CN112043710A - Medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity - Google Patents

Medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity Download PDF

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CN112043710A
CN112043710A CN202011045107.XA CN202011045107A CN112043710A CN 112043710 A CN112043710 A CN 112043710A CN 202011045107 A CN202011045107 A CN 202011045107A CN 112043710 A CN112043710 A CN 112043710A
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lrrk2
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谢伟东
程星
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Guangzhou Zhirui Medical Technology Co ltd
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Abstract

The invention provides a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity, and belongs to the field of medicines. The medicine comprises at least one of a compound shown in chemical formula 1, an optical isomer thereof, a prodrug thereof, a salt thereof, a hydrate thereof, a solvate thereof, an N-oxide thereof and a deuterated analog thereof, has a good inhibiting effect on LRRK2 kinase or abnormal LRRK2 mutant kinase, and can be used for treating or preventing diseases related to the activity of LRRK2 kinase or abnormal LRRK2 mutant kinase, such as Alzheimer's disease, L-dopa induced dyskinesia, Parkinson's disease, dementia, kidney cancer, breast cancer, prostate cancer, leukemia, papilloma, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.

Description

Medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity.
Background
The protein encoded by the LRRK2 gene includes a leucine-rich repeat (LRR) domain, a kinase domain, a DFG-like motif, a RAS domain, a GTPase domain, an MLK-domain, and a WD40 domain. There is a lot of genetic and biochemical evidence that LRRK2 kinase activity is associated with susceptibility to parkinson's Disease PD, pathogenic mutations in the LRRK2 gene (especially the most common Gly2019Ser mutation) increase LRRK2 kinase activity and decrease the rate of GTP hydrolysis in cells and tissues, and that blocking these activities by small molecule LRRK2 kinase inhibitors may also provide neuroprotection in certain PD models, which discovery has made LRRK2 the most promising target for treating Parkinson's Disease (PD) (Tolosa et al, Nature Reviews in Neurology, vol.16, 2020, pp.97-10; Paisan-Ruiz et al, j.kinson's Disease, vol.3, 2013, pp.85-103; Guo et al, Experimental Research, vol.313(16), 2007, 3658-3670; Andrew b.west, Experimental, pp.298, 2017.245, pp.236). LRRK2 was identified as a gene potentially associated with increased susceptibility to Crohn's disease and susceptibility to leprosy (Zhang et al, New England J.Med., Vol.361, 2009, pp.2609-2618; Barrett et al, Nature Genetics, Vol.40, 2008, pp.955-962); it is also associated with spinal rigidity (ankyissing spondifications) (Danoy et al, PLoS Genetics, Vol 6(12), 2010, pp.1-5) and Amyotrophic lateral Sclerosis (Shtilans et al, Amyotrophic lateral Sclerosis, 2011, pp.1-7).
LRRK2 is also associated with Alzheimer's disease conversion from mild cognitive impairment (WO 2007149798); l-dopa-induced dyskinesia (Hurley et al, Eur. J, Neurosci, Vol.26, 2007, pp.171-177); CNS disorders associated with proliferation and migration of neuroblasts, and modulation of LRRK2 can be used to improve neurological outcome after ischemic injury and stimulate CNS functional recovery after neuronal injury, such as ischemic stroke, traumatic brain injury, or spinal cord injury (Milosevic et al, neuroregen, vol.4, 2009, 25; Zhang et al, j.neurosci.res, vol.88, 2010, pp.3275-3281). Other related diseases: including diabetes, obesity, motor neuron disease, epilepsy, and some cancers (Rubinsztein et al, nat. rev. drug Discovery, vol.11, 2012, 709-. Cancers such as renal, breast, prostate (e.g. solid tumors), blood and lung cancers and Acute Myeloid Leukemia (AML) (WO 2011038572); lymphomas and leukemias (Ray et al, j.immunolo., vol.230, 2011, 109); papillary renal and thyroid carcinomas (Bredan D Looyenga et al, Proc Natl Acad Sci U S A, Vol.108(4), 2011, pp.1439-44); multiple myeloma (Chapman et al, Nature, Vol.471, 2011, pp.467-472). Diseases of the immune system: including rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure erythrodysgenesis, Idiopathic Thrombocytopenic Purpura (ITP), Evans syndrome, vasculitis, bullous skin Disease, type I diabetes, Huggen's syndrome (Sjogren's syndrome), Devickers ' Disease, and inflammatory diseases (Nakamura et al, DNA Res., Vol.13(4), 2006, pp.169-183; Engel et al, Pharmacol. Rev., Vol.63, 2011, 127. minus 156; Homam et al, J.Clin. Neurocusu Disease, Vol.12, 2010, 91-102.) pulmonary diseases such as chronic obstructive pulmonary Disease and idiopathic pulmonary fibrosis (Araya et al, Intern.52, Internally. 2013, as inhibitors of bacterial infection by bacteria such as LR kinase, intracellular kinase (RK et al, RK. 19. 2, RK 3, and RK kinase) for increasing the host cell infection, nat.rev., 2012, 709-; araya et al, lntern.med., vol.52, 2013, 95-2303; gutierrez, Biochemical Society Conference, Leucine rich repeat kinase 2. ten year eyes from the road to the therapeutic intervention, Henley Business School, UK 12July 2016), HIV, West Nile virus, and Cherokee virus (Shoji-Kawata et al, Nature, Vol.494, 2013, pp.201-206). Also for other a-synucleinopathies (Orenstein et al, Nature Neurosci., Vol.16, 2013, 394-406), Tau proteinopathies (Li et al, neuroodegen.Dis., Vol.7, 2010, pp.265-271), Alzheimer's disease and other neurodegenerative diseases (Nixon, Nat.Med., Vol.19, 2013, pp.983-97) and gaucher's disease (Westbrook et al, trends.mol.Med., Vol.17, 2011, 485-493); tauopathies characterized by hyperphosphorylation of Tau, such as granule disease of argentism, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, and hereditary frontotemporal dementia and parkinson's disease associated with chromosome 17 (Jakes R et al, biochemica Acta, vol.1739,2005, pp. 240-250); microglial proinflammatory responses (Moehle et al, J.Neuroscience, Vol.32, 2012, pp.1602-1611).
Thus, compounds effective to modulate LRRK2 activity may provide treatment for diseases or conditions mediated by LRRK2 that are neurodegenerative diseases, cancer, inflammatory diseases, bacterial and viral infections, and other diseases.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a medicament for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity.
To achieve the above objects, the present invention provides a medicament for treating or preventing diseases associated with LRRK2 kinase or abnormal LRRK2 mutant kinase activity, comprising an LRRK2 inhibitor, wherein the LRRK2 inhibitor comprises at least one of a compound represented by chemical formula 1, an optical isomer thereof, a prodrug thereof, a salt thereof, a hydrate thereof, a solvate thereof, an N-oxide thereof, and a deuterated analog thereof;
[ chemical formula 1]
Figure BDA0002706714620000031
In chemical formula 1, L1、L2、L3、L4Independently C, O or N;
A1is-H, keto, C1-10Hydrocarbyl, -O (CH)2)nAa、-NH(CH2)nAa、-(CH2)nAa、-NHSO2CH＝CH2、NHAbOr is
Figure BDA0002706714620000032
A2is-H, -OH, halogen, -CN, nitro, -NH2、-NHArCH2Aa、
Figure BDA0002706714620000033
Or
Figure BDA0002706714620000041
A3Independently is unsubstituted, -H, -Ar (CH)2)nAaOr is
Figure BDA0002706714620000042
A4Independently is-H, keto or
Figure BDA0002706714620000043
A5Independently is unsubstituted, -H, substituted or unsubstituted C3-10A cycloalkyl group, a,
Figure BDA0002706714620000044
Figure BDA0002706714620000045
Or unsubstituted or substituted 3-to 8-membered cycloheterocycloalkyl containing at least one heteroatom selected from N and O, wherein C3-10When cycloalkyl and 3-to 8-membered cycloheterocycloalkyl are substituted, the substituents are OH, - (CH)2)nOH、-NH2、C1-10At least one of the hydrocarbon groups, wherein,
or A3And A4Are linked to form an unsubstituted or substituted 5-to 8-membered heterocyclic ring aryl containing at least one N, wherein when the 5-to 8-membered heterocyclic ring aryl is substituted, the substituent is-OH, halo, -CN, nitro, -NH2、C1-10Hydrocarbyl, substituted or unsubstituted C3-10At least one of cycloalkyl, unsubstituted or substituted 5-to 8-membered ring heterocycloalkyl containing at least one heteroatom selected from N and O,
or A4And A5Linked to form an unsubstituted or substituted aryl group;
each n is independently an integer from 0 to 6;
each AaIndependently represented by-H, substituted or unsubstituted C3-6Cycloalkyl or epoxyalkyl, substituted or unsubstituted C1-10Straight or branched chain alkyl, or unsubstituted or substituted 5 to 8 membered ring heterocycloalkyl containing at least one heteroatom selected from N and O, wherein AaIs substituted with at least one of the following substituents: c1-10Hydrocarbyl, halogen, methoxy, amino, -COCH2OH；
AbRepresented by-H, substituted or unsubstituted unsaturated 1, 6-naphthyridine, substituted or unsubstituted C3-10Cycloalkyl radicals, wherein AbIs substituted with at least one of the following substituents: c1-10Hydrocarbyl, halogen, methoxy, amino, -COCH2OH；
AcIs represented by-H, a benzodioxole or a benzazepine ring;
Adrepresents one of the following unsubstituted or substituted groups: aryl, heterocyclyl, wherein AdIs substituted with at least one of the following substituents: -H, alkyl, -CN, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, heterocyclyl;
Aerepresents one of the following unsubstituted or substituted groups: alkylene, -C (O) N-, -C (O) -, -NHC (O) -, alkylene-C (O) -, -C (O) -alkylene, alkylene C (O) -alkylene, -NC (O) NH-, wherein A iseIs substituted with at least one of the following substituents: -H, alkyl, -CN, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, heterocyclyl;
Afrepresents one of the following unsubstituted or substituted groups: c3-10 cycloalkyl, 3-to 8-membered ring heterocycloalkyl containing at least one heteroatom selected from N and O, wherein AfIs substituted with at least one of the following substituents: -H, alkyl, -CN, halo, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, heterocyclyl.
Preferably, the structural formula of the compound represented by chemical formula 1 is as follows:
Figure BDA0002706714620000051
further preferably, said L3Is C or N; a is described1is-H, keto, -NH (CH)2)nAaOr NHAb(ii) a A is described2is-H, -NH2、-NHArCH2AaOr is
Figure BDA0002706714620000052
A is described3Independently is unsubstituted, -H, or-Ar (CH)2)nAaSaid A is4Independently is-H, or A3And A4Linked to form an unsubstituted or substituted 5-to 8-membered heterocyclic ring aryl containing at least one N; a is described5Is unsubstituted, -H, substituted or unsubstituted C3-10Cycloalkyl, or unsubstituted or substituted 3 to 8 membered ring heterocycloalkyl containing at least one heteroatom selected from N and O; each AaIndependently represented by-H, substituted or unsubstituted C3-6Cycloalkyl or epoxyalkyl, or unsubstituted or substituted 5 to 8 membered ring heterocycloalkyl containing at least one heteroatom selected from N and O, wherein AaIs substituted with at least one of the following substituents: c1-10Hydrocarbyl, amino; a. thebRepresented by substituted or unsubstituted unsaturated 1, 6-naphthyridine, substituted or unsubstituted C3-10Cycloalkyl radicals, wherein AbIs substituted with at least one of the following substituents: c1-10Hydrocarbyl, amino, -COCH2OH。
Still further preferably, said A is1is-H, a keto group,
Figure BDA0002706714620000061
Or
Figure BDA0002706714620000062
A is described2is-H, -NH2、
Figure BDA0002706714620000063
Or
Figure BDA0002706714620000064
A is described3Independently is unsubstituted, -H or
Figure BDA0002706714620000065
A is described4Independently is-H, or A3And A4Connection formation
Figure BDA0002706714620000066
A is described5is-H,
Figure BDA0002706714620000067
Or
Figure BDA0002706714620000068
Preferably, the structural formula of the compound represented by chemical formula 1 is as follows:
Figure BDA0002706714620000071
further preferably, said L3、L4Independently N, C or O; a is described1is-H, -O (CH)2)nAa、-(CH2)nAaOr is
Figure BDA0002706714620000072
A is described2is-H or
Figure BDA0002706714620000073
A is described3Is unsubstituted, -H, or
Figure BDA0002706714620000074
A is described4Independently is-H or
Figure BDA0002706714620000075
A is described5Independently is unsubstituted, -H or
Figure BDA0002706714620000076
Or A4And A5Linked to form an unsubstituted or substituted aryl group; each AaIndependently represent unsubstituted or substituted C3-6Cycloalkyl radicals, or containing at least one of the substituentsUnsubstituted or substituted 5-to 8-membered ring heterocycloalkyl from the heteroatoms N and O, wherein AaIs substituted with at least one of the following substituents: amino group, -COCH2OH；AcIs represented by benzodioxole.
Still further preferably, said A is1is-H, -OCH3、
Figure BDA0002706714620000077
Or
Figure BDA0002706714620000081
A is described2is-H or
Figure BDA0002706714620000082
A is described3Unsubstituted, -H or
Figure BDA0002706714620000083
A is described4Independently is-H, or
Figure BDA0002706714620000084
A is described5Independently is unsubstituted, -H, or
Figure BDA0002706714620000085
Or A4And A5Linked to form an unsubstituted phenyl group.
Preferably, the compound represented by chemical formula 1 is any one of the following compounds:
(1)4- [2- (butylamino) -5- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] pyrrolo [2,3-d ] pyrimidin-7-yl ] cyclohexan-1-ol;
(2)4- [2- (2-cyclopropylamino) -5- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] pyrrolo [2,3-d ] pyrimidin-7-yl ] cyclohexan-1-ol;
(3) 2-hydroxy-1- [2- [ [8- (4-methylcyclohexyl) -4,6,8, 11-tetraazatricyclo [7.4.0.02,7] tridec-1 (9), 2,4,6,10, 12-hex-5-yl ] amino ] -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] ethanone;
(4) n- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] -4- (7H pyrrolo [2,3-d ] pyrimidin-4-ylamino) -1H-pyrazole-5-carboxamide;
(5)2-N- (4-aminocyclohexyl) -9-cyclopentyl-6-N- [4- (morpholin-4-ylmethyl) phenyl ] purine-2, 6-diamine;
(6) 6-amino-9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) oxo-2-yl ] -1H-purin-2-one;
(7)1- [2- [5- [ (3-methyloxyethan-3-yl) methoxy ] benzimidazol-1-yl ] quinolin-8-yl ] piperidin-4-amine;
(8) 1-cyclopropyl-3- [5- [6- (morpholin-4-ylmethyl) -1H-benzoimidazol-2-yl ] -1H-pyrazol-4-yl ] urea;
(9) n- (1, 3-benzodioxazol-5-ylmethyl) -4- ([1] benzofuran [3,2-d ] pyrimidin-4-yl) piperazine-1-carbosulfanyl;
(10) n- (5-tert-butyl-1, 3, 4-thiadiazol-2-yl) -1- [2- (5-methoxy-1H-indol-3-yl) ethyl ] -5-oxopyrrolidine-3-carboxamide;
(11) n- [5- (1, 3-benzodioxazol-5-yl) -1H-pyrazol-3-yl ] -4- [ (1-methylpiperidin-4-yl) amino ] benzamide;
(12) n- [2- (diethylamino) ethyl ] -5- [ (Z) - [5- (vinylsulfonylamino) -2-oxo-1H-indol-3-ylidene ] methyl ] -2, 4-dimethyl-1H-pyrrole-3-carboxamide.
Preferably, the disease includes at least one of neurodegenerative diseases, pre-cancerous conditions and cancers, autoimmune diseases, inflammation.
Preferably, the disease comprises at least one of alzheimer's disease, L-dopa induced dyskinesia, parkinson's disease, enhanced cognitive memory, central nervous system disorders, dementia, amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
It should be noted that the dotted line in the six-membered ring or the five-membered ring in chemical formula 1 indicates whether or not a double bond is present, and if a double bond is present, the position is not determined, and other similar descriptions indicate the same meaning;the above hydrocarbon groups each include an alkyl group and an unsaturated hydrocarbon group such as an alkenyl group; the above halogens include F, Cl, Br, etc.; the above 3-to 8-membered cycloheterocycloalkyl unsubstituted or substituted by hetero atoms selected from N and O means that the atoms constituting the 3-to 8-membered ring contain at least one hetero atom of N, O in addition to carbon atoms, and the 3-to 8-membered ring is unsubstituted or substituted by a substituent, and the meanings as expressed in other similar descriptions are similar, as in A3And A4Linked to form an unsubstituted or substituted 5-to 8-membered heterocyclic ring aryl containing at least one N, meaning that the atoms making up the 5-to 8-membered ring contain at least one N atom in addition to carbon atoms, and the 5-to 8-membered ring is unsubstituted or substituted with a substituent; ar represents an aryl group such as phenyl, naphthyl, etc.; a. the5Independently is unsubstituted, -H, substituted or unsubstituted C3-10A cycloalkyl group, a,
Figure BDA0002706714620000101
Or unsubstituted or substituted 3-to 8-membered cycloheterocycloalkyl containing at least one heteroatom selected from N and O, means A5Independently is unsubstituted, -H, C with substituents3-10Cycloalkyl, unsubstituted C3-10A cycloalkyl group, a,
Figure BDA0002706714620000102
Figure BDA0002706714620000103
3-to 8-membered cycloheterocycloalkyl having at least one unsubstituted hetero atom selected from N and O, or 3-to 8-membered cycloheterocycloalkyl having at least one substituted hetero atom selected from N and O, the same other similar description applies; a. thedRepresents one of the following unsubstituted or substituted groups: aryl, heterocyclyl, wherein AdIs substituted with at least one of the following substituents: -H, alkyl, -CN, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, heterocyclyl, the term A referring todIs represented by unsubstituted aryl, unsubstituted heterocyclic group, substituted aryl or substituted heterocyclic group, wherein substituted aryl means arylThe substituted heterocyclic group means that the heterocyclic group is substituted by at least one of-H, alkyl, -CN, halogen, haloalkyl, hydroxyl, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, and heterocyclic group.
Compared with the prior art, the invention has the beneficial effects that: the medicaments of the invention comprise specific inhibitors of LRRK2, are effective in the treatment or prevention of diseases associated with the activity of LRRK2 kinase or any mutant thereof (e.g. LRRK2 mutant G2019S), e.g. are useful in the prevention and treatment of neurodegenerative diseases such as parkinson's disease and other lewy body type diseases, including diffuse lewy body disease, the lewy body variant of alzheimer's disease, combined parkinson's disease and alzheimer's disease, multiple system atrophy and dementia with lewy bodies, etc.; can also be used for preventing and treating cancer such as renal cancer, breast cancer, prostate cancer, blood cancer, papilloma, lung cancer, acute myelogenous leukemia, multiple myeloma, melanoma, etc.; it can also be used for preventing and treating autoimmune diseases and inflammations, such as leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
Drawings
FIG. 1 is the kinase bioactivity Kd curves of LRRK2 WT and LRRK2G2019S determined by experimental example 13 for the compound of example 1;
FIG. 2 is the kinase bioactivity Kd curves of LRRK2 WT and LRRK2G2019S determined by experimental example 13 for the compound of example 4;
FIG. 3 is the kinase bioactivity Kd curves of LRRK2 WT and LRRK2G2019S determined by experimental example 13 for the compound of example 7;
fig. 4 is a kinase bioactivity Kd curve of LRRK2 WT and LRRK2G2019S determined by experimental example 13 for the compound of example 8.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
The present invention relates to a drug for treating or preventing diseases associated with LRRK2 kinase or abnormal LRRK2 mutant kinase activity, comprising LRRK2 inhibitor, wherein the LRRK2 inhibitor comprises at least one of compound represented by chemical formula 1, optical isomer thereof, prodrug thereof, pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, N-oxide thereof, deuterated analog thereof.
According to the present invention, the compound represented by chemical formula 1 can be used for preventing and treating related disorders caused by mutation of LRRK2 or abnormal LRRK2, such as alzheimer's disease, L-dopa induced dyskinesia, parkinson's disease, dementia, amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papilloma, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, ankylosing spondylitis, and the like.
According to the present invention, the compound represented by chemical formula 1 may be used for preventing and treating diseases or conditions mediated at least in part by LRRK2 or abnormal LRRK2 mutation, which are neurodegenerative diseases, for example, Central Nervous System (CNS) disorders such as Parkinson's Disease (PD), Alzheimer's Disease (AD), dementia including lewy body dementia and vascular dementia, Amyotrophic Lateral Sclerosis (ALS), age-related memory dysfunction, mild cognitive impairment (e.g., including transition from mild cognitive impairment to alzheimer's disease), silvery particle disease, lyhehal disease (e.g., niemann-pick C, gaucher's disease), corticobasal degeneration, progressive supranuclear palsy, hereditary frontopal dementia and parkinson's disease associated with chromosome 17 (FTDP-17), withdrawal symptoms/relapse associated with drug addiction, L-dopa-induced dyskinesia, Huntington's Disease (HD), and HIV-associated dementia (HAD). Disorders are ischemic diseases of organs including, but not limited to, the brain, heart, kidney, and liver.
In some embodiments, the compound of formula 1 is used for treating a disease or condition mediated at least in part by LRRK2 or an aberrant LRRK2 mutation is cancer, such as thyroid cancer, renal cancer (including papillary renal cancer), breast cancer, lung cancer, blood cancer, and prostate cancer (e.g., solid tumors), leukemia (including Acute Myeloid Leukemia (AML), or lymphoma.
In other embodiments, the compound of formula 1 is used to treat a disease or condition mediated at least in part by LRRK2 or an aberrant LRRK2 mutation is an inflammatory disorder. The inflammatory disorder is an inflammatory bowel disease, such as crohn's disease or ulcerative colitis (the two together generally being referred to as inflammatory bowel disease). The inflammatory disease is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
In other embodiments, the compounds of formula 1 are useful for treating other diseases mediated at least in part by LRRK2 or aberrant LRRK2 mutations: multiple sclerosis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, Idiopathic Thrombocytopenic Purpura (ITP), Evan's syndrome, vasculitis, bullous skin disease, type 1 diabetes, Hugger's syndrome, Devkker's disease, and inflammatory myopathy.
According to the present invention, the compound represented by chemical formula 1 may be used in the form of a pharmaceutically acceptable salt thereof. Here, the pharmaceutically acceptable salt may be an acid addition salt formed from a pharmaceutically acceptable free acid. Acid addition salts can be obtained from inorganic acids (e.g., hydrochloric, nitric, phosphoric, sulfuric, bromic, hydroiodic, nitrous, phosphorous, and the like), nontoxic organic acids (e.g., aliphatic mono-and di-carboxylic acid esters, phenyl-substituted alkanoates, hydroxyalkanoates and alkanoates, aromatic acids, aliphatic and aromatic sulfonic acids, and the like), or organic acids (e.g., acetic, benzoic, citric, lactic, maleic, gluconic, methanesulfonic, 4-toluenesulfonic, tartaric, fumaric, and the like). The acid addition salts may be obtained from pharmaceutically non-toxic salts including sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate (decanoate), octanoate, acrylate, formate, isobutyrate, decanoate (caprate), heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioleate, hexane-1, 6-oleate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxykorate, tolylbenzoate phthalate, terephthalate, benzenesulfonate, tosylate, Chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, bane-2-sulfonate, mandelate and the like.
According to the present invention, the acid addition salt may be prepared by a conventional method, for example, by dissolving the compound represented by chemical formula 1 or a derivative thereof in an organic solvent such as methanol, ethanol, acetone, dichloromethane or acetonitrile, and adding an organic acid or an inorganic acid thereto to obtain a precipitate, and then filtering and drying the precipitate, or subjecting the solvent and an excess of the acid to vacuum distillation, drying and then crystallizing in the presence of the organic solvent.
In addition, according to the present invention, the compound represented by chemical formula 1 may be prepared and used in the form of a pharmaceutically acceptable metal salt thereof. Specifically, the alkali metal or alkaline earth metal salt can be obtained by the following method: for example, the compound is dissolved in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, the undissolved compound salt is filtered off, and the filtrate is evaporated to dryness. Here, sodium, potassium or calcium salts are pharmaceutically suitable as metal salts. Furthermore, the corresponding salts can be obtained by reacting alkali metal or alkaline earth metal salts with suitable silver salts (e.g. silver nitrate).
According to the present invention, the compound represented by chemical formula 1 may be prepared and used in the form of at least one of its pharmaceutically acceptable deuterated analog, prodrug, stereoisomer, salt thereof, hydrate thereof, solvate thereof, and N-oxide thereof.
In the pharmaceutical according to the present invention, the compound represented by chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be administered in a single dose or multiple dose form at the time of clinical administration. The agents of the invention may be administered using a variety of methods including, for example, rectal, pulmonary, oral, buccal, intranasal, and transdermal routes. In certain embodiments, the medicament may be administered by intraarterial injection, intravenously, intraperitoneally, enterally, parenterally, intramuscularly, subcutaneously, orally, topically, or in the form of an inhalant.
The pharmaceutical preparation of the present invention may be prepared using commonly used diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like.
Examples of the pharmaceutical of the present invention used as a preparation for oral administration include tablets, pills, hard/soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, lozenges and the like. In addition to the active ingredient, these preparations may contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine) or lubricants (e.g., silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose, and polyethylene rebuke pyrrolidine, and the like, and may optionally contain disintegrating agents (e.g., starch, agar, alginic acid or a sodium salt thereof, or boiling mixtures), absorbing agents, coloring agents, flavoring agents, sweetening agents, and the like.
One mode of administration of the agents of the invention is parenteral, e.g., by injection, and may be formulated as an aqueous or oily suspension or emulsion containing one of sesame oil, corn oil, cottonseed oil, peanut oil, and elixirs, mannitol and dextrose, or as a sterile aqueous solution and similar pharmaceutical vehicles.
When the medicament of the present invention is used by inhalation or insufflation, it may include pharmaceutically acceptable aqueous or organic solvents of solutions and suspensions, or mixtures thereof, and powders. The liquid or solid medicament may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the medicament is administered by the oral or nasal respiratory route for local or systemic effects. In other embodiments, the drug in a pharmaceutically acceptable solvent may be nebulized by using an inert gas. The nebulized solution may be inhaled directly from the nebulizing device or the nebulizing device may be connected to a face mask support or intermittent positive pressure ventilator. May be a solution, suspension or powder composition suitable for administration by a delivery device, preferably orally or nasally.
Furthermore, the present invention relates to a pharmaceutical kit for preventing or treating a disorder associated with LRRK2 or aberrant LRRK2 mutations, the kit comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof, and a label and/or instructions for using the compound for treating an indication, including a disease or condition described herein. Including a compound described herein or a pharmaceutically acceptable salt, deuterated analog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The containers may be vials, jars, ampoules, preloaded syringes and intravenous bags.
Further, in another aspect of the present disclosure, the compound represented by chemical formula 1 may be administered in combination with other agents including (but not limited to): compounds that are inhibitors of apoptosis, PARP poly (ADP-ribose) polymerase inhibitors, Src inhibitors, agents for the treatment of vascular disease, hypertension, hypercholesterolemia, and type II diabetes, anti-inflammatory agents, anti-embolic agents, fibrinolytic agents, anti-platelet agents, lipid lowering agents, direct thrombin inhibitors, glycoprotein IIb/IIla receptor inhibitors, calcium channel blockers, B adrenergic receptor blockers, cyclooxygenase (e.g., COX-1 and COX-2) inhibitors, angiotensin system inhibitors (e.g., Angiotensin Converting Enzyme (ACE) inhibitors), renin inhibitors, and/or agents that bind to cell adhesion molecules and inhibit the ability of white blood cells to attach to such molecules (e.g., polypeptide antibodies, polyclonal antibodies, and monoclonal antibodies). In addition, the compounds of the present disclosure may be administered in combination with additional agents having activity in the treatment of neurodegenerative diseases. For example, in some embodiments, the compound may be administered in combination with one or more additional therapeutic agents useful in the treatment of parkinson's disease. In some embodiments, the additional therapeutic agent is L-dopa (e.g., sinemet CR), a dopamine agonist (e.g., robininol or Pramipexole), a catechol-0-methyltransferase (COMT) inhibitor (e.g., Entacapone (Entacapone)), an L-monoamine oxidase (MAO) inhibitor (e.g., selegiline or rasagiline), or an agent that increases dopamine release (e.g., Zonisamide (Zonisamide)).
Example 1
Reference is made to WO2013052417A1 for the preparation of 4- [2- (butylamino) -5- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] pyrrolo [2,3-d ] pyrimidin-7-yl ] cyclohex-1-ol, of the formula:
Figure BDA0002706714620000161
example 2
Reference is made to WO2013052417A1 for the preparation of 4- [2- (2-cyclopropylamino) -5- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] pyrrolo [2,3-d ] pyrimidin-7-yl ] cyclohex-1-ol, which has the following structural formula:
Figure BDA0002706714620000162
example 3
Reference is made to patent WO2012129344 a1 for the preparation of 2-hydroxy-1- [2- [ [8- (4-methylcyclohexyl) -4,6,8, 11-tetraazatricyclo [7.4.0.02,7] tridec-1 (9), 2,4,6,10, 12-hex-5-yl ] amino ] -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] ethanone of the formula:
Figure BDA0002706714620000163
example 4
Reference is made to patent WO2014108053 a1 for the preparation of N- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] -4- (7H pyrrolo [2,3-d ] pyrimidin-4-ylamino) -1H-pyrazole-5-carboxamide, of the formula:
Figure BDA0002706714620000171
example 5
Reference is made to WO2018171819A1 for the preparation of 2-N- (4-aminocyclohexyl) -9-cyclopentyl-6-N- [4- (morpholin-4-ylmethyl) phenyl ] purine-2, 6-diamine, which has the following structural formula:
Figure BDA0002706714620000172
example 6
Reference is made to WO9312130A1 for the preparation of 6-amino-9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) oxo-2-yl ] -1H-purin-2-one of the formula:
Figure BDA0002706714620000173
example 7
Reference is made to patent WO 2004020431A 2 for the preparation of 1- [2- [5- [ (3-methyloxyethan-3-yl) methoxy ] benzimidazol-1-yl ] quinolin-8-yl ] piperidin-4-amine of the formula:
Figure BDA0002706714620000181
example 8
Reference is made to WO 2008001115A2 for the preparation of 1-cyclopropyl-3- [5- [6- (morpholin-4-ylmethyl) -1H-benzimidazol-2-yl ] -1H-pyrazol-4-yl ] urea, which has the following formula:
Figure BDA0002706714620000182
example 9
Reference is made to WO2005037825A2 for the preparation of N- (1, 3-benzodioxazol-5-ylmethyl) -4- ([1] benzofuran [3,2-d ] pyrimidin-4-yl) piperazine-1-carbothioyl, which has the following formula:
Figure BDA0002706714620000183
example 10
N- (5-tert-butyl-1, 3, 4-thiadiazol-2-yl) -1- [2- (5-methoxy-1H-indol-3-yl) ethyl ] -5-oxopyrrolidine-3-carboxamide, having the formula STK288775, was purchased at Vitas-M Laboratory:
Figure BDA0002706714620000191
example 11
Reference (European Journal of Medicinal Chemistry) (2019),176, 248-:
Figure BDA0002706714620000192
example 12
Reference is made to Journal of Medicinal Chemistry (2019),62(5),2428-2446 for the preparation of N- [2- (diethylamino) ethyl ] -5- [ (Z) - [5- (vinylsulfonylamino) -2-oxo-1H-indol-3-alkylene ] methyl ] -2, 4-dimethyl-1H-pyrrole-3-carboxamide, of the formula:
Figure BDA0002706714620000193
comparative example
Reference is made to WO2011151360 for the preparation of [4- [ [ 5-chloro-4- (methylamino) pyrimidin-2-yl ] amino ] -3-methoxyphenyl ] morpholin-4-yl methanone, of the formula:
Figure BDA0002706714620000201
the structures of the compounds prepared in examples 1 to 12 are shown in table 1.
TABLE 1
Figure BDA0002706714620000202
Figure BDA0002706714620000211
Example 13: determination of biological Activity of Compounds
(1) Material
LRRK2G2019S enzyme, substrate (LRRK peptide), ATP, TR-FRET diluent buffer, pLRRK peptide antibody, 384-well assay plates, and DMSO.
(2) Enzyme reaction conditions: 50mM Tris pH7.5, 10mM MgCl21mM EGTA, 0.01% Brij-35, 2mM DTT, 5nM LRRK2, 134. mu.M ATP, 60 min reaction time, 23 ℃ reaction temperature, 10. mu.L total reaction volume.
Detecting the reaction conditions: 1 XDilute buffer, 10mM EDTA, 2nM antibody, reaction temperature 23 ℃ 10 u L total reaction volume.
(3) Experimental procedure
Dilution of test compounds with 100% DMSO to give stock stocks of 10mM or 100 μ M), in proportions: dilutions of buffer at 1:3.16(20 μ L +43.2 μ L) gave the highest assay concentration 100 μ M or 1 μ M. mu.L of the test solution was transferred to the assay plate and untreated blank control wells containing 5. mu.L of DMSO and 5. mu.L of a DMSO solution of a control of a known inhibitor comparative example were added sequentially to the source culture dish (384 well assay dish, Labcyte). The plates were centrifuged at 2500rpm for 1 minute and sealed with foil. A 3-fold serial dilution was performed using reaction buffer to obtain 11 test spots, and blanks of 100nL of test compound solution, known inhibitor comparative compound solution, DMSO solution after dilution were transferred to assay plates, 2 duplicate wells per concentration. The assay plates were centrifuged at 2500rpm for 1 minute and sealed with foil.
For the enzyme reaction, 5. mu.L of 50mM Tris pH7.5, 10mM MgCl2, 1mM EGTA, 0.01% Brij-35, 2mM DTT buffer containing 5nM LRRK2 enzyme was added to all wells of the assay plate. The culture dish was centrifuged to concentrate the mixture at the bottom of the well. The assay plates were incubated at 23 ℃ for 20 minutes. After incubation, 5 μ L of 1X kinase reaction buffer 2X LRRKtide succinate and ATP were added to each well and the culture dish was centrifuged to concentrate the mixture at the bottom of the well. The plates were incubated at 23 ℃ for 60 minutes.
For detection of the reaction, 10 μ L of TR-FRET dilution buffer detection reagent containing antibody reagent and 10mM EDTA was added to all wells of each well of the assay plate, and the plate was centrifuged to concentrate the mixture at the bottom of the well. Subsequently, the plates were incubated at 23 ℃ for 60 minutes. The plates were read on a Perkin elmer envision 2104 instrument in TR-FRET mode using a 340m excitation filter, a 520nm fluorescence emission filter and a 490 or 495nm terbium emission filter. The inhibitory effect of variant G2019S LRRK2 was measured in exactly the same way. All final concentrations of substrate ATP and enzyme were the same.
Data analysis was performed using Graphpad software and Kd activity was calculated.
Several compounds disclosed herein were tested according to the methods above, each concentration tested being a duplicate well, averaged, and the corresponding Kd activity values of LRRK2 and LRRK2G2019S are provided in table 2.
TABLE 2
Figure BDA0002706714620000221
Figure BDA0002706714620000231
All patents and other publications identified in this specification and examples are expressly incorporated herein by reference for all purposes. These publications are provided solely for their disclosure prior to the filing date of the present application. In this regard, no admission should be made that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims (10)

1. A medicament for treating or preventing a disease associated with LRRK2 kinase or abnormal LRRK2 mutant kinase activity, wherein the medicament contains an LRRK2 inhibitor, and the LRRK2 inhibitor comprises at least one of a compound represented by chemical formula 1, an optical isomer thereof, a prodrug thereof, a salt thereof, a hydrate thereof, a solvate thereof, an N-oxide thereof, and a deuterated analog thereof;
[ chemical formula 1]
Figure FDA0002706714610000011
In chemical formula 1, L1、L2、L3、L4Independently C, O or N;
A1is-H, keto, C1-10Hydrocarbyl, -O (CH)2)nAa、-NH(CH2)nAa、-(CH2)nAa、-NHSO2CH＝CH2、NHAbOr is
Figure FDA0002706714610000012
A2is-H, -OH, halogen, -CN, nitro, -NH2、-NHArCH2Aa、
Figure FDA0002706714610000013
Figure FDA0002706714610000014
A3Independently is unsubstituted, -H, -Ar (CH)2)nAaOr is
Figure FDA0002706714610000015
A4Independently is-H, keto or
Figure FDA0002706714610000021
A5Independently is unsubstituted, -H, substituted or unsubstituted C3-10A cycloalkyl group, a,
Figure FDA0002706714610000022
Figure FDA0002706714610000023
Or unsubstituted or substituted 3-to 8-membered cycloheterocycloalkyl containing at least one heteroatom selected from N and O, wherein C3-10When cycloalkyl and 3-to 8-membered cycloheterocycloalkyl are substituted, the substituents are OH, - (CH)2)nOH、-NH2、C1-10At least one of the hydrocarbon groups, wherein,
or A3And A4Are linked to form an unsubstituted or substituted 5-to 8-membered heterocyclic ring aryl containing at least one N, wherein when the 5-to 8-membered heterocyclic ring aryl is substituted, the substituent is-OH, halo, -CN, nitro, -NH2、C1-10Hydrocarbyl, substituted or unsubstituted C3-10Cycloalkyl, unsubstituted or substituted 5 to 8 membered ring containing at least one heteroatom selected from N and OAt least one of the cyclic heterocycloalkyl groups,
or A4And A5Linked to form an unsubstituted or substituted aryl group;
each n is independently an integer from 0 to 6;
each AaIndependently represented by-H, substituted or unsubstituted C3-6Cycloalkyl or epoxyalkyl, substituted or unsubstituted C1-10Straight or branched chain alkyl, or unsubstituted or substituted 5 to 8 membered ring heterocycloalkyl containing at least one heteroatom selected from N and O, wherein AaIs substituted with at least one of the following substituents: c1-10Hydrocarbyl, halogen, methoxy, amino, -COCH2OH；
AbRepresented by-H, substituted or unsubstituted unsaturated 1, 6-naphthyridine, substituted or unsubstituted C3-10Cycloalkyl radicals, wherein AbIs substituted with at least one of the following substituents: c1-10Hydrocarbyl, halogen, methoxy, amino, -COCH2OH；
AcIs represented by-H, a benzodioxole or a benzazepine ring;
Adrepresents one of the following unsubstituted or substituted groups: aryl, heterocyclyl, wherein AdIs substituted with at least one of the following substituents: -H, alkyl, -CN, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, heterocyclyl;
Aerepresents one of the following unsubstituted or substituted groups: alkylene, -C (O) N-, -C (O) -, -NHC (O) -, alkylene-C (O) -, -C (O) -alkylene, alkylene C (O) -alkylene, -NC (O) NH-, wherein A iseIs substituted with at least one of the following substituents: -H, alkyl, -CN, halogen, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, heterocyclyl;
Afrepresents one of the following unsubstituted or substituted groups: c3-10 cycloalkyl, 3-to 8-membered ring heterocycloalkyl containing at least one heteroatom selected from N and O, wherein AfIn (1)The substitution is substituted with at least one of the following substituents: -H, alkyl, -CN, halo, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl, heterocyclyl.
2. The pharmaceutical agent of claim 1, wherein the compound of formula 1 has a structural formula as follows:
Figure FDA0002706714610000031
3. the medicament of claim 2, wherein L is3Is C or N; a is described1is-H, keto, -NH (CH)2)nAaOr NHAb(ii) a A is described2is-H, -NH2、-NHArCH2AaOr is
Figure FDA0002706714610000032
A is described3Independently is unsubstituted, -H, or-Ar (CH)2)nAaSaid A is4Independently is-H, or A3And A4Linked to form an unsubstituted or substituted 5-to 8-membered heterocyclic ring aryl containing at least one N; a is described5Is unsubstituted, -H, substituted or unsubstituted C3-10Cycloalkyl, or unsubstituted or substituted 3 to 8 membered ring heterocycloalkyl containing at least one heteroatom selected from N and O; each AaIndependently represented by-H, substituted or unsubstituted C3-6Cycloalkyl or epoxyalkyl, or unsubstituted or substituted 5 to 8 membered ring heterocycloalkyl containing at least one heteroatom selected from N and O, wherein AaIs substituted with at least one of the following substituents: c1-10Hydrocarbyl, amino; a. thebRepresented by substituted or unsubstituted unsaturated 1, 6-naphthyridine, substituted or unsubstituted C3-10Cycloalkyl radicals, wherein AbIs substituted with at least one of the following substituents: c1-10Hydrocarbyl, amino, -COCH2OH。
4. The medicament of claim 3, wherein A is1is-H, a keto group,
Figure FDA0002706714610000041
A is described2is-H, -NH2、
Figure FDA0002706714610000042
A is described3Independently is unsubstituted, -H or
Figure FDA0002706714610000043
A is described4Independently is-H, or A3And A4Connection formation
Figure FDA0002706714610000044
A is described5is-H,
Figure FDA0002706714610000045
5. The pharmaceutical agent of claim 1, wherein the compound of formula 1 has a structural formula as follows:
Figure FDA0002706714610000051
6. the medicament of claim 5, wherein L is3、L4Independently N, C or O; a is described1is-H, -O (CH)2)nAa、-(CH2)nAaOr is
Figure FDA0002706714610000052
A is described2is-H or
Figure FDA0002706714610000053
A is described3Is unsubstituted, -H, or
Figure FDA0002706714610000054
A is described4Independently is-H or
Figure FDA0002706714610000055
A is described5Independently is unsubstituted, -H or
Figure FDA0002706714610000056
Or A4And A5Linked to form an unsubstituted or substituted aryl group; each AaIndependently represent unsubstituted or substituted C3-6Cycloalkyl, or unsubstituted or substituted 5 to 8 membered ring heterocycloalkyl containing at least one heteroatom selected from N and O, wherein AaIs substituted with at least one of the following substituents: amino group, -COCH2OH；AcIs represented by benzodioxole.
7. The medicament of claim 6, wherein A is1is-H, -OCH3、
Figure FDA0002706714610000057
A is described2is-H or
Figure FDA0002706714610000061
A is described3Unsubstituted, -H or
Figure FDA0002706714610000062
A is described4Independently is-H, or
Figure FDA0002706714610000063
A is described5Independently is unsubstituted, -H, or
Figure FDA0002706714610000064
Or A4And A5Linked to form an unsubstituted phenyl group.
8. The pharmaceutical agent according to claim 1, wherein the compound represented by chemical formula 1 is any one of the following compounds:
(1)4- [2- (butylamino) -5- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] pyrrolo [2,3-d ] pyrimidin-7-yl ] cyclohexan-1-ol;
(2)4- [2- (2-cyclopropylamino) -5- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] pyrrolo [2,3-d ] pyrimidin-7-yl ] cyclohexan-1-ol;
(3) 2-hydroxy-1- [2- [ [8- (4-methylcyclohexyl) -4,6,8, 11-tetraazatricyclo [7.4.0.02,7] tridec-1 (9), 2,4,6,10, 12-hex-5-yl ] amino ] -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] ethanone;
(4) n- [4- [ (4-methylpiperazin-1-yl) methyl ] phenyl ] -4- (7H pyrrolo [2,3-d ] pyrimidin-4-ylamino) -1H-pyrazole-5-carboxamide;
(5)2-N- (4-aminocyclohexyl) -9-cyclopentyl-6-N- [4- (morpholin-4-ylmethyl) phenyl ] purine-2, 6-diamine;
(6) 6-amino-9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) oxo-2-yl ] -1H-purin-2-one;
(7)1- [2- [5- [ (3-methyloxyethan-3-yl) methoxy ] benzimidazol-1-yl ] quinolin-8-yl ] piperidin-4-amine;
(8) 1-cyclopropyl-3- [5- [6- (morpholin-4-ylmethyl) -1H-benzoimidazol-2-yl ] -1H-pyrazol-4-yl ] urea;
(9) n- (1, 3-benzodioxazol-5-ylmethyl) -4- ([1] benzofuran [3,2-d ] pyrimidin-4-yl) piperazine-1-carbosulfanyl;
(10) n- (5-tert-butyl-1, 3, 4-thiadiazol-2-yl) -1- [2- (5-methoxy-1H-indol-3-yl) ethyl ] -5-oxopyrrolidine-3-carboxamide;
(11) n- [5- (1, 3-benzodioxazol-5-yl) -1H-pyrazol-3-yl ] -4- [ (1-methylpiperidin-4-yl) amino ] benzamide;
(12) n- [2- (diethylamino) ethyl ] -5- [ (Z) - [5- (vinylsulfonylamino) -2-oxo-1H-indol-3-ylidene ] methyl ] -2, 4-dimethyl-1H-pyrrole-3-carboxamide.
9. The medicament of claim 1, wherein the disease comprises at least one of neurodegenerative disease, precancerous and cancerous conditions, autoimmune disease, inflammation.
10. The medicament of claim 1, wherein the disease comprises at least one of alzheimer's disease, L-dopa-induced dyskinesia, parkinson's disease, cognitive memory enhancement, central nervous system disorders, dementia, amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
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