluoromethylsulfonyl)methanesulfonamide or trifluoromethanesulfonic anhydride in the presence of a suitable base (e.g., LiHMDS) and a solvent (e.g., THF) at a suitable temperature to give the triflate enol ether T-15, wherein X is _{an OSO2CF3} group (Step 1). Suzuki cross-coupling of triflate T-15 with boronic acid or boronic ester of formula T-15A in the presence of a catalyst (e.g., Pd(dppf)Cl ₂ ), a base (e.g., Cs ₂ CO ₃ ), in a solvent (e.g., DMF), at a suitable temperature can afford the intermediate ketone T-16 (step 2). Boronic acid or boronic ester of formula T-15A can be commercially available or can be synthesized by one skilled in the art of organic chemistry using a variety of methods described in the literature. The double bond of the cyclic amine intermediate T-16 can then be reduced during hydrogenation using H ₂ in the presence of a catalyst (e.g., Pd/C or Pd(OH) ₂ ) in a solvent (e.g., MeOH) to afford the corresponding saturated amine intermediate T-17 (step 3). Halogenation of ketone T-17 can be carried out using, for example, NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at a suitable temperature to afford the halo-ketone T-18 (step 4). The halo-ketone T-18 can then be reacted with a thiol heteroaryl derivative of formula Y ¹ -SH in the presence of a base (e.g. MeONa or K ₂ CO ₃ ) in a solvent (e.g. DMF or ACN) at a suitable temperature to give the heteroaryl intermediate T-19 (step 5). The protected amine T-19 can be deprotected in acidic, neutral or basic medium, depending on the choice of the protecting group, e.g., removal of the BoC-protecting group using formic acid or aqueous HCl in acidic medium to give the corresponding amine intermediate T-20 (step 6).

The final compound of formula (I), wherein Z ¹ is CO-R ⁹ , can be obtained by reacting the cyclic amine T-20 with an acid chloride of formula R ⁹ -COCl in the presence of a base (such as Et ₃ N), a solvent (such as DCM or THF) at a suitable temperature; or with a carboxylic acid of formula R ⁹ -CO ₂ HCl in the presence of a coupling agent (such as EDCI/HOBt or HATU), a base (such as Et ₃ N), a solvent (such as DMF) at a suitable temperature (step 7a). The final compound of (I), wherein Z ¹ is SO ₂ -R ⁹ , can be obtained by reacting the cyclic amine T-20 with a sulfonyl chloride of formula R ⁹ -SO ₂ Cl in the presence of a base (such as Et ₃ N), a solvent (such as DCM or THF) at a suitable temperature (step 7b).

Compounds of formula (I) can also be obtained according to the following Scheme 4 (Method 4), wherein L and R ⁹ of the Z ¹ group are linked together to form a cyclic heterocycle, such as a cyclic amide:

Solution 4/Method 4

Intermediates T-21, wherein X is a halide, are commercially available or can be synthesized by those skilled in the art of organic chemistry using a variety of methods described in the literature, such as from the corresponding alcohol (X = OH) using a halogenating agent (such as SOCl ₂ ) in a solvent (such as THF) at a suitable temperature. The halide T-21 can be reacted with a heterocyclic amide of formula T-21A in the presence of a base (such as NaH) in a solvent (such as THF) at a suitable temperature to give the corresponding intermediate T-22 (step 1). Alternatively, compound T-22, wherein R ¹ is H, can be prepared from the above intermediate T-1 in a 2-step sequence (step 5, method 4a), by reacting the above intermediate T-1 with a chloroalkyl chloride, such as 3-chloropropionyl chloride, in the presence of a base (such as Et ₃ N), in a solvent (such as DCM), at a suitable temperature (step 1), followed by intramolecular cyclization in the presence of a base (such as NaH), in a solvent (such as DMF), at a suitable temperature (step 2). The keto group can be introduced on T-22 using the methods described in the above scheme 1 (steps 2 and 3; or steps 2 to 6) or in scheme 2 (step 2) to give the keto derivative T-23 (step 2). The keto intermediate T-23 can be subjected to a halogenation reaction using, for example, NBS or phenyltrimethylammonium tribromide in a solvent (such as ACN or DCM or THF) at a suitable temperature to give the halo-ketone T-24 (step 3).

The halo-ketone T-24 is then reacted with a thiol heteroaryl derivative of formula Y ¹ -SH in the presence of a base such as MeONa or K ₂ CO ₃ in a solvent such as DMF or ACN at a suitable temperature to give the final compound of formula (I) (step 4).

Synthesis of compounds - Experimental results

Several methods for preparing the compounds of the invention are exemplified in the following examples. Unless otherwise noted, all raw materials were obtained from commercial suppliers and used without further purification. In particular, the following abbreviations may be used throughout the examples and this specification.

Materials and analytical methods

All reactions were monitored by TLC using 0.25 mm E. Merck pre-coated silica gel plates (60F254) and Waters liquid chromatography-mass spectrometry (LCMS).

LCMS (Method 1) : LC-MS spectra were recorded on a Waters Acquity I class UPLC system using the following system. Formic acid and acetonitrile were used as HPLC grade. For analytical RP-HPLC analysis, the following gradient conditions were used:

LCMS (Method 2) : LCMS was recorded on an Agilent 1200 & 6120B instrument. High performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode-array or UV detector. The flow from the column was introduced into a mass spectrometer (MS) configured with an atmospheric pressure ion source. It is within the knowledge of those skilled in the art to set the tuning parameters to obtain ions of the nominal monoisotopic molecular weight (MW) and/or the exact mass monoisotopic molecular weight that allow identification of the compound. Data acquisition was performed using appropriate software. An ES MS detector was used to obtain the ions in positive or negative ionization mode. Compounds can be described by their molecular ions corresponding to [M+H ⁺ ] (protonated molecules) or [MH ⁺ ] (deprotonated molecules). For molecules with multiple isotopic patterns (Br, Cl), the reported values are those obtained for the lowest isotopic mass. All results with experimental uncertainties generally associated with the method used were obtained. The gradient conditions used are as follows:

LCMS (Method 3): Liquid chromatography-mass spectrometry (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions used were as follows:

LCMS (Method 4): Liquid chromatography-mass spectrometry (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions used were as follows:

LCMS (Method 5) : LCMS spectra were recorded on a Waters Acquity I class UPLC system using the following system. Formic acid and ammonia or TFA were used as HPLC grade. The following gradient conditions were used:

LCMS (Method 6) : LCMS was recorded on an Agilent 1200 instrument. High performance liquid chromatography (HPLC) measurements were performed using LC pumps, diode-array or UV detectors. The following gradient conditions were used:

LCMS (Method 7) : LCMS was recorded on an Agilent 1200 instrument. High performance liquid chromatography (HPLC) measurements were performed using an LC pump, diode-array or UV detector. The following gradient conditions were used:

LCMS (Method 8) : LCMS was recorded on Agilent 1200. High performance liquid chromatography (HPLC) measurements were performed using LC pump, diode-array or UV detector. The following gradient conditions were used:

RP-HPLC: Reverse phase HPLC was performed on a Waters HPLC system using the following system [Solvent A: acetonitrile, solvent B: 0.1% NH ₃ in water] or [Solvent A: acetonitrile, solvent B: 0.1% TFA in water]. Ammonia was used as HPLC grade. All separations were performed at ambient temperature.

Flash column chromatography: Purification of the reaction products was performed by column chromatography using commercially available silica or flash chromatography using CombiflashRf with Teledyne Isco RediSep Rf High Performance Gold or Silicycle SiliaSep High Performance columns (40, 80 or 120 g). All final compounds were more than 95% pure and were analyzed using a Waters LCMS system.

^1H NMR : ^1H NMR spectra were recorded on a Varian 400 MHz spectrometer and reported in ppm with the solvent resonance used as internal standard [CDCl ₃ at 7.26 ppm, DMSO-d ₆ at 2.50 ppm]. Peaks are reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad signal, coupling constants in Hz, integrated).

DSC: Melting point was determined using Differential Scanning Calorimetry. The following instrument, parameters and procedure were used:

abbreviation

The following abbreviations are used.

Preparation of synthetic intermediates

Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)carbamate (I-1) according to Method 1 (Scheme 1):

Synthesis of tert-butyl (thiophen-2-ylmethyl)carbamate (I-1a): To a solution mixture of thiophen-2-ylmethylamine (50.0 g, 441.770 mmol) in THF (500 mL) was slowly added NaHCO ₃ (37.1 g, 485.947 mmol) and (Boc) ₂ O (111.5 mL, 441.770 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with 30% EtOAc in hexanes and passed through silica gel to give compound (I-1a) (100 g, quantitative) as a white gummy solid. Synthesis of tert-butyl ((5-bromothiophen-2-yl)methyl)carbamate (I-1b): To a solution mixture of compound I-1a (50 g, 234.741 mmol) in DMF (500.0 mL) was added NBS (45.9 g, 258.215 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. Cold water was added to the reaction mixture and extracted with EtOAc (2×500 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) and the compound was eluted with 10% EtOAc in hexane to give compound (I-1b) (60.5 g, yield: 87%) as a brown colloidal liquid. Synthesis of tert-butyl ((5-formylthiophen-2-yl)methyl)carbamate (I-1c): To a solution mixture of compound I-1b (30.0 g, 102.739 mmol) in dry THF (600.0 mL) was added n-BuLi (1.6 M in hexane) (321 mL, 513.698 mmol) at -78°C and stirred at the same temperature for 30 minutes. DMF (39 mL, 513.698 mmol) was added dropwise at -78°C and stirring was continued for 2 hours. After the reaction was completed, the reaction mixture was quenched with saturated NH ₄ Cl solution (200 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) and eluted with 12% EtOAc in hexane to give compound I-1c (12.0 g, yield: 49%) as a brown gummy liquid. ¹ H NMR [400 MHz, CDCl ₃ ]: 9.83 (s, 1H), 7.63 (d, J=3.6 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 5.0 (s, 1H) 4.52 (d, J=6 Hz, 2H) 1.41 (s, 9H). Synthesis of tert-butyl ((5-(1-hydroxyethyl)thiophen-2-yl)methyl)carbamate (I-1d): To a solution of compound Ic (18.5 g, 76.7 mmol) in dry THF (400.0 mL) was added methylmagnesium bromide (1.0 M in THF) (767 mL, 767.0 mmol) at 0°C. Thereafter, it was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated _NH4Cl solution (500 mL) and washed with _EtOAc (2 x 500 mL). The combined organic layers were dried over _Na2SO4 and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) and the compound was eluted with 20% EtOAc in hexane to afford compound I-1d (13.0 g, yield: 66%) as a brown gummy liquid. ¹ H NMR [400 MHz, DMSO-d ₆ ]: 8.13 (s, 1H), 7.43 (s, 1H), 7.00 (s, 1H), 4.85 (d, J = 5.6 Hz, 2H), 4.19 (d, J = 2.0 Hz, 1H) 1.38-1.23 (m, 12H). Synthesis of tert-butyl ((5-acetylthiophen-2-yl)methyl)carbamate (I-1e): PCC (13.6 g, 63.15 mmol) was added to a solution mixture of compound I-1d (6.5 g, 25.26 mmol) in DCM (65.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was vacuum filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh), and the compound was eluted with 20% EtOAc in hexane to obtain compound I-1e (4.9 g, yield: 75%), which was a brown colloidal liquid. Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophene-2-yl)methyl)carbamate (I-1): Phenyltrimethylammonium tribromide (4.95 g, 13.1 mmol) was added to a solution mixture of compound-6 (4.8 g, 18.8 mmol) in THF (50 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered through a diatomaceous earth pad and concentrated in vacuo. Combi-fast C-18 purification was used to purify the crude compound to obtain compound I-1 (1.5 g, yield: 24%), which was a light brown solid. ¹ H NMR [400MHz, DMSO-d ₆ ]: 7.91 (d, J = 4Hz, 1H), 7.65 (t, J = 6Hz, 1H), 7.06 (d, J = 3.6Hz, 1H), 4.77 (s, 2H), 4.31 (d, J = 6Hz, 2H), 1.39 (s, 9H).

Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)carbamate (I-2) according to Method 1 (Scheme 1):

[0136] Synthesis of tert-butyl (2-(thiophen-2-yl)ethyl)carbamate (I-2a): To a stirred solution of 2-(thiophen-2-yl)ethan-1-amine (20.0 g, 157.22 mmol) in dichloromethane (200 mL) cooled to 0 °C was added (Boc) _2O (41.1 g, 188.66 mmol) followed by _Et3N (24.6 g, 243.10 mmol). The resulting mixture was stirred at room temperature for 16 hours. Thereafter, it was concentrated under reduced pressure. The crude product was diluted with water (100 mL), extracted with DCM (2 x 100 mL), and the combined organic layers _were dried over _Na2SO4 and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh), eluted with 10% EtOAc in hexane, and the pure fractions were evaporated to obtain compound I-2a (28 g, yield: 74%) as a brown colloidal liquid. Synthesis of tert-butyl (2-(5-bromothiophen-2-yl)ethyl)carbamate (I-2b): To a solution of compound I-2a (28 g, 123.172 mmol) in DMF (400 mL) cooled to 0°C was added NBS (21.9 g, 123.172 mmol) in portions. The mixture was then stirred at room temperature for 2 hours, and then poured into a mixture of ice water (100 mL) and EtOAc (200 mL). The organic layer was separated, washed with _brine solution (100 mL), dried over _Na2SO4 , and then concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (100-200 mesh) using 10% EtOAc in hexane to elute the compound to give compound I-2b (37.08 g, yield: 98%) as an off-white solid. Synthesis of tert-butyl (2-(5-formylthiophen-2-yl)ethyl)carbamate (I-2c): n-BuLi (1.6 M in hexane) (204.0 mL, 326.563 mmol) was added dropwise to a solution of compound I-2b (20.0 g, 65.312 mmol) in dry THF (200 mL) cooled to -78°C, and the resulting mixture was stirred for 15 minutes, after which dry DMF (35.9 g, 491.80 mmol) was added and stirring was continued for 30 minutes at the same temperature. After completion of the reaction, the reaction mixture was quenched with saturated NH ₄ Cl aqueous solution (150 mL) and extracted with EtOAc (2×200 mL). The organic layer was separated, dried over _Na2SO4 , and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (100-200 mesh) and eluted with 15% _EtOAc in hexane to obtain compound I-2c (10.0 g, yield: 57%) as a colloidal liquid. Synthesis of tert-butyl (2-(5-(1-hydroxyethyl)thiophene-2-yl)ethyl)carbamate (I-2d): Methylmagnesium bromide (1.0 M in THF) (705.0 mL, 70.496 mmol) was added dropwise to a solution of compound I-2c (18.0 g, 70.496 mmol) in dry THF (180 mL) cooled to 0°C, and thereafter, slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (2× ₃₀₀ mL). The organic layer was separated, dried over _Na2SO4 , and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (100-200 mesh) and eluted with 20% EtOAc in hexane to give compound I-2d (15.0 g, yield: 78%) as a gummy solid. Synthesis of tert-butyl (2-(5-acetylthiophene-2-yl)ethyl)carbamate (I-2e): Dess-Martin periodinane (46.8 g, 110.547 mmol) was added to a solution of compound I-2d (10 g, 36.849 mmol) in dry DCM (100 mL) cooled to 0°C, then slowly heated to room temperature and stirred for 16 hours. The reaction mixture was filtered through a diatomaceous earth pad and washed with dichloromethane, then the solvent was evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography (100-200 mesh) eluting with 15% EtOAc in hexane to give compound I-2e (7.1 g, yield: 72%) as a gummy solid. Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophene-2-yl)ethyl)carbamate (I-2): To a solution of compound I-2e (7.0 g, 25.987 mmol) in dry THF (70.0 mL) was added trimethylphenylammonium tribromide (7.8 g, 20.789 mmol), and the mixture was stirred at room temperature for 16 hours. The solvent was then evaporated, and the crude material was purified by combi-flash reverse phase chromatography to give I-2 (2.05 g, yield: 23%) as an off-white solid.

Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)(methyl)carbamate (I-3) according to Method 1 (Scheme 1):

Synthesis of tert-butyl ((5-bromothiophen-2-yl)methyl)(methyl)carbamate (I-3a): To a solution mixture of tert-butyl ((5-bromothiophen-2-yl)methyl)carbamate (I-1b) (40 g, 136.986 mmol) in DMF (400.0 mL) was added NaH (6.56 g, 273.0 mmol) at 0°C, followed by iodomethane (12.8 mL, 205.479 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with ice water (150 mL) and extracted with EtOAc (2×500 mL), and dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude 43 g of compound I-3a, which was used in the next step without further purification. Synthesis of tert-butyl ((5-formylthiophen-2-yl)methyl)(methyl)carbamate (I-3b): To a solution mixture of compound (I-3a) (22.0 g, 71.89 mmol) in dry THF (400.0 mL) was added n-BuLi (1.6 M in hexanes) (224 mL, 359.47 mmol) at -78°C and stirred for 30 minutes at -78°C. After adding DMF (27.9 mL, 359.47 mmol) at -78°C and stirring for 2 hours, the reaction mixture was quenched with saturated NH ₄ Cl solution (200.0 mL) and extracted with EtOAc (2×500 mL), and the combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) eluted with 12% EtOAc in hexane to give compound I-3b (6.5 g, yield: 35%) as a colloidal liquid, which was used without further purification. Synthesis of tert-butyl ((5-(1-hydroxyethyl)thiophen-2-yl)methyl)(methyl)carbamate (I-3c): To a solution mixture of compound I-3b (13.0 g, 50.9 mmol) in dry THF (250.0 mL) was added methylmagnesium bromide (1.0 M in THF) (509 mL, 509.0 mmol) at 0°C, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NH ₄ Cl solution (500 mL) and washed with EtOAc (2×500 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) and eluted with 20% EtOAc in hexane to obtain compound I-3c (10 g, yield: 72%) as a colloidal liquid, which was used without further purification. Synthesis of tert-butyl ((5-acetylthiophene-2-yl)methyl)(methyl)carbamate (I-3d): PCC (19.8 g, 92.2 mmol) was added to a solution mixture of compound I-3c (10.0 g, 36.9 mmol) in DCM (100.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Thereafter, the reaction mixture was filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) and eluted with 20% EtOAc in hexane to obtain compound I-3d (7.6 g, yield: 77%) as a colloidal liquid, which was used without further purification. Synthesis of ((5-(2-bromoacetyl)thiophene-2-yl)methyl)(methyl)-tert-butyl carbamate (I-3): To a solution mixture of compound I-3d (4.3 g, 15.9 mmol) in THF (50 mL) was added phenyltrimethylammonium tribromide (4.20 g, 11.1 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a diatomaceous earth pad and concentrated in vacuo. Combi-fast reverse phase purification was used to purify the crude compound (using ACN and 0.001% TFA in water) to obtain compound I-3 (1.5 g, yield: 27%) as a light brown solid.

Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pivalamide (I-4) according to Method 2 (Scheme 2):

Synthesis of N-(thiophen-2-ylmethyl)pivalamide (I-4a): To a solution mixture of thiophen-2-ylmethylamine (30 g, 265.062 mmol) in DCM (300.0 mL) was added Et ₃ N (55.7 mL, 398.230 mmol) at 0°C. The resulting reaction mixture was stirred at 0°C for 10 minutes, after which pivaloyl chloride (39.14 mL, 318.584 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (500.0 mL) and washed with water (2×100 mL), and the organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) eluted with 10% EtOAc in hexane to give compound I-4a (40 g, yield: 77%) as a gummy liquid, which was used without further purification. Synthesis of N-((5-acetylthiophen-2-yl)methyl)pivalamide (I-4b): To a solution mixture of AlCl ₃ (14.05 g, 105.30 mmol) in DCM (166.0 mL) was added dropwise acetyl chloride (3.60 mL, 50.5 mmol) at 0°C. After 5 minutes, compound I-4a (8.3 g, 42.1 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. Thereafter, the reaction mixture was quenched with cold water (100 mL) and extracted with DCM (2×300 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) eluted with 20% EtOAc in hexane to afford compound I-4b (8.0 g, yield: 80%) as a white solid. Synthesis of N-((5-(2-bromoacetyl)thiophene-2-yl)methyl)pivalamide (I-4): To a solution mixture of compound I-4b (25 g, 104.6 mmol) in THF (460 mL) was added phenyltrimethylammonium tribromide (27.53 g, 73.2 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a diatomaceous earth bed and concentrated in vacuo. The crude compound was purified using combi-fast reverse phase purification (using ACN and 0.001% TFA in water) to give I-4 (6.2 g, yield: 19%) as an off-white solid. ¹ H NMR [400MHz, DMSO-d ₆ ]: 8.37-8.32 (m, 1H), 7.91-7.86 (m, 1H), 7.13-7.06 (m, 1H), 4.76 (s, 2H), 4.44 (d, J = 5.6Hz, 2H), 1.11 (s, 9H).

Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)pyrrolidine-1-carboxylate (I-5) according to Method 3 (Scheme 3):

Synthesis of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-5a): LiHMDS (1.0M in THF) (6.0 mL, 5.934 mmol) was added dropwise to a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.398 mmol) in dry THF (10 mL) cooled to -78 ° C, and the resulting mixture was stirred for 60 minutes. N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide in THF (2.33 g, 5.934 mmol) was added to the solution and stirred at the same temperature for 30 minutes. Next, the reaction mixture was warmed to room temperature, quenched with saturated NaHCO ₃ aqueous solution (10 mL), and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over _Na2SO4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( _60-120 mesh) eluting with 10% EtOAc in hexanes to give compound I-5a (0.63 g, 37% yield) as a gummy liquid. Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-5b): To a stirred solution of (5-acetylthiophen-2-yl)boronic acid (1.6 g, 9.463 mmol) and tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate 2 (3 g, 9.463 mmol) in dioxane:H ₂ O (30 mL, 3:1) was added K ₂ CO ₃ (3.9 g, 28.389 mmol) and Pd(dppf)Cl ₂ (1.0 g, 0.9463 mmol). The reaction system was purged with N ₂ for 15 min and then heated to 100 °C for 16 h. Next, the mixture was quenched with saturated NaHCO ₃ aqueous solution (20 mL), and then extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (60-120 mesh, eluent: 50% EtOAc in hexane) to obtain the title compound I-5b (2.7 g, 75% yield) as a colloidal liquid. Synthesis of tert-butyl 3-(5-acetylthiophene-2-yl)pyrrolidine-1-carboxylate (I-5c): 10% Pd-C (2.0 g) was added to a stirred solution of tert-butyl 3-(5-acetylthiophene-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate I-5b (2 g, 6.825 mmol) in MeOH (20 mL), and H ₂ gas was passed at 60 psi for 5 hours. The reaction mixture was vacuum filtered through a diatomaceous earth bed. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (60-120 mesh, eluent: 50% EtOAc in hexane) to obtain the title compound I-5c (1.5 g, 74% yield) as a yellow liquid. Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophene-2-yl)pyrrolidine-1-carboxylate (I-5): Tetrabutylammonium tribromide (0.8 g, 1.360 mmol) was added to a solution of compound I-5c (0.2 g, 0.680 mmol) in dry THF (5 mL), followed by stirring at room temperature for 16 hours. The reaction mixture was concentrated to obtain a crude compound, which was purified by Combi-fast reverse phase chromatography to obtain I-5 (0.07 g, 27% yield) as a white solid. ¹ H NMR[400MHz,DMSO-d ₆ ]:7.95(d,J＝3.6Hz,1H),7.15(d,J＝4Hz,1H),4.78(s,2H),3.73-3.69(m,2H),3.40-3.23(m,4H),2.33-2.29(m,1H),1.40(s,9H)。

Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6) according to Method 4 (Scheme 4):

Synthesis of 2-(chloromethyl)thiophene (I-6a): According to method 4, step 1: To a solution of thiophen-2-ylmethanol (2.0 g, 17.518 mmol) in THF (20 mL) was added SOCl ₂ (2.5 g, 21.021 mmol) at 0°C. The reaction mixture was stirred at 50°C for 3 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was concentrated. The crude residue was used in the next step without further purification. Synthesis of 3-methyl-1-(thiophen-2-ylmethyl)pyrrolidin-2-one (I-6b): To a solution of compound I-6a (0.5 g, 5.043 mmol) in dry THF (5.0 mL) was added NaH (60% in oil) (0.3 g, 7.575 mmol) at 0°C. 3-methylpyrrolidin-2-one (0.66 g, 5.043 mmol) was added at the same temperature, and the mixture was stirred for 30 minutes. Thereafter, the reaction mixture was allowed to reach room temperature and stirred for another 16 hours. After the reaction was complete, the reaction mixture was concentrated and purified by silica gel column chromatography (60-120 mesh, eluent: 10% EtOAc in hexane) to obtain compound I-6b (0.45 g, 50% yield) as a yellow colloidal liquid. Synthesis of 1-((5-bromothiophene-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6c): NBS (0.4 g, 2.304 mmol) was added to a solution of compound I-6b (0.45 g, 2.304 mmol) in acetonitrile (5.0 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated, diluted with water (20 mL), and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na ₂ SO ₄ , and the solvent was concentrated under reduced pressure. The crude material was purified by combi-flash reverse phase chromatography to give compound I-6c (0.5 g, 79% yield) as a yellow colloidal liquid. Synthesis of 1-((5-acetylthiophene-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6d): A stirred solution of compound I-6c (0.5 g, 1.824 mmol) in toluene was purged with N ₂ , followed by the addition of tributyl(1-ethoxyvinyl)stannane (0.78 g, 2.160 mmol) and Pd(PPh ₃ ) ₄ (0.2 g, 0.182 mmol). The reaction mixture was stirred at 110° C. for 16 hours. Saturated KF solution was added to the reaction mixture and stirring was continued at room temperature for 30 minutes. The organic layer was separated and concentrated under reduced pressure to give the crude compound. THF (20 mL) and concentrated HCl were added to the crude reaction mixture. After stirring for 30 minutes, solid Na ₂ CO ₃ was added until pH~7. The mixture was diluted with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (60-120 mesh, eluent: 20% EtOAc in hexane) to give compound I-6d (0.3 g, 70% yield) as a white solid. Synthesis of 1-((5-(2-bromoacetyl)thiophene-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6): Tetrabutylammonium tribromide (0.6 g, 1.265 mmol) was added to a solution of compound I-6d (0.3 g, 1.265 mmol) in dry THF (5 mL), and the reaction mixture was stirred at room temperature for 16 hours. Next, the reaction mixture was concentrated, and the residue was purified by Combi-fast reverse phase chromatography to give I-6 (0.07 g, 16% yield) as a white solid.

Synthesis of N-((5-(2-bromoacetyl)-3-fluorothiophen-2-yl)methyl)pivalamide (I-7) according to Method 2 (Scheme 2)

Synthesis of (3-fluorothiophene-2-yl)methanol (I-7a): Lithium aluminum hydride (1M in THF, 30 mL) was added dropwise to a stirred solution of methyl 3-fluorothiophene-2-carboxylate (5.0 g, 31.25 mmol) in dry THF (50 mL) at 0°C, and the reaction mixture was stirred at 0°C in nitrogen for 1 hour. After the reaction was complete, the mixture was quenched with 10 mL of water, 15% NaOH solution (10 mL), and stirred for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the diatomaceous earth pad was washed with _EtOAc and THF. The aqueous layer was extracted, and the combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 8% EtOAc/hexane to give pure light yellow liquid compound I-7a (3.0 g, yield: 73%). ¹ H NMR [400 MHz, DMSO-d ₆ ]: 7.464-7.440 (m, 1H), 6.936-6.920 (m, 1H), 5.46 (t, J = 5.6 Hz, 1H), 4.54 (dd, J = 6.0, 1.6 Hz, 2H). Synthesis of 2-(azidomethyl)-3-fluorothiophene (I-7b): To a stirred solution of compound I-7a (3 g, 22.7 mmol) in toluene (30 mL) was added DPPA (5.8 mL, 27.2 mmol), followed by DBU (4 mL, 27.2 mmol) at 0° C., and the resulting mixture was stirred at room temperature in N ₂ for 1 hour. After completion of the reaction (TLC monitoring), the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with 2% EtOAc/hexane to give compound I-7b (2.5 g, yield: 71%) as a colorless oil. ¹ H NMR [400 MHz, CDCl ₃ ]: 7.22-7.19 (m, 1H), 6.83-6.61 (m, 1H), 4.44 (s, 2H). Synthesis of (3-fluorothiophene-2-yl)methylamine (I-7c): To a stirred solution of compound I-7b (2.6 g, 16.5 mmol) in dry THF (40 mL) was added a THF solution of LAH (1.2 g, 33.1 mmol) at 0°C. The reaction mixture was then stirred at 0°C for 30 minutes. The reaction was monitored by TLC. After the reaction was complete, the mixture was quenched with water and 10% NaOH solution. The reaction mixture was washed with EtOAc (2×50 mL). The combined organic layers _were dried over _Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 2% MeOH/DCM to give compound I-7c (2 g, yield: 95%) as a pale yellow oil. ^1H NMR [400MHz, DMSO- _d6 ]: 7.37-7.35 (m, 1H), 6.92-6.89 (m, 1H), 3.83 (s, 2H). Synthesis of N-((3-fluorothiophen-2-yl)methyl)pivalamide (I-7d) according to Method 2 (Step 1): To a stirred solution of compound I-7c (2.5 g, 19.08 mmol) in DCM (25 mL) was added TEA (6.7 mL, 47.7 mmol), followed by pivaloyl chloride (3.5 mL, 28.6 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC, and after completion, the mixture was quenched with water and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified using column chromatography using 10%-30% ethyl acetate: petroleum ether as eluent to afford compound I-7d (2.5 g, yield: 61%). Synthesis of N-((5-bromo-3-fluorothiophen-2-yl)methyl)pivalamide (I-7e) according to Method 2 (Step 2): To a stirred solution of compound I-7d (1.2 g, 5.6 mmol) in ACN (12 mL) was added NBS (1 g, 5.6 mmol), and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the crude compound was purified using RP combi-flash column chromatography using 10% acetonitrile:H ₂ O (0.01% FA) as eluent to afford compound I-7e (400 mg, yield: 25%). Synthesis of N-((5-acetyl-3-fluorothiophen-2-yl)methyl)pivalamide (I-7f) according to Method 2 (Step 3): To a stirred solution of compound I-7e (770 mg, 2.6 mmol) in dioxane (10 mL) was added tributyl(1-ethoxyvinyl)tin (1.2 g, 3.4 mmol), followed by Pd(PPh ₃ ) ₄ (0.3 g, 2.6 mmol), and the resulting mixture was stirred at 110° C. in N ₂ for 16 hours. After the reaction was complete, the mixture was cooled to room temperature. Saturated KF solution was added, and the mixture was stirred for 30 minutes, after which EtOAc (20 mL) was added. The aqueous layer was extracted, and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The solid residue was dissolved in 2N HCl, and the mixture was stirred for 30 minutes. Next, solid Na ₂ CO ₃ was added to the mixture until pH>7, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by column chromatography using 20% ethyl acetate: petroleum ether as eluent to obtain pure compound I-7f (290 mg, yield: 43%). Synthesis of N-((5-(2-bromoacetyl)-3-fluorothiophene-2-yl)methyl)pivalamide (I-7) according to method 2 (step 4): tetrabutylammonium tribromide (1 g, 2.2 mmol) was added to a stirred solution of compound 7 (290 mg, 1.1 mmol) in dry THF (4 mL) at 0°C, and the resulting mixture was stirred at 50°C for 16 hours. After the reaction was complete, the solvent was concentrated under reduced pressure to obtain a crude compound, which was purified using combi-flash chromatography to obtain compound I-7 (130 mg, yield: 34%) as a colloidal solid.

Synthesis of N-((2-(2-bromoacetyl)thiazol-5-yl)methyl)pivalamide (I-8) according to Method 2 (Scheme 2).

Synthesis of (2-bromothiazol-5-yl)methanol (I-8a): To a solution of methyl 2-bromothiazol-5-carboxylate (24.0 g, 101.69 mmol) in dry THF (200 mL) was added DIBAL-H (1.0 M in toluene) (203.0 mL, 203.38 mmol) at 0°C. The resulting mixture was stirred for 15 minutes and slowly warmed to room temperature for 2 hours. Next, the reaction mixture was quenched with saturated aqueous NH ₄ Cl solution (200 mL) and extracted with EtOAc (2×200 mL). The organic layer was separated, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60-120 mesh, eluent: 10% EtOAc in hexanes) to give compound I-8a (11.1 g, 56% yield) as a gummy solid. Synthesis of 2-((2-bromothiazol-5-yl)methyl)isoindoline-1,3-dione (I-8b): To a stirred solution of triphenylphosphine (16.2 g, 61.8 mmol) in dry THF (100 mL) was added DEAD (9.8 g, 56.6 mmol) dropwise at 0°C, and the reaction mixture was stirred at this temperature for 15 minutes. Compound I-8a (10.0 g, 51.5 mmol) in THF (20 mL) was added to the reaction mixture, followed by isoindoline-1,3-dione (8.3 g, 56.6 mmol) at 0°C. The reaction mixture was then concentrated under reduced pressure. The crude residue was diluted with water (150 mL), extracted with DCM (2×100 mL), and the organic layer was separated, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (60-120 mesh, eluent: 30% EtOAc in hexane) to give compound I-8b (8.0 g, 50% yield) as a white solid. Synthesis of (2-bromothiazol-5-yl)methylamine (I-8c): To a stirred solution of compound I-8b (8.0 g, 24.76 mmol) in EtOH (80 mL) at 0°C was added hydrazine hydrate (3.9 g, 123.8 mmol). The mixture was stirred at 0°C for 15 minutes and then at 75°C for 2 hours. The reaction mixture was then concentrated under reduced pressure. The crude residue was diluted with water (100 mL) and extracted with DCM (2×100 mL). The organic layer was separated, dried over Na ₂ SO ₄ , and concentrated under reduced pressure to give crude compound I-8c (4.0 g crude material, 46% pure by LCMS). The crude material was used in the next step without further purification. [0136] Synthesis of N-((2-bromothiazol-5-yl)methyl)pivalamide (I-8d) according to Method 2 (Step 1): To a stirred solution of compound I-8c (1.0 g, 5.177 mmol) in DCM (10 mL) was added _Et3N (1.0 g, 10.354 mmol) followed by pivaloyl chloride (0.92 g, 7.765 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude residue was diluted with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers _were dried over _Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (60-120 mesh, eluent: 20% EtOAc in hexanes) to give crude compound I-8d (0.7 g) as a white solid. [0136] Synthesis of N-((2-acetylthiazol-5-yl)methyl)pivalamide (I-8e) according to Method 1 (Step 2 and Step 3): To _a stirred solution of compound I-8d (2.0 g, 7.220 mmol) and tributyl(1-ethoxyvinyl)stannane (3.3 g, 9.386 mmol) in toluene (20 mL) was added Pd(PPh ₃ ) ₄ (0.8 g, 0.72 mmol) under N 2, and the reaction mixture was stirred to 110°C for 16 hours. Saturated potassium fluoride solution was added to the reaction mixture, and stirring was continued at room temperature for 30 minutes. The organic layer was separated and concentrated under reduced pressure. THF was added to the residue, followed by concentrated HCl, and the biphasic mixture was stirred for 30 minutes. The pH of the reaction mixture was adjusted to >7 by slow addition of solid Na ₂ CO _3. Next, the mixture was diluted with water (80 mL) and extracted with DCM (2×100 mL). The combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure. The crude material was purified by _silica gel column chromatography (60-120 mesh) using 10% ethyl acetate: petroleum ether as eluent to afford crude compound I-8e (0.5 g, 36% product by LCMS) as a gummy solid and used as such. Synthesis of N-((2-(2-bromoacetyl)thiazol-5-yl)methyl)pivalamide (I-8) according to Method 2 (Step 3): To a solution of compound I-8e (0.450 g, 1.87 mmol) in dry THF (4.0 mL) was added tetrabutylammonium tribromide (0.9 g, 1.8 mmol) and stirred at room temperature for 16 hours. The reaction mixture was concentrated and the crude residue was purified by Combi-flash reverse phase chromatography to afford I-8 (0.15 g, 68% yield) as a white solid.

Synthesis of N-(1-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-2-hydroxyacetamide (I-9) according to Method 2 (Scheme 2):

Synthesis of (S,E)-N-((5-bromothiophen-2-yl)methylene)-2-methylpropane-2-sulfinamide (I-9a): To a solution of 5-bromothiophene-2-carboxaldehyde (12.0 g, 62.8 mmol, 7.45 mL) in THF (150 mL) were added Ti(OEt) ₄ (28.7 g, 126 mmol, 26.1 mL) and (S)-2-methylpropane-2-sulfinamide (9.14 g, 75.4 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by the addition of H ₂ O (50.0 mL) at 25 °C, and then extracted with EtOAc (30.0 mL×4). The combined organic layers were washed with brine (30.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1-0/1) to give compound I-9a (17.0 g, 90% yield, 98.1% purity) as a light yellow solid. Synthesis of (S)-N-((S)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (I-9b): MeMgBr (3M, 57.8 mL) was added dropwise to a solution of compound I-9a (17.0 g, 57.8 mmol) in THF (119 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 hour. The reaction mixture was then quenched at 25° C. by the addition of NH ₄ Cl (50.0 mL), followed by extraction with DCM (50.0 mL×3). The combined organic layers were washed with brine (30.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1-0/1) to give compound I-9b (13.4 g, 62% yield, 83.5% purity) as a light yellow solid. Synthesis of (S)-1-(5-bromothiophene-2-yl)ethyl-1-amine (I-9c): Acetyl chloride (2.28 g, 29.0 mmol, 2.07 mL) was added dropwise to a solution of compound I-9b (3.00 g, 9.67 mmol) in MeOH (21.0 mL) at 25° C. After addition, the mixture was stirred at this temperature for 1 hour. The solvent was removed in vacuo, and then TEA (10.3 g, 102 mmol, 14.1 mL) and THF (30.0 mL) were added dropwise at 25° C. The resulting mixture was stirred at 25° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1-0/1) to give compound I-9c (7.40 g, 60.2% yield) as a light yellow oil. Synthesis of (S)-N-(1-(5-bromothiophen-2-yl)ethyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-9d): To a solution of 2-[tert-butyl(diphenyl)silyl]oxyacetic acid (12.4 g, 39.5 mmol) in DCM (66.6 mL) and DMF (7.40 mL) was added HOBt (7.28 g, 53.9 mmol), EDCI (10.3 g, 53.9 mmol) and DIPEA (13.9 g, 108 mmol, 18.8 mL) at 25° C. Then compound I-9c (7.40 g, 35.9 mmol) was added at 25° C. The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by adding _H2O (30.0 mL) at 25° _C , and then extracted with EtOAc (13.0 mL x 3). The combined organic layers were washed with brine (20.0 mL), dried over _Na2SO4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 1/0-0/1) to give compound I-9d (9.60 g, 52% yield, 96.7% purity) as a light yellow oil. Synthesis of N-(1-(5-acetylthiophen-2-yl)ethyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-9e): To a solution of compound I-9d (9.50 g, 18.9 mmol) in toluene (66.5 mL) was added dropwise tributyl(1-ethoxyvinyl)stannane (13.7 g, 37.8 mmol, 12.8 mL) at 25°C, followed by the addition of Pd(PPh ₃ ) ₄ (1.09 g, 945 umol) at 25°C. The resulting mixture was stirred at 120°C for 2 hours. Saturated potassium fluoride solution (50.0 mL) was added to the reaction mixture, and stirred at room temperature for 30 minutes. The organic layer was separated and concentrated under reduced pressure to give a crude compound. THF (50.0 mL) and 1M HCl (20.0 mL) were added to the crude reaction mixture, and stirred for 30 minutes, and solid Na ₂ CO ₃ was added until pH~7. The reaction mixture was diluted with water (50.0 mL) and extracted with DCM (50.0 mL×3). The organic layer was separated, dried over Na ₂ SO ₄ , and concentrated under reduced pressure to give a crude compound. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1) to give compound I-9e (6.40 g, 71% yield, 98.0% purity) as a yellow oil. Synthesis of N-(1-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-2-hydroxyacetamide (I-9): TBATB (6.85 g, 14.2 mmol) was added to a solution of compound I-9e (6.30 g, 13.5 mmol) in DCM (37.8 mL) and MeOH (94.5 mL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was quenched by adding _H2O (20.0 mL) at 25°C, and then extracted with EtOAc (40.0 _mL x 3). The combined organic layers were washed with brine (30.0 mL), dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 1/0-0/1) to give compound I-9 (3.00 g, 61% yield, 83.8% purity) as a light yellow oil.

Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pyrrolidin-2-one (I-10) according to Method 4a (Scheme 4).

Synthesis of 4-chloro-N-(thiophen-2-ylmethyl)butanamide (I-10a) according to Method 4a (Step 1): To a mixture of a solution of thiophen-2-ylmethylamine (5.0 g, 44.1 mmol) and Et ₃ N (19.8 mL, 141.0 mmol) in DCM (130.0 mL) was added dropwise a solution of 4-chlorobutyryl chloride (6.57 mL, 58.3 mmol) in DCM (20.0 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, after which it was quenched with cold water (100 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was used in the next step without further purification to afford compound I-10a (7.0 g, yield: 73%) as a gummy liquid. Synthesis of 1-(thiophen-2-ylmethyl)pyrrolidin-2-one (I-10b) according to Method 4a (Step 2): To a solution mixture of compound I-10a (3.0 g, 13.7 mmol) in DMF (30.0 mL) was added NaH (826 mg, 20.6 mmol (60% in mineral oil)) at room temperature, and the mixture was stirred for 3 hours. Next, the reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (100-200 mesh) eluted with 12% EtOAc in hexane to give compound I-10b (1.8 g, yield: 72%) as a gummy liquid. Synthesis of 1-((5-acetylthiophen-2-yl)methyl)pyrrolidin-2-one (I-10c) according to Method 2 (Step 3): To a solution of AlCl ₃ (1.95 g, 14.91 mmol) in DCM (50.0 mL) was added acetyl chloride (0.80 mL, 11.93 mmol) dropwise at 0°C. After 5 minutes, compound I-10b (1.8 g, 9.94 mmol) was added and stirring was continued at 0°C for 1 hour. The reaction mixture was then quenched with cold water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) eluted with 30% EtOAc in hexane to give compound I-10c (0.99 g, yield: 45%) as a gummy liquid. Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pyrrolidin-2-one (I-10) according to Method 2 (Step 4): To a solution mixture of compound I-10c (500 mg, 2.242 mmol) in THF (10 mL) was added phenyltrimethylammonium tribromide (576.0 mg, 1.569 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours, after which it was filtered through a celite bed and concentrated in vacuo. The crude compound was purified using Combi-fast reverse phase purification (using ACN and 0.001% TFA in water as eluents) to give compound I-10 (0.25 g, yield: 36%) as an off-white solid.

Synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)pyrrolidin-2-one (I-11) according to Method 4a (Scheme 4)

Synthesis of N-((5-(2-bromoacetyl)-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12): According to experimental conditions similar to those of intermediate I-10, starting from 2-(thiophen-2-yl)ethan-1-amine, and reacting with chlorobutyryl chloride to synthesize 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)pyrrolidin-2-one (I-11), compound I-11 (0.45 g, yield: 26%) was obtained as an off-white solid.

Synthesis of N-((5-(2-bromoacetyl)-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12) according to Method 2 (Scheme 2):

Synthesis of 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole (I-12a): To a stirred solution of 2-bromo-5-methyl-1,3,4-thiadiazole (4.5 g, 25.1 mmol) in CCl ₄ (100 mL) cooled to 0° C. was added N-bromosuccinimide (4.4 g, 25.1 mmol) followed by AIBN (0.4 g, 2.51 mmol). The reaction mixture was then stirred at 80° C. for 16 hours, after which it was diluted with water (100 mL) and extracted with DCM (2×200 mL). The combined organic layers were dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (60-120 mesh) eluting with 50% EtOAc in hexanes to give compound I-12a (2.0 g, 31% yield) as a white solid. Synthesis of (5-bromo-1,3,4-thiadiazol-2-yl)methylamine (I-12b): To a stirred solution of 2-bromo-5-(bromomethyl)-1,3,4-thiadiazol I-12a (2.0 g, 7.81 mmol) in MeOH (20 mL) cooled to 0°C was added 7N methanolic ammonia (40 mL). The reaction mixture was then stirred at room temperature for 16 hours, after which it was concentrated in vacuo. The residue was purified by column chromatography using silica gel (60-120 mesh) eluting with 30% EtOAc in hexanes to give compound I-12b (1.5 g) as a gummy solid. Synthesis of N-((5-bromo-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12c): To a stirred solution of (5-bromothiazol-2-yl)methanamine I-12b (1.6 g, 8.24 mmol) in DCM (20 mL) cooled to 0 °C was added Et ₃ N (1.6 g, 16.2 mmol) followed by pivaloyl chloride (1.4 g, 12.3 mmol) and then slowly warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (50 mL) and extracted with DCM (2×80 mL). The combined organic layers were dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (60-120 mesh) eluting with 30% EtOAc in hexanes to give compound I-12c (1.0 g, 45% yield) as a gummy solid. [0136] Synthesis of N-((5-acetyl-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12d): To a stirred solution of N-((5-bromo-1,3,4-thiadiazol-2-yl)methyl)pivalamide I-12c (1.0 g, 3.597 mmol) and tributyl(1-ethoxyvinyl)stannane (1.6 g, 4.676 mmol) in toluene (10 mL) was added Pd(PPh ₃ ) ₄ (0.4 g, 0.346 mmol). Next, the mixture was slowly heated to 110°C for 16 hours. After cooling to room temperature, saturated KF solution was added and stirring was continued at room temperature for 30 minutes. The organic layer was separated, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. THF was added to the residue followed by concentrated HCl, and the resulting biphasic mixture was stirred for 30 minutes. Next, the pH of the mixture was adjusted to >7 by slowly adding solid _Na2CO3 . The mixture was then diluted with water (50 mL) and extracted with _DCM (2×100 mL). The combined organic layers _were dried over _Na2SO4 , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (60-120 mesh) eluting with 30% EtOAc in hexanes to give compound I-12d (0.7 g, 81% yield) as a light yellow solid. Synthesis of N-((5-(2-bromoacetyl)-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12): To a solution of N-((5-acetyl-1,3,4-thiadiazol-2-yl)methyl)pivalamide I-12d (0.4 g, 1.659 mmol) in dry THF (5 mL) was added tetrabutylammonium tribromide (0.8 g, 1.659 mmol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to give a crude compound. The crude material was purified by combi-flash reverse phase chromatography to give compound I-12 (0.2 g, yield: 38%, 70% pure by LCMS) as a white solid.

Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide (I-13) according to Method 2 (Scheme 2):

Synthesis of 2-((tert-butyldiphenylsilyl)oxy)acetic acid (I-13a): TEA (293 g, 2.89 mol, 403 mL), DMAP (17.7 g, 145 mmol) and TBDPSCl (477 g, 1.74 mol, 446 mL) were added to a solution of glycolic acid (110 g, 1.45 mol) in THF (770 mL) at 0 ° C, and the resulting mixture was stirred at 25 ° C for 2 hours. The reaction mixture was acidified with aqueous HCl (1 M) until pH = 1 was reached, and extracted with EtOAc (300 mL × 3). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by SiO ₂ column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to give compound I-13a (283 g, 57% yield, 91.0% purity) as a light red oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.70-7.68 (m, 4H), 7.45-7.43 (m, 6H), 4.28 (s, 2H), 1.13 (s, 9H). Synthesis of 2-((tert-butyldiphenylsilyl)oxy)-N-(thiophen-2-ylmethyl)acetamide (I-13b): To a solution of I-13a (281 g, 894 mmol) in DMF (644 mL) were added DIEA (420 g, 3.25 mol, 566 mL), EDCI (233 g, 1.22 mol) and HOBt (165 g, 1.22 mol) at 15° C., and the mixture was stirred at 15° C. for 30 minutes. To the mixture was added thiophen-2-ylmethylamine (92.0 g, 813 mmol, 83.6 mL). The mixture was stirred at 15°C for 2 hours. The reaction mixture was then diluted with _H2O (1.50 L) and extracted with EtOAc (500 mL x 3). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , ethyl acetate/petroleum ether = 100/1-0/1; TLC: ethyl acetate/petroleum ether = 5/1, compound I-13b _Rf = 0.60) to give compound I-13b (246 g, 70% yield, 94.2% purity) as a light yellow oil. ¹ H NMR: ET45071-646-P1B (400 MHz, CDCl ₃ ) δ 7.53-7.50 (m, 4H), 7.38-7.27 (m, 6H), 7.17-7.16 (m, 1H), 7.69 (s, 1H), 6.92-6.88 (m, 2H), 4.62 (d, J=5.6 Hz, 2H), 4.09 (s, 2H), 0.98 (s, 9H). Synthesis of N-((5-bromothien-2-yl)methyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-13c): Two reactions were carried out in parallel on the same scale. NBS (39.2 g, 220 mmol) was added to a solution of compound I-13b (82.0 g, 200 mmol) in DMF (574 mL). The mixture was stirred at 20°C for 1 hour. The two reactions were combined for post-processing. The reaction mixture was diluted with _H2O (3.40 L) and extracted with EtOAc (1.50 L x 3). The combined organic layers were washed with _H2O (500 mL x ₈ ) and dried over anhydrous _Na2SO4 , filtered, and concentrated in vacuo to give compound I-13c (199 g, 85% yield, 83.1% purity) as a light yellow solid. ¹ H NMR: (400MHz, CDCl ₃ ) δ7.61-7.59 (m, 4H), 7.48-7.37 (m, 6H), 7.20 (s, 1H), 6.92 (d, J = 3.6Hz, 1H), 6.74 (d, J = 3.6Hz, 1H), 4.60 (d, J = 6.0Hz, 2H), 4.18 (s, 2 H),1.08(s,9H). Synthesis of N-((5-acetylthiophen-2-yl)methyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-13d): To a solution of compound I-13c (94.0 g, 192 mmol) in toluene (658 mL) were added tributyl(1-ethoxyvinyl)tin (90.4 g, 250 mmol, 84.5 mL) and Pd(PPh ₃ ) ₄ (22.2 g, 19.2 mmol). The mixture was degassed and purged with N ₂ three times, then stirred at 110° C. in a N ₂ atmosphere for 16 hours. The same reaction was carried out in parallel using 105 g of I-13c, and the two mixtures were combined for post-treatment. Saturated KF solution (2.00 L) was added to the reaction mixture, and the mixture was stirred at 20° C. for 30 minutes. The organic layer was separated, and HCl (0.5M, 2.0L) was added to the crude reaction mixture, and the mixture was stirred for 30 minutes. The organic layer was separated and extracted with EtOAc (500mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1-1/1) to give compound I-13d (124 g, 63% yield, 93.6% purity) as a yellow solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.62-7.58 (m, 5H), 7.48-7.38 (m, 6H), 7.30 (s, 1H), 7.01 (d, J=3.6 Hz, 1H), 4.72 (d, J=3.6 Hz, 1H), 4.20 (s, 2H), 2.55 (s, 3H), 1.09 (s, 9H). Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide (I-13): To a solution of compound I-13d (119 g, 263 mmol) in DCM (714 mL) and MeOH (1.78 L) was added TBATB (133 g, 276 mmol), and the mixture was stirred at 15° C. for 12 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with DCM (100 mL) and washed with H ₂ O (40.0 mL×3). The organic layer was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=0/1-1/0) to give compound I-13 (46.0 g, 55% yield, 91.3% purity) as a colorless oil. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 8.55 (t, J=6.0 Hz, 1H), 7.91 (d, J=4.0 Hz, 1H), 7.09 (d, J=4.0 Hz, 1H), 4.75 (s, 2H), 4.49 (d, J=6.0 Hz, 2H), 3.86 (s, 2H).

4-((5-(2-bromoacetyl)thiophen-2-yl)methyl)morpholin-3-one (I-14) according to Method 4 (Scheme 4):

Synthesis of 2-(chloromethyl)thiophene (I-14a): To a solution of ₂ -thienylmethanol (2.00 g, 17.5 mmol, 1.65 mL) in DCM (14.0 mL) was added dropwise SOCl ₂ (4.17 g, 35.0 mmol, 2.54 mL) at 0° C. under N 2 atmosphere. The mixture was stirred at 0° C. for 30 minutes, after which the mixture was stirred at 25° C. for 30 minutes. The reaction mixture was quenched by NaHCO ₃ (110 mL) and extracted with EtOAc (80.0 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to give compound I-14a (1.50 g, 65% yield) as a brown oil. Synthesis of 4-(thiophen-2-ylmethyl)morpholin-3-one (I-14b): To a solution of morpholin-3-one (2.29 g, 22.6 mmol) in THF (10.0 mL) was added dropwise LiHMDS (1 M, 17.0 mL) at 0°C. After addition, the mixture was stirred at this temperature for 30 minutes, and then compound I-14a (1.50 g, 11.3 mmol) in THF (8.00 mL) was added dropwise at 0°C. The resulting mixture was stirred at 60°C for 7 hours. The reaction was quenched at 0°C by adding 10.0 mL of NH ₄ Cl, then diluted with H ₂ O (10.0 mL), and extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1-0/1) to give compound I-14b (1.10 g, 42% yield, 85.4% purity) as brown oil. ¹ H NMR [400 MHz, CDCl ₃ ]: 7.26 (t, J=1.2 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 4.76 (s, 2H), 4.20 (s, 2H) 3.86-3.83 (m, 2H) 3.36 (t, J=5.2 Hz, 2H). Synthesis of 4-((5-bromothiophen-2-yl)methyl)morpholin-3-one (I-14c): To a solution of compound I-14b (1.10 g, 5.58 mmol) in DMF (7.70 mL) was added NBS (993 mg, 5.58 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with H ₂ O (10.0 mL) and washed with EtOAc (10.0 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative-TLC (SiO ₂ , petroleum ether/ethyl acetate=1/1) to give compound I-14c (crude) (2.00 g, 88.8% purity) as a light yellow solid. ¹ H NMR [400 MHz, CDCl ₃ ]: 6.89 (d, J = 3.6 Hz, 1H), 6.75 (d, J = 3.6 Hz, 1H), 4.64 (s, 2H), 4.19 (s, 2H), 3.85 (t, J = 4.8 Hz, 2H), 3.36 (t, J = 5.2 Hz, 2H), 2.73 (s, 3H). Synthesis of 4-((5-acetylthiophen-2-yl)methyl)morpholin-3-one (I-14d): To a solution of compound I-14c (2.00 g, 7.24 mmol) in toluene (14.0 mL) were added tributyl(1-ethoxyvinyl)stannane (3.22 g, 8.91 mmol, 3.01 mL) and Pd(PPh ₃ ) ₄ (837 mg, 724 umol). The mixture was stirred at 110 ° C for 16 hours. Saturated KF solution (20.0 mL) was added to the reaction mixture, and the mixture was stirred at 20 ° C for 30 minutes. The organic layer was separated, and HCl (0.5M, 20.0 mL) was added to the crude reaction mixture, and the mixture was stirred for 30 minutes. The organic layer was separated and extracted with EtOAc (20.0 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , DCM/ethyl acetate=50/1-0/1) to give compound I-14d (1.00 g, 58% yield) as a black solid. Synthesis of 4-((5-(2-bromoacetyl)thiophen-2-yl)methyl)morpholin-3-one (I-14): To a solution of compound I-14d (1.00 g, 4.18 mmol) in DCM (2.00 mL) and IPA (5.00 mL) was added TBATB (2.32 g, 4.81 mmol). And the mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with H ₂ O (25.0 mL) and washed with EtOAc (25.0 mL×3). The combined organic layers were washed with brine (25.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give compound I-14 (1.00 g, 3.14 mmol, 75% yield) as a brown oil.

Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-hydroxypyrrolidin-2-one (I-15) according to Method 4 (Scheme 4):

Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-1-(thiophen-2-ylmethyl)pyrrolidin-2-one (I-15a): To a solution of 3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (25.0 g, 73.6 mmol) in THF (170 mL) was added dropwise LiHMDS (1 M, 110 mL) at 0°C. After addition, the mixture was stirred at this temperature for 30 minutes, and then 2-(chloromethyl)thiophene (19.5 g, 147 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 60°C for 7 hours. LCMS showed that 3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one was completely consumed, and 27% of the desired compound was detected. The reaction mixture was quenched by adding H ₂ O (100 mL) at 25°C, and then extracted with EtOAc 300 mL (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO ₂ , petroleum ether/ethyl acetate=3/1) to give compound I-15a (9.00 g, 28.0% yield) as a yellow oil. Synthesis of 1-((5-bromothiophen-2-yl)methyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-15b): To a solution of compound I-15a (9.00 g, 20.7 mmol) in DMF (50.0 mL) was added NBS (4.04 g, 22.7 mmol). The mixture was stirred at 20° C. for 2 hours, after which it was quenched at 25° C. by the addition of H ₂ O (100 mL), and then extracted with EtOAc 150 mL (50.0 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1-5/1) to give compound I-15b (6.70 g, 63% yield) as a brown oil. Synthesis of 1-((5-acetylthiophen-2-yl)methyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-15c): To a solution of compound I-15b (6.70 g, 13.0 mmol) in Tol (42.0 mL) were added tributyl(1-ethoxyvinyl)stannane (6.58 g, 18.2 mmol, 6.15 mL) and Pd(PPh ₃ ) ₄ (1.50 g, 1.30 mmol). The mixture was degassed and purged with _N2 for 3 times, and then the mixture was stirred at 110°C in _N2 atmosphere for 16 hours. Saturated potassium fluoride solution was added to the reaction mixture, and stirred at 15°C for 30 minutes. The organic layer was separated and concentrated under reduced pressure to give the crude compound. HCl (0.5M, 90.0mL) was added to the crude material, and the mixture was stirred for 30 minutes, and _{solid Na2CO3} (~5g) was added until pH=~7. The reaction mixture was diluted with water (50.0mL) and extracted with _ethyl acetate (50.0mL×2). The combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=50/1-5/1) to give compound I-15c (5.50g, 88% yield) as a yellow solid. Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-15): To a solution of compound I-15c (0.50 g, 1.05 mmol) in DCM (3.00 mL) and IPA (7.50 mL) was added trimethylphenylammonium tribromide (413 mg, 1.10 mmol). The mixture was stirred at 50 °C for 2 hours. The reaction mixture was quenched by H ₂ O 10.0 mL at 25 °C, and then extracted with EtOAc 15.0 mL (5.00 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound I-15 (0.90 g, 46% yield, 30% purity) as a white solid.

Synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-3-hydroxypyrrolidin-2-one (I-16) according to Method 4 (Scheme 4):

Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-1-(2-(thien-2-yl)ethyl)pyrrolidin-2-one (I-16a): To a solution of 3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (10.8 g, 31.8 mmol) in THF (70.0 mL) was added dropwise LiHMDS (1 M, 47.7 mL) at 0°C. After the addition, the mixture was stirred at this temperature for 30 minutes, and then 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (10.8 g, 38.2 mmol) in THF (30.0 mL) was added dropwise at 0°C. The resulting mixture was stirred at 60°C for 7 hours. The reaction mixture was quenched by the addition of H ₂ O (100 mL) at 25°C, and then extracted with EtOAc 150 mL (50.0 mL×3). The combined organic layers were washed with brine (50.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1-5/1) to give compound I-16a (7.00 g, 49% yield) as a white solid. Synthesis of (S)-1-(2-(5-bromothiophen-2-yl)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-16b): To a solution of compound I-16a (7.00 g, 15.6 mmol) in DMF (56.0 mL) was added NBS (3.05 g, 17.1 mmol). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was quenched at 25° C. by the addition of H ₂ O (50.0 mL), and then extracted with EtOAc (20.0 mL×3). The combined organic layers were washed with brine (50.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1-5/1) to give compound I-16b (4.60 g, 56% yield) as a colorless oil. Synthesis of 1-(2-(5-acetylthiophen-2-yl)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-16c): To a solution of compound I-16b (4.60 g, 8.70 mmol) in toluene (32.0 mL) were added tributyl(1-ethoxyvinyl)stannane (4.40 g, 12.1 mmol, 4.11 mL) and Pd(PPh ₃ ) ₄ (1.01 g, 870 umol). The mixture was degassed and purged with _N2 for 3 times, and then the mixture was stirred at 110°C in _N2 atmosphere for 16 hours. Saturated potassium fluoride solution was added to the reaction mixture, and stirred at 15°C for 30 minutes. The organic layer was separated and concentrated under reduced pressure to obtain a crude compound. HCl (0.5M, 90.0mL) was added to the crude reaction mixture, and stirred for 30 minutes, and _{solid Na2CO3} (~15.0g) was added until pH=~7. The reaction mixture was diluted with water (50.0mL) and extracted with _ethyl acetate (10.0mL×2). The combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure to obtain a crude compound. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=50/1-5/1) to obtain compound I-16c (3.49g, 82% yield) as a yellow oil. Synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-16): To a solution of compound I-16c (1.00 g, 2.03 mmol) in MeOH (5.00 mL) and DCM (1.50 mL) was added TBATB (1.03 g, 2.14 mmol). The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched by the addition of H ₂ O (10.0 mL) at 25°C, and then extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1-5/1) to give compound I-16 (0.80 g, 69% yield) as a yellow oil.

Preparation of intermediate compounds of formula Y ¹ -SH, wherein R ² ＝H:

Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (J-1)

Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (J-1-1): A solution mixture of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (10 g, 59.1 mmol) in formamide (40 mL) was stirred at 180°C for 4 hours. The reaction mixture was cooled to room temperature, after which a precipitate was formed. The obtained precipitate was vacuum filtered, washed with hexane, and vacuum dried to give J-1-1 (7.2 g, yield: 79%) as an off-white solid. Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (J-1): Lawesson reagent (5.4 g, 13.5 mmol) was added to a solution of compound J-1-1 (3.4 g, 22.6 mmol) in toluene (50.0 mL) at 0°C. The reaction mixture was stirred at 120°C for 2 hours. Next, the mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (60-120 mesh) eluting with 10% EtOAc in hexanes to give J-1 (3.0 g, yield: 81%) as a pale yellow solid.

Synthesis of 1,7-naphthyridine-8-thiol (J-5)

Synthesis of 1,7-naphthyridine-8-thiol (J-5): To a solution of 8-chloro-1,7-naphthyridine (500 mg, 3.04 mmol) in DMF (3.00 mL) was added NaSH (681 mg, 12.2 mmol). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was used directly in the next step without post-treatment.

Using the above experimental conditions, the following compounds were prepared from commercially available or art known hydroxy-substituted heteroaryl groups of formula Y ¹ —OH by sulfidation using P ₂ S ₅ reagent or Lawesson reagent, alternatively, from chloro-substituted heteroaryl groups of formula Y ¹ —Cl by thiol substitution using NaSH or Na ₂ S. Alternatively, some of the following compounds can be obtained commercially:

Preparation of intermediate compounds of formula Y ¹ -SH, wherein R ² = haloalkyl, CF ₃ or CHF ₂ :

Synthesis of 2-(Trifluoromethyl)quinazoline-4-thiol (K-1)

Synthesis of 2-(trifluoromethyl)quinazoline-4-ol (K-1-1): trifluoroacetic anhydride (1.7g, 8.022mmol), pyridine (1.0mL) and DMAP (0.018mg, 0.147mmol) were added to a solution of 2-aminobenzamide (1.0g, 7.344mmol) in dry DCM at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC, and the raw material was exhausted. After the raw material was exhausted, the reaction mixture was diluted with water and extracted with DCM. The organic layer combined was dried over Na ₂ SO ₄ , and the solvent was concentrated under reduced pressure. The column chromatography residue was purified by using silica gel (100:200 mesh, solvent: 10% EtOAc in hexane) to obtain K-1-1 (1.0g, 63% yield). Synthesis of 2-(trifluoromethyl)quinazoline-4-thiol (K-1): In a dry argon atmosphere, to a solution of 2-(trifluoromethyl)quinazoline-4(1H)-one (K-1-1) (0.5g, 7.344mmol) in dry toluene stirred, add Lawesson reagent (1.01g, 7.344mmol), then react at reflux for 16 hours, until raw material can no longer be detected by TLC. Next, in the mixture, add 3N NaOH solution. After neutralization with 1N HCl, filter the formed solid, and vacuum drying, obtain K-1 (0.28g, 52% productive rate), as an off-white solid.

Synthesis of 3-(Trifluoromethyl)isoquinoline-1-thiol (K-22)

Synthesis of 3-(trifluoromethyl)-1H-isochromen-1-one (K-22-1): To a stirred solution of 2-(carboxymethyl)benzoic acid (2.0 g, 11.10 mmol) was added trifluoroacetic anhydride (2.1 mL) at room temperature, and the reaction mixture was stirred at 100° C. for 48 hours. The reaction mixture was concentrated under reduced pressure to give K-22-1 (2.5 g, crude product), which was used in the next step without further purification. Synthesis of 3-(trifluoromethyl)isoquinolin-1(2H)-one (K-22-2): 3-(trifluoromethyl)-1H-isochromen-1-one K-22-1 (2.5 g (crude product), 11.62 mmol) was added to NH ₄ OH (37.0 mL) at room temperature. The resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give crude compound K-22-2 (160 mg, yield: 7%) as a white solid. Synthesis of 3-(trifluoromethyl)isoquinoline-1-thiol (K-22): To a stirred solution of 3-(trifluoromethyl)isoquinolin-1(2H)-one K-22-2 (160 mg, 0.751 mmol) in dry toluene (6.0 mL) was added Lawesson reagent (303 g, 0.751 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 120° C. for 4 hours and then concentrated in vacuo. The residue was purified using combi-flash reverse phase purification (eluent: ACN and 0.001% TFA in water) to give compound K-22 (50 mg, yield 29%) as an off-white solid.

Using the above experimental conditions, the following intermediate compounds (K-2)-(K-21) are prepared by reacting substituted carbamoyl aryl and heteroaryl groups with trifluoroacetic anhydride or _CHF2 -based reagents. Alternatively, they are prepared by sulfidation of hydroxy-substituted heteroaryl groups of formula ^Y1 -OH known in the art or commercially available using _P2S5 reagents or _Lawesson reagents. Alternatively, some of the following compounds can be obtained commercially:

Preparation of intermediate compounds of formula Y ¹ -SH, wherein R ² = alkyl, etc.:

Synthesis of 7-Chloro-2-methylquinazoline-4-thiol (M-1)

Synthesis of 7-chloro-2-methylquinazolin-4-ol (M-1-1): DIPEA (1.61 mL, 9.264 mmol) was added to a solution of 2-amino-4-chlorobenzamide (1.5 g, 8.823 mmol) in dioxane (10 mL) at 0°C, followed by acetyl chloride (0.63 mL, 8.823 mmol), and the reaction mixture was stirred at 0°C for 15 minutes. The reaction mixture was heated to reflux for 16 hours, after which it was concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude 7-chloro-2-methylquinazolin-4-ol (M-1-1) was used in the next step without further purification. Synthesis of 7-chloro-2-methylquinazoline-4-thiol (M-1): To a solution of compound M-1-1 (400 mg, 2.061 mmol) in toluene (6.0 mL) was added P ₂ S ₅ (457.7 mg, 2.061 mmol) at 0°C. The reaction mixture was stirred at 120°C for 2 hours, after which it was concentrated in vacuo. The residue was diluted with DCM (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residual compound was washed with hexane and dried in vacuo to give 7-chloro-2-methylquinazoline-4-thiol (M-1) (190 mg, crude).

Synthesis of 6-methoxy-2-methylquinazoline-4-thiol (M-11)

Synthesis of 6-methoxy-2-methylquinazoline-4-ol (M-11-1): NaH (42.1 g, 1.05 mol, 60% purity) was added in batches to EtOH (500 mL) at 0 ° C, followed by 2-amino-5-methoxybenzamide (25.0 g, 150 mmol), followed by EtOAc (53.0 g, 601 mmol, 58.91 mL). The resulting mixture was stirred at 90 ° C for 12 hours. The reaction mixture was quenched by 1M HCl (500 mL) and filtered. The filter cake was collected. The collected filter cake was dissolved in EtOAc/MeOH (V/V=1/1, 200 mL) and filtered. The filtrate was concentrated in vacuo to give compound M-11-1 (34.0 g, crude product) as an off-white solid. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 12.2 (s, 1H), 7.51 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 2.8 Hz), 7.36 (dd, J = 8.8 Hz, 1H), 3.84 (s, 1H), 2.32 (s, 3H). Synthesis of 6-methoxy-2-methylquinazoline-4-thiol (M-11): To a solution of compound M-11-1 (20.0 g, 105 mmol) in toluene (140 mL) was added Lawesson reagent (46.8 g, 115 mmol), and the mixture was stirred at 120° C. in a N ₂ atmosphere for 12 hours. The reaction was run twice more with 18.0 g scale and 7.20 g scale of M-11-1, and the crude mixture of all three runs was combined for work-up. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was triturated with EtOAc/MeOH (V/V=10/1, 10 V, 3 times) at 25°C for 6 hours to give compound M-11 (25.5 g, 72% yield, 85.3% purity) as a yellow solid. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ13.9 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.51 (dd, J=8.8 Hz, 1H), 3.87 (s, 3H), 2.48 (s, 3H).

Using the above experimental conditions, the following intermediate compounds M-2 to M-48 are prepared by reacting substituted carbamoyl aryl and heteroaryl groups with trifluoroacetic anhydride or _CHF2 -based reagents. Alternatively, they are prepared by sulfidation of hydroxy-substituted heteroaryl groups of formula ^Y1 -OH known in the art or commercially available using _P2S5 reagents or _Lawesson reagents. Alternatively, some of the following compounds can be obtained commercially:

Preparation of intermediate compounds of formula Y ¹ -SH, wherein R ² ＝NR ₂ :

Synthesis of 2-(Dimethylamino)quinazoline-4-thiol (N-1)

Synthesis of 2-(dimethylamino)quinazolin-4-ol (N-1-1): To a solution mixture of 2-iodobenzoic acid (1.0 g, 4.00 mmol) and compound-2 (743 mg, 6.0 mmol) in ACN (10 mL) were added K ₂ CO ₃ (2.2 g, 16.1 mmol) and cupric chloride hydrate (13 mg, 0.08 mmol) at room temperature. The reaction mixture was heated at 90° C. for 16 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give compound N-1-1 (700 mg, yield: 91%) as an off-white solid, which was used in the next step without further purification. Synthesis of 2-(dimethylamino)quinazoline-4-thiol (N-1): To a stirred solution of compound N-1-1 (300 mg, 1.67 mmol) in dry toluene (4.0 mL) was added Lawesson reagent (677 g, 1.675 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 4 hours and then concentrated in vacuo. The crude compound was purified by silica gel column chromatography (100-200 mesh) to give compound N-1 (150 mg, yield: 46%) as a yellow solid.

Preparation of intermediate compounds of formula Y ¹ -SH, wherein G ¹ =N:

Synthesis of 4-Methylphthalazine-1-thiol (O-1)

To a solution mixture of 4-methylphthalazin-1(2H)-one (300 mg, 1.875 mmol) in toluene (5.0 mL) was added Lawesson's reagent (757.5 mg, 1.875 mmol) at 0°C. The reaction mixture was stirred at 110°C for 2 hours, after which it was concentrated in vacuo. The residue (O-1) was used in the next step without further purification.

Synthesis of 4-(Trifluoromethyl)phthalazine-1-thiol (O-2)

Synthesis of 3-hydroxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one (O-2-1): To a stirred solution of isobenzofuran-1,3-dione (0.5 g, 3.378 mmol) in THF was added cuprous iodide (0.062 g, 0.337 mmol) in an argon atmosphere. PPh ₃ (0.086 g, 0.338 mmol) and anhydrous KF (0.38 g, 6.551 mmol). TMSCF ₃ (0.5 g, 3.378 mmol) was added to the reaction mixture and stirred at 50 °C for 6 hours. The reaction progress was monitored by TLC. After the starting material was exhausted, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give O-2-1 (0.25 g, 35% yield) as an off-white solid. Synthesis of ethyl 2-(2,2,2-trifluoroacetyl)benzoate (O-2-2): To a stirred solution of 3-hydroxy-3-(trifluoromethyl)isobenzofuran-1(3H)-one (O-2-1) (0.2 g, 0.917 mmol) in NMP were added bromoethane (0.1 g, 0.929 mmol) and K ₂ CO ₃ (0.15 g, 1.086 mmol) at 0° C., and the resulting mixture was stirred at 70° C. for 6 hours. The reaction progress was monitored by TLC. After the starting material was exhausted, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by column chromatography using silica gel to give O-2-2 (0.18 g, 48% pure by LCMS) as a white solid. [0136] Synthesis of 4-(trifluoromethyl)phthalazin-1(2H)-one (O-2-3): To a stirred solution of ethyl 2-(2,2,2-trifluoroacetyl)benzoate (O-2-2) (0.2 g, 0.81 mmol) in EtOH (2.0 mL) was added hydrazine hydrate (0.052 g, 1.60 mmol) at 0 °C and slowly warmed to 90 °C for 16 hours. The reaction was monitored by TLC. After the starting material was consumed, the mixture was diluted with water and extracted with _EtOAc . The combined organic layers were dried over _Na2SO4 and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give O-2-3 (0.18 g, 78% yield) as a white solid. Synthesis of 4-(trifluoromethyl)phthalazine-1-thiol (O-2): To a stirred solution of 4-(trifluoromethyl)phthalazin-1(2H)-one (O-2-3) (0.2 g, 0.934 mmol, 1.0 eq) in dry toluene was added Lawesson's reagent (0.37 g, 0.936 mmol, 1.0 eq) under a dry argon atmosphere. The reaction mixture was then heated at 110° C. for 1 hour under μW conditions. The crude material was purified by silica gel column chromatography to give compound (O-2) (0.07 g, 10% pure by LCMS) as a yellow solid.

Using the above experimental conditions, the following intermediate compound O-3 was prepared from a commercially available hydroxy-substituted heteroaryl of formula Y ¹ —OH by sulfidation using P ₂ S ₅ reagent or Lawesson reagent:

Preparation of intermediate compounds of formula Y ¹ -SH having a [5,6] bicyclic heteroaryl group wherein G ² ═O or NR ⁴ :

Synthesis of 5-(Trifluoromethyl)oxazolo[5,4-b]pyridine-2-thiol (P-1)

Synthesis of 3-amino-6-(trifluoromethyl)pyridine-2-ol (P-1-1): To a stirred solution of 3-nitro-6-(trifluoromethyl)pyridine-2-ol (200 mg, 0.961 mmol) in MeOH (1 mL) was added 15% Pd-C (30 mg). H _gas was then passed at 60 psi for 3 hours, after which the mixture was heated to 50° C. for 3 hours. The reaction mixture was vacuum filtered through a celite bed. The solvent was evaporated under reduced pressure to give the title compound P-1-1 (142 mg, 75% yield). Synthesis of 5-(trifluoromethyl)oxazolo[5,4-b]pyridine-2-thiol (P-1): To a solution of 3-amino-6-(trifluoromethyl)pyridine-2-ol P-1-1 (1.8 g, 0.010 mol) in EtOH (18 mL) was added KOH (1.13 g, 0.0202 mol), followed by CS ₂ (1.13 mL, 0.0202 mol) at 0°C. The resulting reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and purified by C18-reverse phase combi-flash chromatography (eluent: 0.1% formic acid in ACN) to give the title compound P-1 (1.8 g, 81% yield) as an off-white solid.

Synthesis of 6-(Trifluoromethyl)oxazolo[4,5-c]pyridine-2-thiol (P-6)

Synthesis of 5-nitro-2-(trifluoromethyl)pyridin-4-ol (P-6-1): To a solution of 2-(trifluoromethyl)pyridin-4-ol (7.50 g, 45.9 mmol) in H ₂ SO ₄ (40.0 mL) was added fuming nitric acid (68.6 g, 980 mmol) and H ₂ SO ₄ (82.8 g, 844 mmol) at 0° C. The mixture was stirred at 120° C. for 8 hours. The reaction mixture was quenched by the addition of ice-cold water (300 mL) at 0° C. and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1-0/1) to give 5-nitro-2-(trifluoromethyl)pyridin-4-ol (P-6-1) (3.62 g, 38% yield) as a yellow solid. Synthesis of 5-amino-2-(trifluoromethyl)pyridin-4-ol (P-6-2): Compound P-6-1 (13.5 g, 64.8 mmol) was added to a solution of Pd/C (2.00 g, 64.8 mmol, 10% purity) in MeOH (100 mL) in Ar. The suspension was degassed in vacuo and purged with H ₂ several times, after which the mixture was stirred in H ₂ (15 psi) at 25 ° C for 5 hours. The suspension was filtered and the filter cake was washed with MeOH (100 mL×3). The combined filtrate was concentrated to dryness. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1-0/1) to give 5-amino-2-(trifluoromethyl)pyridin-4-ol (P-6-2) (9.10 g, 67% yield) as a brown solid. Synthesis of 6-(trifluoromethyl)oxazolo[4,5-c]pyridine-2-thiol (P-6): To a solution of compound P-6-2 (1.00 g, 5.61 mmol) in Py (10.0 mL) was added dropwise potassium ethyl xanthate (1.08 g, 6.74 mmol) at 25° C. The resulting mixture was stirred at 110° C. for 12 hours. The reaction mixture was poured into 1N HCl to pH = 4-5, and then extracted with EtOAc (30.0 mL×3). The combined organic layers were washed with brine (30.0 mL×2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1-0/1, petroleum ether/ethyl acetate = 2/1, R _f = 0.2) to give 6-(trifluoromethyl)oxazolo[4,5-c]pyridine-2-thiol (P-6) (400 mg, 32% yield) as a brown solid.

Synthesis of 6-(Trifluoromethyl)oxazolo[4,5-b]pyridine-2-thiol (P-7)

Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (P-7-1): To a solution of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (8.00 g, 33.2 mmol) in dioxane (40.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolan) (9.27 g, 36.5 mmol), KOAc (9.77 g, 99.6 mmol) and Pd(dppf) _Cl2 (729 mg, 996 umol). The mixture was stirred at 90 °C for 6 hours. The reaction mixture was quenched by adding H ₂ O (20.0 mL) at 25° C., and then extracted with EtOAc (20.0 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1-0/1) to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine P-7-1 (9.00 g, 94% yield) as a white solid. Synthesis of 2-amino-5-(trifluoromethyl)pyridin-3-ol (P-7-2): To a solution of compound P-7-1 (9.00 g, 31.2 mmol) in THF (90.0 mL) was added H ₂ O ₂ (43.4 g, 383 mmol, 36.8 mL, 30% purity). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was quenched at 5° C. by the addition of saturated aqueous NH ₄ Cl solution (80.0 mL), and then extracted with EtOAc (40.0 mL×3). The combined organic layers were washed with brine (30.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (40.0 mL), and then extracted with 1 M HCl (40 mL). The aqueous phase was adjusted to pH = 8 with NaHCO ₃ , and then extracted with EtOAc (40.0 mL × 3) to give 2-amino-5-(trifluoromethyl)pyridin-3-ol (P-7-2) (5.00 g, 79% yield, 87.5% purity) as a light yellow solid. Synthesis of 6-(trifluoromethyl)oxazolo[4,5-b]pyridine-2-thiol (P-7): CS ₂ (3.85 g, 50.5 mmol, 3.05 mL) and KOH (2.84 g, 50.5 mmol) were added to a solution of compound P-7-2 (3.00 g, 16.8 mmol) in EtOH (30.0 mL). The mixture was stirred at 80 ° C for 16 hours. The reaction mixture was quenched by adding 2M HCl (30.0 mL) at 25 ° C, and then extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with 2M HCl (30.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6-(trifluoromethyl)oxazolo[4,5-b]pyridine-2-thiol (P-7) (2.47 g, 67% yield) as a yellow solid.

Using the experimental conditions described above for K-1, the following intermediate thiols (P-2)-(P-15) were prepared by reacting substituted bicyclic oxazole 2-hydroxyl groups with Lawesson's reagent. Alternatively, some of the following compounds are commercially available:

Preparation of Example Compounds

Example 1 : N-((5-(2-((2-isopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

According to method 2 (Scheme 2), step 4: NaOMe (29.12 mg, 0.539 mmol) was added to a solution mixture of intermediate M-3 (100 mg, 0.49 mmol, 1 eq.) in DMF (3.0 mL) at 0°C. The resulting reaction mixture was stirred for 30 minutes at 0°C, and compound I-4 (171 mg, 0.539 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, cold water was added to the reaction mixture, extracted with EtOAc (2×50 mL), the total organic layer was dried over Na ₂ SO ₄ , and concentrated in vacuo. The crude compound was purified by Combi-flash chromatography to give Example 1 (70 mg, 30% yield).

Example 60: 2-Hydroxy-N-((5-(2-((6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

To a solution of M-11 (10.0 g, 48.5 mmol) in DMF (108 mL) was added NaOMe (2.62 g, 48.5 mmol) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Compound I-13 (15.6 g, 53.3 mmol) was then added to the mixture, and the mixture was stirred at 25°C for 2 hours. The reaction was run three more times at 5.0 g scale, 10 g scale, and 10 g scale M-11, and the crude mixtures of all four runs were combined for post-processing. The combined reaction mixture was poured into H ₂ O (651 mL) and filtered to collect the solid. The solid was ground with MTBE (10 V×2) at 25°C for 2 hours to give Example 60 (16.25 g, 31.7% yield, 98.9% purity) as a light-yellow solid. 1H NMR: (400MHz, DMSO-d ₆ ) δ8.55 (t, J = 12.0Hz, 1H), 8.09 (d, J = 4.00Hz, 1H), 7.80 (d, J = 9.20Hz, 1H), 7.57-7.60 (m, 1H), 7.28 (d, J = 4.00Hz, 1H), 5.55-5.58 (m,1H),4.84(s,2H),4.52(d,J＝6.40Hz,2H),3.94(s,3H),3.87(d,J＝6.00Hz,2H),2.41(s,4H). LCMS: [M+H] ⁺ 418.1. MP(DSC): 185.65°C.

The following examples were prepared using similar experimental conditions as described above for the synthesis of Example 1 (General Method 2, Scheme 2, Step 4) from the reaction of an intermediate of formula Y ¹ -SH M, N, O or P with compound I-4:

The following examples were prepared using similar experimental conditions (Method 2, Scheme 2, Step 4) as described above for the synthesis of compound (1), and the intermediate obtained from the formula Y ¹ -SH K was reacted with compound I-4:

The following examples were prepared using the experimental conditions described above for the synthesis of compound (1) (according to Method 4, Scheme 4, Step 4) from the reaction of intermediate compounds of formula Y ¹ -SH J, M or K with intermediate compound In, where applicable:

The following examples were prepared using the experimental conditions described above for the synthesis of compound (1) (according to Method 2, Scheme 2, Step 4) from intermediate compounds of formula Y ¹ -SH J, M or K reacted with intermediate compound In, where applicable:

The following examples were prepared using the experimental conditions described above for the synthesis of compound (1) (according to Method 2, Scheme 2, Step 4), and the intermediate compound obtained from the formula Y ¹ -SH K-11 was reacted with the intermediate compound I-15, followed by separation of the enantiomers using chiral SFC (Waters SFC80 preparative SFC; column: DAICEL CHIRALPAK IH (250 mm×30 mm, 10 um); mobile phase: A CO ₂ , B MeOH; gradient: B%=40% isocratic elution mode; flow rate: 70 g/min; wavelength: 220 nm; column temperature: 40° C.; system back pressure: 100 bar):

Synthesis of 1-(5-(2-aminoethyl)thiophen-2-yl)-2-((2-(trifluoromethyl)quinazolin-4-yl)thio)ethan-1-one (Q-1)

To a solution mixture of compound K-1 (390 mg, 130 mmol) in DMF (5 mL) was added NaOMe (77 mg, 1.43 mmol) at 0°C. The resulting reaction mixture was stirred at 0°C for 30 minutes, and compound I-2 (549 mg, 156 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with cold water and extracted with EtOAc (2×50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (60-120 mesh). The compound was eluted with 30% EtOAc in hexane to obtain compound (Q-1-1). 4M HCl (6.0 mL) in dioxane was added to a solution mixture of compound (Q-1-1) in dioxane (3.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The crude compound was washed with n-pentane and dried in vacuo to obtain the hydrochloride of compound (Q-1) as a white solid.

Using the experimental conditions described above (General Procedure 1), the following intermediate compounds Q were prepared from compounds J, K and M of formula ^Y1 -SH with bromo-ketone 1-1, 1-2, 1-3 or 1-5 followed by deprotection of the Boc protecting group to provide the terminal amino group.

Example 190: tert-Butyl ((5-(2-((6-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)carbamate

Example 190 was prepared by reacting Intermediate M-39 with Intermediate 1-1 using the experimental conditions described above for Intermediate Q-1-1.

Example 189: Synthesis of 3-((5-(2-((6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-1,1-dimethylurea

To a solution of compound Q-11 (100 mg, 278 μmol) in THF (2.00 mL) was added DIEA (108 mg, 835 μmol, 145 μL) and dimethylcarbamoyl chloride (32.9 mg, 306 μmol, 28.1 μL). The mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative-HPLC (column: waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 30%-60% B over 8 minutes) to give Example 189 (32 mg, 27% yield, 100% purity) as a light yellow solid.

Example 29 : N-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)pivalamide

To a solution mixture of compound Q-1 (190 mg, 25 mmol) in DCM (2.0 mL) was added Et ₃ N (2 eq) and (CH ₃ ) ₃ CCOCl (29 mg, 1.5 eq) at 0° C. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (2×20 mL), and the combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residual compound was purified by column chromatography to give Example Compound (29) as a white solid (60 mg, 50% yield).

Using the experimental conditions described above in Example 29, the following examples were prepared by reaction of compound Q with an acid chloride of formula ^R9 -COCl:

Example 63 : 2-Hydroxy-N-((5-(2-((2-methyl-6-morpholinoquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

Synthesis of 2-((tert-butyldiphenylsilyl)oxy)-N-((5-(2-((2-methyl-6-morpholino-quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide (R-1-1): To a solution of 2-((tert-butyldiphenylsilyl)oxy)acetic acid I-13a (699 mg, 2.22 mmol) in DMF (4.00 mL) was added HATU (699 mg, 2.02 mmol) at 0°C. After the addition, the mixture was stirred at 0°C, and a mixture of compound Q-37 (837 mg, 2.02 mmol) and DIEA (1.41 mL, 8.08 mmol) in DMF (4.00 mL) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (20.0 mL×3). _The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give 2-((tert-butyldiphenylsilyl)oxy)-N-((5-(2-((2-methyl-6-morpholinoquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide (R-1-1), which was used without further purification. Synthesis of 2-hydroxy-N-((5-(2-((2-methyl-6-morpholinoquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide (63): To a solution of compound R-1-1 (0.60 g, 862 umol) in THF (6.00 mL) was added TBAF (1 M, 905 uL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was quenched by adding _H2O (10.0 mL) at 25°C, and then extracted with EtOAc ( _5.00 mL x 3). The combined organic layers were washed with brine (5.00 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 50/1-5/1) TLC (petroleum ether/ethyl acetate = 1/1, product RT = 0.2) to give compound 63 (200 mg, 57.4% yield).

Using the experimental conditions described above in Example 63, the following examples were prepared by reaction of compound Q with protected hydroxy-acid derivatives of formula HO ₂ C—CH ₂ —OTBDPS and HO ₂ C—CH ₂ —OTBS:

The following examples were prepared by reacting compound Q with a carboxylic acid R ⁹ —CO ₂ H using the above experimental conditions. In some cases, the R ⁹ group comprises an alcohol group, which is protected with a suitable protecting group such as TBS or TBDPS and then removed similarly to the method described herein for converting R-1-1 to Example Compound 63. In other cases, the R ⁹ group comprises an amino group, which is protected with a suitable protecting group known in the art such as Boc and then removed using conditions known in the art such as TFA/DCM.

Example 87 : N-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)methanesulfonamide

To a solution mixture of compound Q-2 (100 mg, 0.281 mmol, 1 eq.) in DCM (3.0 mL) was added _Et3N (0.075 mL, 2 eq.) at 0°C. The resulting reaction mixture was stirred at 0°C for 10 minutes, and methanesulfonyl chloride (0.032 mL, 0.422 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. Cold water (10 mL) was added to the crude compound, and extracted with EtOAc to obtain the crude compound, which was finally purified to obtain compound (87) as a white solid (40 mg, 31% yield).

Using the experimental conditions described above in Example 87, the following examples were prepared by reaction of compound Q with a sulfonyl chloride derivative of formula ^R9 - _SO2Cl :

Properties of Example Compounds The properties of the synthesized Example compounds are shown in Table 4 below.

Table 4

Example 2: Cellular target engagement assay - NanoBRET

Materials and methods

NanoBRET target binding was performed on the catalytic domain 2 (CD2) of HDAC6 with minor modifications to the kit manufacturer's protocol (Promega). Expression of exogenous NanoLuc-HDAC6 (CD2) fusions in HEK293T was achieved following transient transfection with FuGENE HD transfection reagent (Promega). Intracellular target binding assays on HDAC6 (CD2) were performed in a 384-well plate format with 8,000 cells per well and tracer concentrations of HDAC6 (CD2) of 0.125 μM or 0.600 μM. The compound (dissolved in 100% DMSO) or DMSO (vehicle) was diluted in culture medium at 8× final assay concentration manually, and then 5 μL was added to the assay plate, or in an automated manner by adding 160 nL of the compound to 5 μL of OptiMEM (Gibco) without phenol red using Echo650 (Labcyte), adding the compound (dissolved in 100% DMSO) or DMSO (vehicle). The tracer solution was added to the cells, and then 35 μL of the cell/tracer mixture was inoculated in the assay plate. The final reaction volume was 40 μL, and the final DMSO concentration was 1.4% (manual compound addition) or 1.25% (automatic compound addition). The assay plate was incubated for 2 hours at 37°C in a humidified atmosphere containing 5% CO _2. NanoBRET Nano-glo substrate/inhibitor was prepared by diluting NanoBRET Nano-Glo substrate (1:332) and extracellular inhibitor (1:1000) in assay medium (Promega). NanoBRET TE Nano-glo substrate/inhibitor was added to the cells, and 1-2 minutes after the addition of the NanoLuc substrate, the NanoBRET donor and acceptor signals (460-80 and 647-75, respectively) were measured at room temperature using an EnVision Xcite (PerkinElmer) or CLARIOstar (BMGLabtech) plate reader. The BRET ratio was calculated from the acceptor/donor signal ratio (mBRET=acceptor/donor*1000) and calibrated for each plate. The percentage of inhibition was calculated by setting the mBRET obtained with cells without tracer to 100% and the mBRET obtained with uninhibited cells with tracer to 0%. IC50-values were calculated based on the percentage of inhibition using log (inhibitor) versus response-variable slope (four parameters) nonlinear regression in GraphPad Prism software.

result

The results of this assay are shown in Table 5 below, wherein "+" means: 1000 nM < IC ₅₀ ≤ 10000 nM, "++" means: 500 nM < IC ₅₀ ≤ 1000 nM, "+++" means: 100 nM < IC ₅₀ ≤ 500 nM and "++++" means: IC ₅₀ < 100 nM.

Table 5

The results clearly demonstrate that the compounds of formula (I) effectively inhibit the interaction between HDAC6 catalytic domain 2 and its substrate, thereby inhibiting its deacetylation activity. Therefore, this assay shows that the compounds of formula (I) can be used to treat and/or prevent HDAC6-related diseases.

Example 3: In vitro determination of acetylated α-tubulin

Materials and methods

HeLa cells were cultured in UltraCulture serum-free medium (Lonza) supplemented with 2mM glutamine (Lonza). The assay was performed in 96-well or 384-well formats, and the differences in the assay protocols are detailed in Table 6. The cells of each well were plated and incubated overnight at 37°C in a humid atmosphere containing 5% CO2. The cell density and inoculation volume are detailed in Table 6. The compounds (dissolved in 100% DMSO) or DMSO (vehicle) were diluted in the culture medium at 10× final assay concentration and 10 μL (96-well protocol) was added manually. Alternatively, 50 nL of the compound was added directly to the cell culture using Echo650 (Labcyte) (384-well protocol). In this assay, the final assay concentration of DMSO was 0.1%-0.4%. Trichostatin A (TSA) was used as a positive control. The cells were incubated with the compound at 37°C in a humid atmosphere containing 5% CO2 for 6 hours. The level of acetylated tubulin (Lys40) was assessed by immunocytochemistry using target-specific antibodies. As detailed in Table 6, cells were fixed with 4% PFA at room temperature. After 2-3 steps of washing with PBS, cells were permeabilized with 0.5% Triton in PBS for 10 minutes at room temperature, and then washed 1-2 times with PBS. In order to avoid non-specific antibody staining, cells were blocked with 3% BSA in PBS for 1 hour at room temperature. Then, cells were incubated with 1:3000 anti-acetylated tubulin (mouse monoclonal antibody, acetylated tubulin Lys40, clone 6-11B, Sigma) and 1:1000 anti-α-tubulin (rabbit monoclonal, abcam) diluted in 1% BSA for 1 hour at room temperature. The cells were washed 2-3 times with PBS and labeled with goat anti-mouse conjugated to Alexa 647 (Thermofisher) and goat anti-rabbit conjugated to Alexa555 (Thermofisher) secondary antibodies diluted to a final concentration of 1:1000 in 1% BSA for 1 hour at room temperature. The nuclei were stained with 1:10000-1:15000 Hoechst (Thermofisher). The incubation time and temperature of the primary antibody are detailed in Table 6. The cells were washed 2-3 times with PBS and imaged with Operetta CLS or Opera Phenix (PerkinElmer). Imaging is further detailed in Table 6. For imaging analysis, Harmony analysis software (PerkinElmer) was used. The cytoplasm (defined by total α-tubulin staining) intensity of each well was used for α-tubulin (acetylated and total) quantification. The intensity of each cell was measured and then averaged per well. The average intensity level of acetylated tubulin was calibrated to the average intensity level of total tubulin. GraphPad Prism software was used to calibrate the changes in acetylated tubulin for each plate: tubulin acetylation in vehicle (DMSO) treated cells was set to 0%, while tubulin acetylation in TSA treated cells was set to 100%. EC50 values were calculated in GraphPad Prism software using log(inhibitor) versus response-variable slope (four parameters) nonlinear regression.

Table 6

result

The results of this assay are shown in Table 7 below, wherein "+" means: 1000nM < _IC50 ≤ 3333nM, "++" means: 500nM < _IC50 ≤ 1000nM, "+++" means: 100nM < _IC50 ≤ 500nM, "++++" means: _IC50 < 100nM and "-" means: _IC50 > 3333nM.

Table 7

The results clearly demonstrate that the compound of formula (I) increases the ratio of acetylated α-tubulin to total α-tubulin in HeLa cells, indicating inhibition of HDAC6, which is the only HDAC enzyme capable of deacetylation of α-tubulin. Therefore, this assay shows that the compound of formula (I) can be used to treat and/or prevent HDAC6-related diseases.

Example 4: HDAC6 enzyme activity assay

Materials and methods

The dose response test of HDAC6 and HDAC1 was carried out at Reaction Biology Corporation (RBC). The inhibition of HDAC enzyme was carried out using human full-length recombinant HDAC6 (H88-30G, SignalChem) with N-terminal GST label and human full-length recombinant HDAC1 (KDA-21-365, RBC) with C-terminal FLAG His label produced in insect cells. The enzyme reaction was carried out in 50mM Tris-HCl, pH 8.0, 137mM NaCl, 2.7mM KCl and 1mMMgCl2 containing freshly added 1mg/ml BSA, 1% DMSO. 2× enzymes were delivered to the wells of the reaction plate, except for the "no enzyme" control wells. In the latter, buffer was added. The compounds in 100% DMSO were made to penetrate into the enzyme mixture by acoustic technology (Echo550). The plate was rotated down, and the compound was incubated with the enzyme at room temperature for 10 minutes. 2× fluorescent peptides from p53 residues 379-382 (RHKKAc, 10 μM final concentration) were added to all wells to initiate the reaction, followed by incubation at 30°C for 1 hour. A developer containing trichostatin A was added to terminate the reaction and produce fluorescent color. Kinetic measurements were performed at 5-minute intervals for 20 minutes on an Envision plate reader (Perkin Elmer, Ex/Em=360/460). Endpoint readings (i.e., the platform of the development reaction) were used for analysis. Data were reported by RBC as percentage of enzyme activity. The percentage of inhibition was calculated by subtracting the percentage of enzyme activity from 100. IC50 values were calculated using GraphPad Prism9 based on the log (inhibitor) versus response-variable slope (four-parameter) equation.

result

The results of this assay are shown in Table 8 below, wherein "+" means: 1000 nM < IC ₅₀ ≤ 10000 nM, "++" means: 500 nM < IC ₅₀ ≤ 1000 nM, "+++" means: 100 nM < IC ₅₀ ≤ 500 nM, "++++" means: IC ₅₀ < 100 nM, "-" means IC ₅₀ > 10000 nM, and "NT" means "not tested".

Table 8

The results clearly demonstrate that the compounds of formula (I) inhibit the fluorescent substrate conversion of HDAC6 but not HDAC1. Therefore, this assay provides direct evidence that the compounds of formula (I) specifically inhibit HDAC6 relative to HDAC1, and therefore can be used to treat and/or prevent HDAC6-related diseases without toxicity or reduced toxicity due to inhibition of other HDAC proteins.

Example 5: HDAC6 enzyme assay (alternative protocol)

Materials and methods

Inhibition of HDAC enzymes was performed in a 384-well plate format using human full-length recombinant HDAC1 and HDAC6 isolated from a baculovirus expression system in Sf9 cells (BPS Bioscience). The reaction buffer for HDAC1 contained 50 mM Tris·HCl pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl ₂ , 0.1 mg/mL BSA, and the reaction buffer for HDAC6 contained 50 mM Tris/HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 250 μM EDTA, 1 mM DTT, 0.1 mg/mL BSA. Compounds (dissolved in 100% DMSO) or DMSO (vehicle) were diluted in assay buffer at 3× final assay concentration and then added to the assay plate. SAHA (10 μM) was used as a positive control. The recombinant enzyme (the final assay concentrations of HDAC1 and HDAC6 are 4nM and 5nM, respectively) of 3× final assay concentrations was pre-incubated with the test compound at room temperature for 10 minutes. Thereafter, the acetylated fluorescent peptide (Ac-Gly-Ala-Lys (Ac))-AMC, Bachem, of 3× final assay concentrations; the final assay concentrations of HDAC1 and HDAC6 are 12μM and 40μM, respectively) was added to the assay plate, and the deacetylase reactants were incubated at room temperature for 60 minutes. A developer containing 5μM SAHA and 50μM trypsin was added to terminate the deacetylase reaction and produce AMC-fluorescence. After adding the developer for 15 minutes, the end point measurement was performed using a CLARIOstar (BMG Labtech) plate reader (excitation/emission: 360/450). The fluorescence signal of each plate was calibrated using GraphPad Prism software: the reaction HDAC-substrate in the presence of DMSO was set to 100%, while the reaction HDAC-substrate in the presence of 10 μM SAHA was set to 0%. IC50-values were calculated from the calibrated measurements using GraphPad Prism software and nonlinear regression with 0% bottom and 100% top constraints.

result

The results of this assay are shown in Table 9 below, wherein "+" means: 1000 nM < IC ₅₀ ≤ 10000 nM, "++" means: 500 nM < IC ₅₀ ≤ 1000 nM, "+++" means: 100 nM < IC ₅₀ ≤ 500 nM, "++++" means: IC ₅₀ < 100 nM and "-" means IC ₅₀ > 10000 nM.

Table 9

The results clearly demonstrate that the compounds of formula (I) inhibit the fluorescent substrate conversion of HDAC6 but not HDAC1. Therefore, this assay provides direct evidence that the compounds of formula (I) specifically inhibit HDAC6 relative to HDAC1, and therefore can be used to treat and/or prevent HDAC6-related diseases without toxicity or reduced toxicity due to inhibition of other HDAC proteins.

In conclusion, the above results demonstrate that the compound of formula (I) acts as a specific HDAC6 inhibitor.

Claims (25)

1. A compound for use in the treatment and/or prophylaxis of HDAC 6-related diseases;

Wherein the compound is a compound of formula (I)

Or a pharmaceutically acceptable salt and/or solvate thereof;

Wherein the method comprises the steps of

-Y ¹ is a 9-or 10-membered bicyclic heteroaryl selected from the following formulae

Wherein the method comprises the steps of

A ¹、A²、A³、A⁴、A⁵、A⁶ and A ⁷ are each independently selected from C-R ⁷ and N;

Each of A ⁸、A⁹、A¹⁰ and A ¹¹ is independently selected from C-R ⁷ and N, provided that at least one of A ⁸、A⁹、A¹⁰ or A ¹¹ is N;

G ¹ is selected from C-R ³ and N;

G ² is selected from O and N-R ⁴;

B is selected from O, S and N-R ⁵,

Provided that when A ⁵、A⁶ and A ⁷ are C-R ⁷, B is not S; and

R ² is selected from hydrogen, halogen, cyano, amino, hydroxy, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, Aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, -OR ¹⁵、-(C₁-C₆) alkylene-OR ¹⁵、-O-(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁶(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-O-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-SO ₂-NR¹⁷R¹⁸、-NR¹⁶-SO₂-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷-SO₂-R¹⁵、-C(O)-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-O-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-C(O)-R¹⁵、-C(O)OR¹⁵、-(C₁-C₆) alkylene-C (O) OR ¹⁵、-O-(C₁-C₆) alkylene-C (O) OR ¹⁵、-NR¹⁶-(C₁-C₆) alkylene-C (O) OR ¹⁵.

R ³ is selected from halogen, cyano, amino, hydroxy, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, Aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, -OR ¹⁵、-(C₁-C₆) alkylene-OR ¹⁵、-O-(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁶(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-O-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-SO ₂-NR¹⁷R¹⁸、-NR¹⁶-SO₂-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷-SO₂-R¹⁵、-C(O)-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-O-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-C(O)-R¹⁵、-C(O)OR¹⁵、-(C₁-C₆) alkylene-C (O) OR ¹⁵、-O-(C₁-C₆) alkylene-C (O) OR ¹⁵、-NR¹⁶-(C₁-C₆) alkylene-C (O) OR ¹⁵.

R ⁴ is selected from the group consisting of hydrogen, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-aryl, - (C ₁-C₆) alkylene-heteroaryl, - (C ₁-C₆) alkylene-OR ¹⁵、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-C (O) OR ¹⁵ and- (C ₁-C₆) alkylene-OC (O) -R ¹⁵;

R ⁵ is selected from the group consisting of hydrogen, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-aryl, - (C ₁-C₆) alkylene-heteroaryl, - (C ₁-C₆) alkylene-OR ¹⁵、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-C (O) OR ¹⁵ and- (C ₁-C₆) alkylene-OC (O) -R ¹⁵;

r ⁷ is independently selected from hydrogen, halogen, amino, hydroxy, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl, heteroaryl, -OR ¹⁵、-(C₁-C₆) alkylene-OR ¹⁵、-O-(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁶(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-O-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-NR¹⁶-(C₂-C₆) alkylene -NR¹⁷R¹⁸、-SO-R¹⁵、-SO₂-R¹⁵、-SO₂NR¹⁷R¹⁸、-(C₁-C₆) alkylene-SO ₂-NR¹⁷R¹⁸、-NR¹⁶-SO₂-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷-SO₂-R¹⁵、-C(O)-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-O-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷C(O)-R¹⁵、-C(O)-R¹⁵、-C(O)-OR¹⁵、-(C₁-C₆) alkylene-C (O) -OR ¹⁵、-O-(C₁-C₆) alkylene-C (O) -OR ¹⁵、-NR¹⁶-(C₁-C₆) alkylene-C (O) -OR ¹⁵、-OC(O)-R¹⁵、-(C₁-C₆) alkylene-OC (O) -R ¹⁵、-O-(C₂-C₆) alkylene-OC (O) -R ¹⁵、-NR¹⁶-(C₂-C₆) alkylene-OC (O) -R ¹⁵ OR-NR ¹⁶-C(O)-OR¹⁵;

Wherein the method comprises the steps of

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ²、R³、R⁴、R⁵ or R ⁷ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl or heteroaryl groups in R ²、R³、R⁴、R⁵ or R ⁷ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

R ¹⁵、R¹⁶、R¹⁷ and R ¹⁸ are each independently selected from the group consisting of hydrogen, - (C ₁-C₆) haloalkyl, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-heteroaryl, and- (C ₁-C₆) alkylene-aryl; and/or two groups selected from R ¹⁵、R¹⁶、R¹⁷ and R ¹⁸ together form a ring selected from- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl and heteroaryl;

Wherein the method comprises the steps of

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ¹⁵、R¹⁶、R¹⁷ or R ¹⁸ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl or heteroaryl groups in R ¹⁵、R¹⁶、R¹⁷ or R ¹⁸ is optionally substituted by at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl,

-CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

-Y ² is a 5-membered heteroaryl selected from the following formulae

Wherein R ¹²、R¹³ and R ¹⁴ are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl) and-N- ((C ₁-C₆) alkyl) ₂;

Wherein each of the- (C ₁-C₆) alkyl groups in R ¹²、R¹³ or R ¹⁴ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

-L is selected from- (CR ¹⁰R¹¹)_n、-(C₃-C₇) cycloalkyl and (C ₃-C₇) heterocycloalkyl;

Wherein the method comprises the steps of

N is an integer selected from 1,2, 3 and 4;

R ¹⁰ and R ¹¹ are independently selected from hydrogen, halogen, hydroxy, amino, - (C ₁-C₃) alkyl, - (C ₁-C₂) haloalkyl, - (C ₁-C₂) hydroxyalkyl, - (C ₁-C₂) aminoalkyl, -O- (C ₁-C₄) alkyl, -NH- (C ₁-C₃) alkyl and-N- ((C ₁-C₃) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl or (C ₃-C₇) heterocycloalkyl groups in L is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

-Z ¹ is selected from (c=o) -R ⁹ and S (O ₂)-R⁹;

Wherein R ⁹ is selected from amino, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, Aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-aryl, - (C ₁-C₆) alkylene-heteroaryl, - (C ₁-C₆) alkylene-OR ²¹、-(C₁-C₆) alkylene-NR ²³R²⁴、-(C₁-C₆) alkylene-C (O) -NR ²³R²⁴、-(C₁-C₆) alkylene-C (O) -NR ²³R²⁴、-(C₁-C₆) alkylene-NR ²²-C(O)-R²¹、-(C₁-C₆) alkylene-C (O) OR ²¹、-OR²¹、-NR²³R²⁴、-NR²²-(C₂-C₆) alkylene-OR ²¹、-NR²²-(C₂-C₆) alkylene-NR ²³R²⁴、-NR²²-(C₁-C₆) alkylene-C (O) OR ²¹;

Wherein the method comprises the steps of

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ⁹ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl or heteroaryl groups in R ⁹ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

R ²¹、R²²、R²³ and R ²⁴ are each independently selected from the group consisting of hydrogen, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) halocycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-heteroaryl, and- (C ₁-C₆) alkylene-aryl; and/or two groups selected from R ²¹、R²²、R²³ and R ²⁴ together form a ring selected from- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl and heteroaryl;

Wherein the method comprises the steps of

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ²¹、R²²、R²³ or R ²⁴ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl or heteroaryl groups in R ²¹、R²²、R²³ or R ²⁴ is optionally substituted by at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl,

-CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂; and

-R ¹ is selected from the group consisting of hydrogen, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-OR ¹⁹ and- (C ₁-C₆) alkylene-NR ¹⁹R²⁰, wherein

R ¹⁹ and R ²⁰ are each independently selected from hydrogen, - (C ₁-C₆) alkyl and- (C ₃-C₇) cycloalkyl; or R ¹⁹ and R ²⁰ together form a ring selected from- (C ₃-C₇) cycloalkyl and- (C ₃-C₇) heterocycloalkyl;

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ¹、R¹⁹ and R ²⁰ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl or- (C ₃-C₇) heterocycloalkyl in R ¹⁵、R¹⁶、R¹⁷ or R ¹⁸ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

R ¹ and one of R ¹⁰ or R ¹¹ together form a (C ₃-C₇) heterocycloalkyl containing at least one nitrogen atom;

Wherein the (C ₃-C₇) heterocycloalkyl in R ¹ and R ¹⁰ or R ¹¹ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂; or (b)

R ¹ and R ⁹ together form a (C ₃-C₇) heterocycloalkyl group containing at least one nitrogen atom;

Wherein in R ¹ and R ⁹ the (C ₃-C₇) heterocycloalkyl is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂.

2. A compound of formula (I)

Or a pharmaceutically acceptable salt and/or solvate thereof;

Wherein the method comprises the steps of

-Y ¹ is a 9-or 10-membered bicyclic heteroaryl selected from the following formulae

Wherein the method comprises the steps of

A ¹、A²、A³、A⁴、A⁵、A⁶ and A ⁷ are each independently selected from C-R ⁷ and N;

Each of A ⁸、A⁹、A¹⁰ and A ¹¹ is independently selected from C-R ⁷ and N, provided that at least one of A ⁸、A⁹、A¹⁰ or A ¹¹ is N;

G ¹ is selected from C-R ³ and N;

G ² is selected from O and N-R ⁴;

B is selected from O, S and N-R ⁵,

Provided that when A ⁵、A⁶ and A ⁷ are C-R ⁷, B is not S; and

R ² is selected from hydrogen, halogen, cyano, amino, hydroxy, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, Aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, -OR ¹⁵、-(C₁-C₆) alkylene-OR ¹⁵、-O-(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁶(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-O-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-SO ₂-NR¹⁷R¹⁸、-NR¹⁶-SO₂-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷-SO₂-R¹⁵、-C(O)-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-O-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-C(O)-R¹⁵、-C(O)OR¹⁵、-(C₁-C₆) alkylene-C (O) OR ¹⁵、-O-(C₁-C₆) alkylene-C (O) OR ¹⁵、-NR¹⁶-(C₁-C₆) alkylene-C (O) OR ¹⁵.

R ³ is selected from halogen, cyano, amino, hydroxy, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, Aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, -OR ¹⁵、-(C₁-C₆) alkylene-OR ¹⁵、-O-(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁶(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-O-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-SO ₂-NR¹⁷R¹⁸、-NR¹⁶-SO₂-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷-SO₂-R¹⁵、-C(O)-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-O-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-C(O)-R¹⁵、-C(O)OR¹⁵、-(C₁-C₆) alkylene-C (O) OR ¹⁵、-O-(C₁-C₆) alkylene-C (O) OR ¹⁵、-NR¹⁶-(C₁-C₆) alkylene-C (O) OR ¹⁵.

R ⁴ is selected from the group consisting of hydrogen, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-aryl, - (C ₁-C₆) alkylene-heteroaryl, - (C ₁-C₆) alkylene-OR ¹⁵、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-C (O) OR ¹⁵ and- (C ₁-C₆) alkylene-OC (O) -R ¹⁵;

R ⁵ is selected from the group consisting of hydrogen, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-aryl, - (C ₁-C₆) alkylene-heteroaryl, - (C ₁-C₆) alkylene-OR ¹⁵、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-C (O) OR ¹⁵ and- (C ₁-C₆) alkylene-OC (O) -R ¹⁵;

r ⁷ is independently selected from hydrogen, halogen, amino, hydroxy, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl, heteroaryl, -OR ¹⁵、-(C₁-C₆) alkylene-OR ¹⁵、-O-(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁶(C₂-C₆) alkylene-OR ¹⁵、-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-NR ¹⁷R¹⁸、-O-(C₂-C₆) alkylene-NR ¹⁷R¹⁸、-NR¹⁶-(C₂-C₆) alkylene -NR¹⁷R¹⁸、-SO-R¹⁵、-SO₂-R¹⁵、-SO₂NR¹⁷R¹⁸、-(C₁-C₆) alkylene-SO ₂-NR¹⁷R¹⁸、-NR¹⁶-SO₂-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶-SO₂-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷-SO₂-R¹⁵、-C(O)-NR¹⁷R¹⁸、-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-O-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶-(C₁-C₆) alkylene-C (O) -NR ¹⁷R¹⁸、-NR¹⁶C(O)-R¹⁵、-(C₁-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-O-(C₂-C₆) alkylene-NR ¹⁶C(O)-R¹⁵、-NR¹⁶-(C₂-C₆) alkylene-NR ¹⁷C(O)-R¹⁵、-C(O)-R¹⁵、-C(O)-OR¹⁵、-(C₁-C₆) alkylene-C (O) -OR ¹⁵、-O-(C₁-C₆) alkylene-C (O) -OR ¹⁵、-NR¹⁶-(C₁-C₆) alkylene-C (O) -OR ¹⁵、-OC(O)-R¹⁵、-(C₁-C₆) alkylene-OC (O) -R ¹⁵、-O-(C₂-C₆) alkylene-OC (O) -R ¹⁵、-NR¹⁶-(C₂-C₆) alkylene-OC (O) -R ¹⁵ OR-NR ¹⁶-C(O)-OR¹⁵;

Wherein the method comprises the steps of

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ²、R³、R⁴、R⁵ or R ⁷ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl or heteroaryl groups in R ²、R³、R⁴、R⁵ or R ⁷ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

R ¹⁵、R¹⁶、R¹⁷ and R ¹⁸ are each independently selected from the group consisting of hydrogen, - (C ₁-C₆) haloalkyl, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-heteroaryl, and- (C ₁-C₆) alkylene-aryl; and/or two groups selected from R ¹⁵、R¹⁶、R¹⁷ and R ¹⁸ together form a ring selected from- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl and heteroaryl;

Wherein the method comprises the steps of

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ¹⁵、R¹⁶、R¹⁷ or R ¹⁸ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl or heteroaryl groups in R ¹⁵、R¹⁶、R¹⁷ or R ¹⁸ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

-Y ² is a 5-membered heteroaryl selected from the following formulae

Wherein R ¹²、R¹³ and R ¹⁴ are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl) and-N- ((C ₁-C₆) alkyl) ₂;

Wherein each of the- (C ₁-C₆) alkyl groups in R ¹²、R¹³ or R ¹⁴ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

-L is selected from- (CR ¹⁰R¹¹)_n、-(C₄-C₇) cycloalkyl and (C ₄-C₇) heterocycloalkyl;

Wherein the method comprises the steps of

N is an integer selected from 1 or 2;

R ¹⁰ and R ¹¹ are independently selected from hydrogen, halogen, hydroxy, amino, - (C ₁-C₃) alkyl, - (C ₁-C₂) haloalkyl, - (C ₁-C₂) hydroxyalkyl, - (C ₁-C₂) aminoalkyl, -O- (C ₁-C₄) alkyl, -NH- (C ₁-C₃) alkyl and-N- ((C ₁-C₃) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl or (C ₃-C₇) heterocycloalkyl groups in L is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

-Z ¹ is selected from-C (O) -R ⁹ and-SO ₂-R⁹;

Wherein R ⁹ is selected from amino, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, Aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-aryl, - (C ₁-C₆) alkylene-heteroaryl, - (C ₁-C₆) alkylene-OR ²¹、-(C₁-C₆) alkylene-NR ²³R²⁴、-(C₁-C₆) alkylene-C (O) -NR ²³R²⁴、-(C₁-C₆) alkylene-C (O) -NR ²³R²⁴、-(C₁-C₆) alkylene-NR ²²-C(O)-R²¹、-(C₁-C₆) alkylene-C (O) OR ²¹、-OR²¹、-NR²³R²⁴、-NR²²-(C₂-C₆) alkylene-OR ²¹、-NR²²-(C₂-C₆) alkylene-NR ²³R²⁴、-NR²²-(C₁-C₆) alkylene-C (O) OR ²¹;

Wherein the method comprises the steps of

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ⁹ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl or heteroaryl groups in R ⁹ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

R ²¹、R²²、R²³ and R ²⁴ are each independently selected from the group consisting of hydrogen, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) halocycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl, heteroaryl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-heteroaryl, and- (C ₁-C₆) alkylene-aryl; and/or two groups selected from R ²¹、R²²、R²³ and R ²⁴ together form a ring selected from- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl and heteroaryl;

Wherein the method comprises the steps of

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ²¹、R²²、R²³ or R ²⁴ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, aryl or heteroaryl groups in R ²¹、R²²、R²³ or R ²⁴ is optionally substituted by at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl,

-CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂; and

-R ¹ is selected from the group consisting of hydrogen, - (C ₁-C₆) alkyl, - (C ₃-C₇) cycloalkyl, - (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) cycloalkyl, - (C ₁-C₆) alkylene- (C ₃-C₇) heterocycloalkyl, - (C ₁-C₆) alkylene-OR ¹⁹ and- (C ₁-C₆) alkylene-NR ¹⁹R²⁰, wherein

R ¹⁹ and R ²⁰ are each independently selected from hydrogen, - (C ₁-C₆) alkyl and- (C ₃-C₇) cycloalkyl; or R ¹⁹ and R ²⁰ together form a ring selected from- (C ₃-C₇) cycloalkyl and- (C ₃-C₇) heterocycloalkyl;

Each of the- (C ₁-C₆) alkyl or- (C ₁-C₆) alkylene groups in R ¹、R¹⁹ and R ²⁰ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, -O- (C ₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl, and-N- ((C ₁-C₆) alkyl) ₂;

Each of the- (C ₃-C₇) cycloalkyl or- (C ₃-C₇) heterocycloalkyl in R ¹⁵、R¹⁶、R¹⁷ or R ¹⁸ is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

R ¹ and one of R ¹⁰ or R ¹¹ together form a (C ₃-C₇) heterocycloalkyl containing at least one nitrogen atom;

Wherein in R ¹ and R ¹⁰ or R ¹¹ the (C ₃-C₇) heterocycloalkyl is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂; or (b)

R ¹ and R ⁹ together form a (C ₃-C₇) heterocycloalkyl group containing at least one nitrogen atom;

Wherein in R ¹ and R ⁹ the (C ₃-C₇) heterocycloalkyl is optionally substituted with at least one group selected from halogen, cyano, hydroxy, oxo, amino, - (C ₁-C₆) alkyl, -CH ₂-O-(C₁-C₆) alkyl, -CH ₂-NH-(C₁-C₆) alkyl, -CH ₂-N-((C₁-C₆) alkyl) ₂、-O-(C₁-C₆) alkyl, -NH- (C ₁-C₆) alkyl and-N- ((C ₁-C₆) alkyl) ₂;

provided that it is

-When Y ¹ is quinazolinyl and R ¹ is hydrogen, Z ¹ is not selected from-C (O) -methyl and-S (O) ₂ -methyl;

-when Y ¹ is 1H-pyrazolo [3,4-d ] pyrimidinyl and R ¹ is hydrogen, Z ¹ is not selected from-C (O) -methyl, -C (O) -tert-butyl and-SO ₂ -methyl; and

The compound of formula (I) is not N- (2- (5- (2- ((5-methyl oxazolo [4,5-b ] pyridin-2-yl) thio) acetyl) thiophen-2-yl) ethyl) acetamide.

3. A compound for use according to claim 1 or a compound according to claim 2, wherein Y ¹ is a 9-or 10-membered bicyclic heteroaryl selected from:

The following steps are adopted

Wherein a ¹-A⁴、A⁶、A⁷、G¹ and R ² are independently as defined in claim 1 or claim 2; and

The following steps are adopted

Wherein a ⁸-A¹¹ and G ² are independently as defined in claim 1 or claim 2.

4. A compound for use according to claim 1 or a compound according to claim 2 wherein Y ¹ is a 10-membered [6,6] bicyclic heteroaryl selected from the following formulae

Wherein R ²、R³ and R ⁷ are independently as defined in claim 1 or claim 2.

5. A compound for use according to claim 1 or a compound according to claim 2, wherein Y ¹ is a 9-membered bicyclo [6,5] heteroaryl selected from:

The following steps are adopted

The following steps are adopted

The following steps are adopted

The following steps are adopted

And the following

Wherein R ²、R³、R⁵ and R ⁷ are independently as defined in claim 1 or claim 2.

6. A compound for use according to claim 1 or a compound according to claim 2, wherein Y ¹ is a 9-membered bicyclo [5,6] heteroaryl selected from:

The following steps are adopted

And the following

Wherein the method comprises the steps of

A ¹、A³、A³、A⁴、R²、R⁴ and R ⁷ are independently as defined in claim 1 or claim 2.

7. A compound for use according to claim 6 or a compound according to claim 6 wherein Y ¹ is a 9-membered bicyclo [5,6] heteroaryl selected from the following formulae

Wherein a ¹、A³、A³、A⁴ and R ⁴ are independently as defined in claim 1 or claim 2.

8. A compound for use according to any one of claims 1 to 7 or a compound according to any one of claims 1 to 7 wherein Y ² is selected from the following formulae

Wherein R ¹²、R¹³ and R ¹⁴ are independently as defined in claim 1,

Preferably, R ¹² and R ¹³, or R ¹² and R ¹⁴ are selected from hydrogen and (C ₁-C₃) alkyl, more preferably R ¹² and R ¹³, or R ¹² and R ¹⁴ are each hydrogen.

9. The compound for use according to any one of claims 1 to 8 or the compound according to any one of claims 1 to 8, wherein R ¹⁰ and R ¹¹ are independently selected from hydrogen and (C ₁-C₃) alkyl, preferably R ¹⁰ and R ¹¹ are each hydrogen.

10. The compound for use according to any one of claims 1 to 9 or the compound according to any one of claims 1 to 9, wherein R ¹ is selected from hydrogen and (C ₁-C₃) alkyl, preferably R ¹ is hydrogen or methyl, more preferably R ¹ is hydrogen.

11. The compound for use according to any one of claims 1 to 9 or the compound according to any one of claims 1 to 9, wherein any one of R ¹ and R ¹⁰ or R ¹¹ together form a 5-membered heterocycloalkyl containing one nitrogen atom, preferably R ¹⁰ or R ¹¹ together form pyrrolidine.

12. The compound for use according to any one of claims 1 to 9 or the compound according to any one of claims 1 to 9, wherein R ¹ and R ⁹ together form a 5-or 6-membered heterocycloalkyl containing one nitrogen atom, preferably R ¹ and R ⁹ together form pyrrolidone or morpholin-3-one.

13. The compound for use according to any one of claims 1 to 12 or the compound according to any one of claims 1 to 12, wherein R ⁹ is selected from the group consisting of methyl, tert-butyl, cyclopropyl, O-tert-butyl, hydroxymethyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 2-hydroxypropyl-2-yl, 1-hydroxycyclopropyl, methoxymethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, phenylmethyl, phenyl 2, 2-difluorocyclopropyl and 2, 3-pentafluoro-propyl, H ₂ N-methyl, N-methyl-NH-methyl, methylazetidinyl, 1-hydroxyethyl and pyrrolidinyl; preferably R ⁹ is selected from cyclopropyl, hydroxymethyl, (S) -3, 3-trifluoro-2-hydroxypropyl, 2-hydroxypropyl-2-yl, 1-hydroxycyclopropyl, 2-difluorocyclopropyl and 2, 3-pentafluoro-propyl.

14. A compound for use according to claim 1, wherein n is an integer selected from 1 and 2, and wherein R ¹⁰ and R ¹¹ are independently selected from hydrogen and (C ₁-C₃) alkyl, preferably R ¹⁰ and R ¹¹ are each hydrogen.

15. A compound for use according to claim 1, wherein the compound is selected from the group consisting of

And pharmaceutically acceptable salts and/or solvates thereof.

16. A pharmaceutical composition for use in the treatment and/or prophylaxis of HDAC 6-related diseases, wherein the pharmaceutical composition comprises a compound as described in any one of claims 1-15 and at least one pharmaceutically acceptable carrier.

17. The compound for use according to claim 1 or any one of claims 3-15 or the pharmaceutical composition for use according to claim 16, wherein the HDAC 6-related disease is selected from inflammatory diseases, autoimmune diseases, proliferative diseases such as cancer, neurodegenerative diseases, pain, neuropathy, psychotic diseases, neurodevelopmental disorders, sleep disorders and cardiovascular diseases.

18. The compound for use of claim 17 or the pharmaceutical composition for use of claim 17, wherein the HDAC 6-related disease is cancer selected from malignant melanoma, multiple myeloma, leukemia, lymphoma, breast cancer, and hodgkin's disease.

19. The compound for use of claim 17 or the pharmaceutical composition for use of claim 17, wherein the HDAC 6-related disease is a neurodegenerative disease selected from alzheimer's disease, parkinson's disease, huntington's disease, frontotemporal dementia, pick's disease, nii-pidi syndrome, down's disease, dementia with lewy bodies, HIV dementia, amyotrophic Lateral Sclerosis (ALS), and multiple sclerosis.

20. The compound for use of claim 17 or the pharmaceutical composition for use of claim 17, wherein the HDAC 6-related disease is a neuropathy selected from the group consisting of guillain-barre syndrome, chronic Inflammatory Demyelinating Polyneuropathy (CIDP), multifocal Motor Neuropathy (MMN), summer-equine-tourette's disease, hereditary sensory and autonomic neuropathy, familial amyloid polyneuropathy, chemotherapy-induced peripheral neuropathy with chemotherapeutic anticancer agents (CIPN), diabetic Peripheral Neuropathy (DPN), neuralgia, pain, and/or neuropathic pain.

21. The compound for use according to claim 17 or the pharmaceutical composition for use according to claim 17, wherein the HDAC 6-related disease is a cardiovascular disease selected from heart failure, cardiomyopathy and/or myocarditis.

22. The compound of claim 2, wherein the compound is selected from the group consisting of

And pharmaceutically acceptable salts and/or solvates thereof.

23. A process for the preparation of a compound according to any one of claims 2 to 13 or claim 22, wherein the process comprises the steps of:

(i) Reacting a linear or cyclic amine with an acyl chloride, carboxylic acid or sulfonyl chloride; or (b)

(Ii) Reacting the halo-ketone with a thiol.

24. A pharmaceutical composition comprising a compound according to any one of claims 2 to 13 or claim 22 and at least one pharmaceutically acceptable carrier.

25. A compound according to any one of claims 2 to 13 or claim 22 or a pharmaceutical composition according to claim 24 for use as a medicament.