阅读说明：本技术 使用ccr3-抑制剂治疗衰老相关损伤的方法及组合物 (Methods and compositions for treating aging-related injuries using CCR 3-inhibitors ) 是由 史蒂文·P·布雷斯韦特 S·樱井·南 卡罗伊·尼科利希 于 2018-04-04 设计创作，主要内容包括：提供使用CCR3调节剂来改善神经退行性疾病的方法。这些方法包括向对象施用治疗有效量的CCR3调节剂,其中在认知、运动或其他受神经退行影响的功能上会有伴随性的改善。本发明方法可改善认知的认知性及运动疾病包括阿兹海默氏症、帕金森氏病、额颞叶型痴呆、亨丁顿氏症、肌萎缩性侧索硬化症、多发性硬化症、青光眼、肌强直性营养不良、血管性痴呆、进行性核上性麻痹症。(Methods of using modulators of CCR3 to ameliorate neurodegenerative diseases are provided. These methods comprise administering to a subject a therapeutically effective amount of a CCR3 modulator wherein there is a concomitant improvement in cognition, exercise or other neurodegenerative affected functions. Cognitive and motor disorders that can improve cognition in the methods of the invention include Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy.)

1. A method of treating a neurodegenerative disease in a subject diagnosed with the neurodegenerative disease, the method comprising administering a therapeutically effective amount of a compound of formula 1 to treat the neurodegenerative disease in the subject:

wherein

A is CH₂O or N-C_1-6-an alkyl group;

R¹is selected from

·NHR^1.1、NMeR^1.1；

·NHR^1.2、NMeR^1.2；

·NHCH₂-R^1.3；

·NH-C_3-6-cycloalkyl in which optionally one carbon atom is replaced by a nitrogen atom, wherein the ring is optionally substituted by a group selected from C_1-6Alkyl, O-C_1-6Alkyl, NHSO₂Phenyl, NHCONH-phenyl, halogen, CN, SO₂-C_1-6-alkyl, COO-C_1-6-one or two residue substitutions of alkyl;

·C_{9 or 10}-bicyclic ring, wherein one or two carbon atoms are replaced by nitrogen atoms, the ring system being bonded to the basic structure of formula 1 via nitrogen atoms, wherein the ring system is optionally selected from C_1-6-alkyl, COO-C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, NO₂Halogen, CN, NHSO₂-C_1-6-alkyl, methoxy-phenyl substituted with one or two residues;

selected from NHCH (pyridyl) CH₂COO-C_1-6Alkyl, NHCH (CH)₂O-C_1-6-alkyl) -benzimidazolyl, optionally substituted with halogen or CN; or

1-aminocyclopentyl radical, which is optionally substituted by methyl-Oxadiazole substitution;

R^1.1is phenyl, optionally via a radical selected from C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_1-6-haloalkyl group, C_1-6alkylene-OH, C_2-6-alkenylene-OH, C_2-6-alkynylene-OH, CH₂CON(C_1-6-alkyl groups)₂、CH₂NHCONH-C_3-6-cycloalkyl, CN, CO-pyridyl, CONR^1.1.1R^1.1.2、COO-C_1-6Alkyl, N (SO)₂-C_1-6-alkyl) (CH₂CON(C_1-4-alkyl groups)₂)O-C_1-6-alkyl, O-pyridyl, SO₂-C_1-6Alkyl, SO₂-C_1-6alkylene-OH, SO₂-C_3-6-cycloalkyl, SO₂Piperidinyl, SO₂NH-C_1-6Alkyl, SO₂N(C_1-6-alkyl groups)₂Halogen, CN, CO-morpholinyl, CH₂-one or two residues of pyridyl, or optionally substituted by a group selected from C_1-6-alkyl, NHC_1-6-alkyl and a heterocycle substituted with one or two residues of ═ O;

R^1.1.1is H, C_1-6Alkyl radical, C_3-6-cycloalkyl, C_1-6-haloalkyl, CH₂CON(C_1-6-alkyl groups)₂、CH₂CO-Azacyclobutyl, C_1-6alkylene-C_3-6-cycloalkyl, CH₂Pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, C_1-6alkylene-OH or thiadiazolyl, optionally via C_1-6-alkyl substitution;

R^1.1.2is H, C_1-6Alkyl, SO₂C_1-6-an alkyl group;

or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one N or O replacing a carbon atom on the ring, and optionally via a substituent selected from C_1-6Alkyl radical, C_1-4-alkylene-OH, ═ O, substituted with one or two residues;

or

R^1.1Is phenyl, wherein two adjacent residues together form a five-or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing, independently of each other, one or two N, S replacing a carbon atom on the ring or SO₂Wherein the five-or six-membered carbocyclic aromatic or nonaromatic ring is optionally via C_1-4-alkyl or ═ O substitution;

R^1.2is selected from

Heteroaryl, optionally via a radical selected from C_1-6Alkyl radical, C_2-6-alkenyl, C_2-6-alkynyl, C_3-6-cycloalkyl, CH₂COO-C_1-6Alkyl, CONR^1.2.1R^1.2.2、COR^1.2.3、COO-C_1-6Alkyl, CONH₂、O-C_1-6Alkyl, halogen, CN, SO₂N(C_1-6-alkyl groups)₂Is substituted by one or two residues, or heteroaryl, optionally substituted by a group selected from C_1-6-one or two residue substitutions of alkyl;

heteroaryl, optionally substituted by a five-or six-membered carbocyclic non-aromatic ring containing, independently of one another, two N, O, S or SO replacing a carbon atom on the ring₂；

Aromatic or non-aromatic C_{9 or 10}Bicyclic ring, in which one or two carbon atoms are replaced by N, O or S, said aromatic or non-aromatic C_{9 or 10}-each of the bicyclic rings is optionally selected from N (C)_1-6-alkyl groups)₂、CONH-C_1-6-alkyl, ═ O substituted with one or two residues;

a heterocyclic non-aromatic ring, optionally substituted with pyridyl;

4, 5-dihydro-naphtho [2,1-d ]]Thiazoles, optionally via NHCO-C_1-6-an alkyl substitution,

R^1.2.1is H, C_1-6Alkyl radical, C_1-6alkylene-C_3-6-cycloalkyl, C_1-4Alkylene-phenyl, C_1-4Alkylene-furyl radical, C_3-6-cycloalkyl, C_1-4alkylene-O-C_1-4Alkyl radical, C_1-6-haloalkyl or a five-or six-membered carbocyclic non-aromatic ring, said five-or six-membered carbocyclic ringThe non-aromatic rings optionally containing, independently of one another, one or two N, O, S or SO substituents replacing a carbon atom on the ring₂And optionally substituted with 4-cyclopropylmethyl-piperazinyl;

R^1.2.2is H, C_1-6-an alkyl group;

R^1.2.3is a five-or six-membered carbocyclic non-aromatic ring optionally containing, independently of one another, one or two N, O, S or SO replacing a carbon atom on the ring₂；

R^1.3Selected from phenyl, heteroaryl or indolyl, each of which is optionally selected from C_1-6Alkyl radical, C_3-6-cycloalkyl, O-C_1-6Alkyl, O-C_1-6-one or two residue substitutions of haloalkyl, phenyl, heteroaryl;

R²is selected from C_1-6Alkylene-phenyl, C_1-6-alkylene-naphthyl, and C_1-6-alkylene-heteroaryl; each of which is optionally selected from C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, O-C_1-6-one, two or three residue substitutions of haloalkyl, halogen;

R³is H, C_1-6-an alkyl group;

R⁴is H, C_1-6-an alkyl group;

or R³And R⁴Together form CH₂-CH₂A group.

2. The method of claim 1, wherein the compound of formula 1,

a is CH₂O or N-C_1-4-an alkyl group;

R¹is selected from

·NHR^1.1、NMeR^1.1；

·NHR^1.2、NMeR^1.2；

·NHCH₂-R^1.3；

·NH-C_3-6Cycloalkyl in which optionally one carbon atom is replaced by a nitrogen atom, in which the ring is optionally substituted by a group selected from C_1-6Alkyl, O-C_1-6Alkyl, NHSO₂Phenyl, NHCONH-phenyl, halogen, CN, SO₂-C_1-6-alkyl, COO-C_1-6-one or two residue substitutions of alkyl;

·C_{9 or 10}-bicyclic ring, wherein one or two carbon atoms are replaced by nitrogen atoms and the ring system is bonded to the basic structure of formula 1 via nitrogen atoms, wherein the ring system is optionally selected from C_1-6-alkyl, COO-C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, NO₂Halogen, CN, NHSO₂-C_1-6-alkyl, m-methoxyphenyl, substituted by one or two residues;

selected from NHCH (pyridyl) CH₂COO-C_1-6Alkyl, NHCH (CH)₂O-C_1-6-alkyl) -benzimidazolyl, optionally substituted with Cl; or

1-aminocyclopentyl, optionally methyl-Substituted by diazole group;

R^1.1is phenyl, optionally via a radical selected from C_1-6Alkyl radical, C_1-6-haloalkyl, CH₂CON(C_1-6-alkyl groups)₂、CH₂NHCONH-C_3-6-cycloalkyl, CN, CONR^1.1.1R^1.1.2、COO-C_1-6Alkyl, O-C_1-6Alkyl, SO₂-C_1-6Alkyl, SO₂-C_1-6alkylene-OH, SO₂-C_3-6-cycloalkyl, SO₂Piperidinyl, SO₂NH-C_1-6Alkyl, SO₂N(C_1-6-alkyl groups)₂Halogen, CN, CO-morpholinyl, CH₂-substitution of one or two residues of pyridyl, or R^1.1Is optionally selected from C_1-6-alkyl, NHC_1-6-alkyl, ═ O, and heterocycles substituted with one or two residues;

R^1.1.1is H, C_1-6Alkyl radical, C_3-6-cycloalkyl, C_1-6-haloalkyl, CH₂CON(C_1-6-alkyl groups)₂、CH₂CO-Azacyclobutyl, C_1-6alkylene-C_3-6-cycloalkyl, CH₂Pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, C_1-6alkylene-OH or thiadiazolyl, optionally via C_1-6-alkyl substitution;

R^1.1.2is H, C_1-6Alkyl, SO₂C_1-6-an alkyl group;

or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one O replacing a carbon atom on the ring, and optionally via a substituent selected from CH₂One or two residue substitutions of OH;

R^1.2is selected from

Heteroaryl, optionally via a radical selected from C_1-6Alkyl radical, C_3-6-cycloalkyl, CH₂COO-C_1-6Alkyl, CONR^1.2.1R^1.2.2、COO-C_1-6Alkyl, CONH₂、O-C_1-6-alkyl, halogen, CN, CO-pyrrolidinyl, CO-morpholinyl, substituted with one or two residues, or heteroaryl, optionally substituted with a group selected from C_1-6-one or two residue substitutions of alkyl;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with a group selected from N (C)_1-6-alkyl groups)₂、CONH-C_1-6-alkyl, ═ O substituted with one or two residues;

piperidinyl, optionally substituted with pyridinyl;

4, 5-dihydro-naphtho [2,1-d ]]Thiazoles, optionally via NHCO-C_1-6-alkyl substitution;

R^1.2.1is H, C_1-6-an alkyl group;

R^1.2.2is H, C_1-6-an alkyl group;

R^1.3selected from phenyl, pyrazolyl, isoAzolyl, pyrimidinyl, indolyl orOxadiazolyl, each of which is optionally selected from C_1-6Alkyl radical, C_3-6-cycloalkyl, O-C_1-6Alkyl, O-C_1-6-one or two residue substitutions of haloalkyl;

R²is selected from CH₂-phenyl or CH₂-naphthyl, both optionally via C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6Alkyl, O-C_1-6-haloalkyl, halogen substituted with one or two residues; or R²Is selected from CH₂-thiophenyl, optionally substituted with one or two residues selected from halogen;

R³is H, C_1-4-an alkyl group;

R⁴is H, C_1-4-an alkyl group;

or R³And R⁴Together form CH₂-CH₂A group.

3. The method of claim, wherein the compound of formula 1 is

A is CH₂O or NMe;

R¹is selected from

·NHR^1.1、NMeR^1.1；

·NHR^1.2、NMeR^1.2；

·NHCH₂-R^1.3；

NH-cyclohexyl, optionally via a radical selected from C_1-4Alkyl, NHSO₂-phenyl, NHCONH-phenyl, halo substituted with one or two residues;

NH-pyrrolidinyl, optionally via a radical selected from SO₂-C_1-4-alkyl, COO-C_1-4-one or two residue substitutions of alkyl;

piperidinyl, optionally via a radical selected from NHSO₂-C_1-4-alkyl, m-methoxyphenyl, substituted by one or two residues;

dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolyl or tetrahydro-isoquinolyl, optionally via a substituent selected from C_1-4-alkyl, COO-C_1-4Alkyl radical, C_1-4-haloalkyl, O-C_1-4Alkyl, NO₂One or two residue substitutions of halogen;

selected from NHCH (pyridyl) CH₂COO-C_1-4Alkyl, NHCH (CH)₂O-C_1-4-alkyl) -benzimidazolyl, optionally substituted with Cl; or

1-aminocyclopentyl, optionally methyl-Substituted by diazole group;

R^1.1is phenyl, optionally via a radical selected from C_1-4Alkyl radical, C_1-4-haloalkyl, CH₂CON(C_1-4-alkyl groups)₂、CH₂NHCONH-C_3-6-cycloalkyl, CN, CONR^1.1.1R^1.1.2、COO-C_1-4Alkyl, O-C_1-4Alkyl, SO₂-C_1-4Alkyl, SO₂-C_1-4alkylene-OH, SO₂-C_3-6-cycloalkyl, SO₂Piperidinyl, SO₂NH-C_1-4Alkyl, SO₂N(C_1-4-alkyl groups)₂Halogen, CO-morpholinyl, CH₂-substitution of one or two residues of pyridyl, or R^1.1Is imidazolidinyl, piperidyl, oxazacyclohexanyl, pyrazolyl, triazolyl, tetrazolyl, triazolyl, and oxaziridinyl,Azolyl group,Oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally selected from C_1-4-alkyl, NHC_1-4-alkyl, ═ O substituted with one or two residues;

R^1.1.1is H, C_1-6Alkyl radical, C_3-6-cycloalkyl, C_1-4-haloalkyl, CH₂CON(C_1-4-alkyl groups)₂、CH₂CO-Azacyclobutyl, C_1-4alkylene-C_3-6-cycloalkyl, CH₂-a pyranyl group,CH₂-tetrahydrofuranyl, CH₂-furyl, C_1-4alkylene-OH or thiadiazolyl, optionally via C_1-4-alkyl substitution;

R^1.1.2is H, C_1-4Alkyl, SO₂C_1-4-an alkyl group;

or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one O replacing a carbon atom on the ring, and optionally via a substituent selected from CH₂One or two residue substitutions of OH;

R^1.2is selected from

Pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoAzolyl, thiazolyl, thiadiazolyl, optionally selected from C_1-4Alkyl radical, C_3-6-cycloalkyl, CH₂COO-C_1-4Alkyl, CONR^1.2.1R^1.2.2、COO-C_1-4Alkyl, CONH₂、O-C_1-4-alkyl, halogen, CO-pyrrolidinyl, CO-morpholinyl, or R^1.2Selected from pyrazolyl, triazolyl, tetrazolyl, iso-pyrazolylAzolyl group,Oxadiazolyl, each of which is optionally selected from C_1-4-one or two residue substitutions of alkyl;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with a group selected from N (C)_1-4-alkyl groups)₂、CONH-C_1-4-alkyl, ═ O substituted with one or two residues;

piperidinyl, optionally substituted with pyridinyl;

4, 5-dihydro-naphtho [2,1-d ]]Thiazoles, optionally via NHCO-C_1-4-alkyl substitution;

R^1.2.1is H, C_1-4-an alkyl group;

R^1.2.2is H, C_1-4-an alkyl group;

R^1.3selected from phenyl, pyrazolyl, isoAzolyl, pyrimidinyl, indolyl orOxadiazolyl, each optionally via C_1-4Alkyl radical, C_3-6-cycloalkyl, O-C_1-4Alkyl, O-C_1-4-one or two residue substitutions of haloalkyl;

R²is selected from CH₂-phenyl or CH₂-naphthyl, both optionally via C_1-4Alkyl radical, C_1-4Haloalkyl, O-C_1-4-haloalkyl, halogen substituted with one or two residues; or R²Is selected from CH₂-thiophenyl, optionally substituted with one or two residues selected from halogen;

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

4. The method of claim 1, wherein formula 1 is

A is CH₂O or NMe;

R¹is selected from

·NHR^1.1、NMeR^1.1；

·NHR^1.2、NMeR^1.2；

·NHCH₂-R^1.3；

NH-piperidinyl, optionally substituted with pyridinyl;

NH-cyclohexyl, optionally via a gas selected from t-Bu, NHSO₂-phenyl, NHCONH-phenyl, substitution of one or two residues of F;

NH-pyrrolidinyl, optionally via a radical selected from SO₂One or two residues of Me and COO-t-Bu;

piperidinyl, optionally via a radical selected from NHSO₂-n-Bu, one or two residue substitutions of m-methoxyphenyl;

dihydro-indolyl, dihydro-isoindolyl, tetrahydro-quinolyl or tetrahydro-isoquinolyl, optionally substituted by a substituent selected from Me, COOMe, CF₃、OMe、NO₂F, Br;

selected from NHCH (pyridyl) CH₂COOMe、NHCH(CH₂OMe) -benzimidazolyl, optionally substituted with Cl; or

1-aminocyclopentyl, optionally methyl-Substituted by diazole group;

R^1.1is phenyl, optionally via a catalyst selected from Me, Et, t-Bu, CF₃、CH₂CONMe₂、CH₂NHCONH-cyclohexyl, CN, CONR^1.1.1R^1.1.2、COOMe、COOEt、OMe、SO₂Me、SO₂CH₂CH₂OH、SO₂Et、SO₂-cyclopropyl, SO₂Piperidinyl, SO₂NHEt、SO₂NMeEt, F, Cl, CO-morpholinyl, CH₂-substitution of one or two residues of pyridyl, or R^1.1Is imidazolidinyl, piperidyl, oxazacyclohexanyl, pyrazolyl, triazolyl, tetrazolyl, triazolyl, and oxaziridinyl,Azolyl group,Oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from Me, NHMe, ═ O;

R^1.1.1is H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH₂-i-Pr、CH₂-t-Bu、CH(CH₃)CH₂CH₃、CH₂CHF₂、CH₂CONMe₂、CH₂CO-AZACYCLOBUTYL, CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂Pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, CH₂CH₂OH or thiadiazolyl, optionally substituted with Me;

R^1.1.2is H, Me, Et, SO₂Me、SO₂Et；

Or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one O replacing a carbon atom on the ring, and optionally via a substituent selected from CH₂One or two residue substitutions of OH;

R^1.2is selected from

Pyridinyl, pyrrolyl, pyrazolyl, isoOxazolyl, thiazolyl, thiadiazolyl, optionally substituted by a group selected from Me, Et, Pr, Bu, cyclopropyl, CH₂COOEt、CONR^1.2.1R^1.2.2、COOMe、COOEt、CONH₂One or two residues of OMe, Cl, Br, CO-pyrrolidinyl, CO-morpholinyl, or R^1.2Selected from pyrazolyl, triazolyl, tetrazolyl, iso-pyrazolylAzolyl group,(ii) oxadiazolyl, each of which is optionally substituted with Me;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each of which is optionally substituted with NMe₂One or two residue substitutions of CONHMe, ═ O;

4, 5-dihydro-naphtho [2,1-d ] thiazole, optionally substituted with NHCOMe,

R^1.2.1h, Me;

R^1.2.2h, Me;

R^1.3selected from phenyl, pyrazolyl, isoAzolyl, pyrimidinyl, indolyl orOxadiazolyl, each of which is optionally substituted with one or more substituents selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF₂One or two residue substitutions;

R²is selected from CH₂-phenyl or CH₂-naphthyl, both optionally via CH₃、CF₃、OCF₃One or two residues of F, Cl, Br, Et; or R²Is selected from CH₂-thiophenyl, optionally substituted with one or two residues selected from Cl, Br;

R³is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

5. The method of claim 1, wherein formula 1 is

A is CH₂O or NMe;

R¹is selected from

NHR^1.1，

NHR^1.2，

R^1.1Is phenyl, optionally via a catalyst selected from Me, Et, Bu, CF₃、CH₂CONMe₂、CH₂NHCONH-cyclohexyl, CN, CONR^1.1.1R^1.1.2、COOMe、COOEt、OMe、SO₂Me、SO₂CH₂CH₂OH、SO₂Et、SO₂-cyclopropyl, SO₂Piperidinyl, SO₂NHEt、SO₂NMeEt, F, Cl, CO-morpholinyl, CH₂-substitution of one or two residues of pyridyl, or R^1.1Is imidazolidinyl, piperidyl, oxazacyclohexanyl, pyrazolyl, triazolyl, tetrazolyl, triazolyl, and oxaziridinyl,Azolyl group,Oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from Me, NHMe, ═ O;

R^1.1.1is H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH₂-i-Pr、CH₂-t-Bu、CH(CH₃)CH₂CH₃、CH₂CHF₂、CH₂CONMe₂、CH₂CO-AZACYCLOBUTYL, CH₂-cyclopropyl, CH₂-cyclobutyl, CH₂Pyranyl, CH₂-tetrahydrofuranyl, CH₂-furyl, CH₂CH₂OH or thiadiazolyl, optionally substituted with Me;

R^1.1.2is H, Me, Et, SO₂Me、SO₂Et；

Or R^1.1.1And R^1.1.2Together form a four-, five-or six-membered carbocyclic ring, optionally containing one O replacing a carbon atom on the ring, and optionally via a substituent selected from CH₂One or two residue substitutions of OH;

R^1.2is selected from

Pyridinyl, pyrrolyl, pyrazolyl, isoOxazolyl, thiazolyl, thiadiazolyl, optionally substituted by a group selected from Me, Et, Pr, Bu, cyclopropyl, CH₂COOEt、CONR^1.2.1R^1.2.2、COOMe、COOEt、CONH₂One or two residues of OMe, Cl, Br, CO-pyrrolidinyl, CO-morpholinyl, or R^1.2Selected from pyrazolyl, triazolyl, tetrazolyl, iso-pyrazolylAzolyl group,(ii) a diazolyl group,each of which is optionally substituted with Me;

benzothiazolyl, indazolyl, dihydro-indolyl, indanyl, tetrahydro-quinolinyl, each optionally substituted with NMe₂One or two residue substitutions of CONHMe, ═ O;

4, 5-dihydro-naphtho [2,1-d ] thiazole, optionally substituted with NHCOMe;

R^1.2.1h, Me;

R^1.2.2h, Me;

R²is selected from CH₂-phenyl or CH₂-naphthyl, both optionally via CH₃、CF₃、OCF₃One or two residues of F, Cl, Br, Et;

R³is H;

R⁴is H.

6. The method of claim 1, wherein formula 1 is

A is CH₂O or NMe;

R¹is selected from

R²Is selected from

R³Is H;

R⁴is H;

or R³And R⁴Together form CH₂-CH₂A group.

7. The method of claim 1, wherein the compound is a co-crystal of the formula

Wherein

R¹Is C_1-6Alkyl radical, C_1-6Haloalkyl, O-C_1-6-haloalkyl, halogen;

m is 1,2 or 3;

R^2aand R^2bEach independently selected from H, C_1-6Alkyl radical, C_1-6-alkenyl, C_1-6-alkynyl, C_3-6-cycloalkyl, COO-C_1-6Alkyl, O-C_1-6Alkyl, CONR^2b.1R^2b.2A halogen;

R^2b.1is H, C_1-6Alkyl radical, C_0-4-alkyl-C_3-6-cycloalkyl, C_1-6-a haloalkyl group;

R^2b.2is H, C_1-6-an alkyl group;

or R^2b.1And R^2b.2Together are C_3-6-an alkylene group forming a heterocyclic ring with a nitrogen atom, wherein optionally one carbon atom of said heterocyclic ring is replaced by an oxygen atom;

R³is H, C_1-6-an alkyl group;

x is an anion selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyltartrate, oxalate, succinate, benzoate, and p-toluenesulfonate;

j is 0, 0.5, 1, 1.5 or 2;

wherein the co-crystal former is selected from the group consisting of: orotic acid, hippuric acid, L-pyroglutamic acid, D-pyroglutamic acid, nicotinic acid, L- (+) -ascorbic acid, saccharin, piperazine, 3-hydroxy-2-naphthoic acid, mucic acid (galactaric acid), pamoic acid (enbo acid), stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L-lysine, L-proline, D-valine, L-arginine, glycine.

8. The method of claim 1, wherein the compound is a crystalline salt of the formula,

9. the method of claim 1, wherein the compound comprises a co-crystal of at least one compound of formula (lb) according to claim 7 and a pharmaceutically acceptable carrier.

10. The method of claim 1, wherein the compound of formula 1 is administered as individual optical isomers, mixtures of individual enantiomers, racemates or as enantiomerically pure compounds.

11. The method of claim 1, wherein the compound is a pharmaceutical composition comprising one or more than one compound of the formula as an active ingredient, a first diluent, a second diluent, a binder, a disintegrant, and a lubricant,

wherein

R¹Is H, C_1-6Alkyl radical, C_0-4-alkyl-C_3-6-cycloalkyl, C_1-6-a haloalkyl group;

R²is H, C_1-6-an alkyl group;

x is an anion selected from chloride or 1/2 dibenzoyl tartrate;

j is 1 or 2.

12. The method of claim 11, wherein the pharmaceutical composition further comprises an additional disintegrant.

13. The method of claim 11 or 12, wherein the pharmaceutical composition further comprises an additional glidant.

14. The method of claim 11, 12 or 13, wherein the diluent of the pharmaceutical composition further comprises cellulose powder, anhydrous dibasic calcium phosphate, dehydrated dibasic calcium phosphate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.

15. The method of any one of the preceding claims, wherein the neurodegenerative disease is selected from alzheimer's disease, parkinson's disease, frontotemporal dementia, huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy.