LRRK2 inhibitor compounds, pharmaceutical compositions, and methods of making and using the same

Abstract

The present application provides a compound shown in formula I, its racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof. Such compounds have good LRRK2 inhibitory effect, and can be used for treating or preventing LRRK2 related diseases and disorders, and preparing drugs for such diseases and disorders.

Description

[0001] This application claims priority to the following patent application:

[0002] A prior application filed on August 23, 2022, with the China National Intellectual Property Office, Patent Application No. 202211015106.X, entitled “LRRK2 Inhibitor Compounds, Pharmaceutical Compositions, and Methods of Preparation and Use Thereof”;

[0003] A prior application filed on October 18, 2022, with the China National Intellectual Property Office, Patent Application No. 202211275749.8, entitled “LRRK2 Inhibitor Compounds, Pharmaceutical Compositions, and Methods of Preparation and Use Thereof”;

[0004] The entire contents of the prior applications are incorporated herein by reference. TECHNICAL FIELD

[0005] The present application belongs to the field of drug synthesis, and specifically relates to LRRK2 inhibitor compounds, pharmaceutical compositions, and methods of preparation and use thereof. BACKGROUND

[0006] Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, and its main pathological manifestations are the degeneration and loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies. The clinical manifestations of Parkinson's disease include static tremor, bradykinesia, muscle rigidity, and postural imbalance. It is often accompanied by sleep disorders, autonomic nervous disorders, mental symptoms, and cognitive impairment. The pathogenesis of Parkinson's disease has not been fully elucidated, and it is generally believed that it is the result of the combined action of multiple factors. Environmental factors and genetic factors work together to ultimately lead to the occurrence of Parkinson's disease. The complexity and insidiousness of the disease often lead to a clear diagnosis in the early stages of the disease, and it is difficult to control symptoms in the terminal stage. The role of genetic factors in the pathogenesis of Parkinson's disease has gradually attracted people's attention. With the maturation of gene sequencing technology, genetic testing methods have been widely used in the field of Parkinson's disease diagnosis. More than 20 pathogenic genes have been found, including Leucine-Rich Repeat Kinase 2 (LRRK2). LRRK2, also known as PARK8, is located on chromosome 12q12, with a length of 144 kb and containing 51 exons. It encodes 2527 amino acids, which are composed of LRR, Ras protein complex (ROC), C-terminal repeat sequence of Ras protein complex (COR), kinase active region (MAPKKK), and WD40 protein domains. ROC and COR have protein kinase activity, WD40 is a repeat sequence composed of 40 tryptophan and aspartic acid, which can interact with other proteins and reversibly bind to proteins, participate in signal transmission and transport. LRRK2 protein combined with GTP and protein kinase can be widely expressed in various tissues and participate in the function of the central nervous system such as the substantia nigra, striatum, and caudate nucleus. LRRK2 gene mutations are a common cause of autosomal dominant Parkinson's disease and are also associated with sporadic Parkinson's disease. Eighty missense mutations have been identified, which are distributed throughout the LRRK2 gene segment and affect all predicted functional domains. Preclinical studies have found that LRRK2 mutations lead to the loss of substantia nigra neurons in Parkinson's disease, and other pathological manifestations include the formation of Lewy bodies. It is speculated that LRRK2 protein may cause Parkinson's disease in the same pathway as alpha-synuclein. Further studies have found that abnormal increases in LRRK2 kinase activity can cause a 3-4-fold increase in kinase activity, leading to damage to dopaminergic neurons and greatly increasing the risk of Parkinson's disease. Clinical studies have also found that Parkinson's disease patients carrying LRRK2 variant genes may develop more severe motor symptoms.Today, scientists have found that LRRK2 kinase inhibitors can protect neurons from neurodegeneration induced by LRRK2 over-activation, block the increased aggregation of alpha-synuclein in neurons, inhibit the formation of inclusion bodies, and slow the progression of the disease. Therefore, LRRK2 is considered a new and very promising target for the treatment of Parkinson's disease. Clinical trials targeting LRRK2 specific treatment for LRRK2 mutation carriers have already begun, highlighting the rapid progress made in this field over the past decade. The progress of the clinical studies carried out has also demonstrated that LRRK2 inhibitors are expected to become a potential disease-modifying therapy for improving LRRK2-Parkinson's disease. The kinase activity of LRRK2 is important for pathogenesis, and the LRRK2 kinase domain can regulate the overall LRRK2 function. Despite the progress in the central research field of LRRK2, there is still a need for inhibitors of LRRK2 receptors suitable for treating various neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. The present invention provides a new class of sulfur-containing heterocyclic compounds with good activity. SUMMARY

[0007] To improve the above technical problems, the present invention provides a compound represented by Formula I, its racemate, stereoisomer, tautomer, isotopically labeled, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof:

[0008]

[0009] wherein,

[0010] X is selected from N or CH;

[0011] R1is selected from H, deuterium, halogen, CN, the following groups which are unsubstituted or optionally substituted by one, two or more R 1a substituents: OH, amino, C 1-10 alkyl, C 6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-14 cycloalkyl; each R 1a is the same or different, independently of each other, selected from deuterium, halogen, CN, the following groups which are unsubstituted or optionally substituted by one, two or more R 1b substituents: C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-14 cycloalkyl; each R 1b is the same or different, independently of each other, selected from deuterium, halogen, CN, C 1-6 alkyl, C 1-6alkyl, halo-C 1-6 alkyl- phosphonyl;

[0012] R2is selected from H, deuterium, halogen, CN, C 1-6 alkyl, halo-C 1-6 alkoxy, C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy;

[0013] R3is selected from H, deuterium, halogen, CN, C 1-6 alkyl, halo-C 1-6 alkoxy, C 1-6 alkylamino, deuterated C 1-6 alkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy;

[0014] or, R1, R2and the atoms to which they are attached together form a 5-14 membered heteroaryl ring, which is unsubstituted or optionally substituted with 1, 2, or more R 21 substituted with 1, 2, or more R 3-14 cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl; each R 21 are the same or different, independently of each other, selected from H, halogen, CN, oxo (=0), C 1-14 alkyl, halo-C 3-14 cycloalkyl;

[0015] or, R2, R3and the atoms to which they are attached together form a 5-14 membered heteroaryl ring, which is unsubstituted or optionally substituted with 1, 2, or more R 22 substituted with 1, 2, or more R 3-14 cycloalkyl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl; each R 22 are the same or different, independently of each other, selected from H, halogen, CN, oxo (=0), C 1-14 alkyl, halo-C 3-14 cycloalkyl;

[0016] Ring A is selected from a S-containing 5-14 membered heteroaromatic ring or a 3-14 membered heterocyclic ring;

[0017] R a is selected from deuterium, halogen, CN, OH, amino, oxo (=0), unsubstituted or optionally substituted with 1, 2, or more R a1 substituted with 1, 2, or more R 1-10 alkyl, halo-C2-10 alkenyl, C 2-10 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyloxy, C 1-10 Alkyl acyl, C 6-14 Aryl acyl, 5-14 membered heteroaryl acyl, 3-14 membered heterocyclic acyl, C 3-14 Cycloalkyl acyl; each R a1 Whether the same or different, they are independently selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 alkoxy group; or, two R groups a The atoms connected to it form C 3-8 cycloalkyl or 3-8 membered heterocyclic groups;

[0018] m is selected from 0, 1, 2, 3, 4, 5, 6.

[0019] According to some implementation schemes, X is selected from N.

[0020] According to some implementation schemes, R1 is selected from H, halogen, CN, unsubstituted or optionally surrounded by one, two or more Rs. 1a The following groups are substituted: OH, amino, C 1-6 Alkyl; each R 1a They may be identical or different, and are independently selected from halogens, CN, unsubstituted or optionally substituted by one, two or more Rs. 1b The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic, C 3-10 cycloalkyl; each R 1b They may be the same or different, and are independently selected from halogens, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, diC 1-6 Alkyl-phosphoryl;

[0021] According to some implementation schemes, R1 is selected from H, halogen, CN, unsubstituted or optionally surrounded by one, two or more Rs. 1a The following groups are substituted: OH, amino, C 1-6 Alkyl; each R 1a They may be identical or different, and are independently selected from halogens, CN, unsubstituted or optionally substituted by one, two or more Rs. 1b The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-10aryl, 5-10 membered heteroaryl; each R 1b the same or different, independently of one another, are selected from the group consisting of halogen, CN, diC 1-6 alkyl-phosphoryl;

[0022] According to some embodiments, R1is selected from H, the following groups which are not substituted or are optionally substituted by one or two R 1a OH, amino; each R 1a the same or different, independently of one another, are selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, diC 1-6 alkyl-phosphoryl-C 6-10 aryl;

[0023] According to some embodiments, R1is selected from methylamino, cyclopropylamino, ethoxy, dimethylphosphorylphenylamino (e.g., );

[0024] According to some embodiments, R2is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy;

[0025] According to some embodiments, R2is selected from Cl or trifluoromethyl.

[0026] According to some embodiments, R3is selected from H, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, haloC 1-6 alkyl, haloC 1-6 alkoxy;

[0027] According to some embodiments, R3is selected from H.

[0028] According to some embodiments, ring A is selected from a 5-12 membered heteroaromatic ring containing S or a 3-12 membered heterocyclic ring.

[0029] According to some embodiments, ring A is selected from a 5-12 membered fused heteroaromatic ring containing S or a 5-12 membered fused heterocyclic ring.

[0030] According to some embodiments, ring A is selected from a 8-12 membered fused heteroaromatic ring containing S or a 8-12 membered fused heterocyclic ring.

[0031] According to some embodiments, ring A is selected from

[0032] According to some embodiments, R aselected from deuterium, halogen, CN, OH, oxo (=0), unsubstituted or optionally substituted with 1, 2 or more R a1 substituted lower alkyl, C 1-3 substituted lower alkyl, C 3-6 substituted lower alkyl, C 1-3 substituted lower alkyl, C 3-6 substituted lower alkyl, C 1-6 substituted lower alkyl, C 6-10 substituted lower alkyl, C 3-6 substituted lower alkyl, C a1 substituted lower alkyl, C 1-3 substituted lower alkyl, C 1-3 substituted lower alkyl, C a substituted lower alkyl, C 3-6 substituted lower alkyl, C

[0033] substituted lower alkyl, C a selected from methyl, CN, CI, oxo (=0), cyclopropyl, 2-fluoroethyl, 2-methoxyethyl, acetyl, propionyl, isobutyryl, pivaloyl, trifluoroacetyl, isoxazoyl, nicotinoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, or two R a substituted lower alkyl, C

[0034] substituted lower alkyl, C

[0035] substituted lower alkyl, C substituted lower alkyl, C

[0036] substituted lower alkyl, C substituted lower alkyl, C substituted lower alkyl, C

[0037] substituted lower alkyl, C substituted lower alkyl, C

[0038] substituted lower alkyl, C substituted lower alkyl, C

[0039] substituted lower alkyl, C 1-6 substituted lower alkyl, C 1-6 substituted lower alkyl, C 1-6 substituted lower alkyl, C 1-6 substituted lower alkyl, C 1-6 substituted lower alkyl, C 3-6 substituted lower alkyl, C 3-6 substituted lower alkyl, C

[0040] R5 may be the same or different, and are independently selected from 0, 1, 2 or more of the following groups: deuterium, halogen, CN, OH, oxo (=O), unsubstituted or optionally surrounded by 1, 2 or more R5 groups. 5a The following groups are substituted: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyloxy, C 1-10 Alkyl acyl, C 6-14 Aryl acyl, 5-14 membered heteroaryl acyl, 3-14 membered heterocyclic acyl, C 3-14 Cycloalkyl acyl; each R 5a Whether the same or different, they are independently selected from deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 alkoxy groups; or, two R5 atoms bonded to them form C. 3-8 Cycloalkyl or 3-8 membered heterocyclic groups.

[0041] According to some implementation schemes, ring B is selected from 5-8 membered aromatic or non-aromatic unsaturated carbon rings or heterocycles;

[0042] According to some implementation plans, ring B is selected from...

[0043] According to some implementation schemes, R4 is selected from H, halogens, CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl;

[0044] According to some implementation schemes, R4 is selected from H, F, Cl, CN, and cyclopropyl.

[0045] According to some implementation schemes, R5 may be the same or different, and may be independently selected from 0, 1, 2 or more of the following groups: halogen, CN, OH, oxo (=O), unsubstituted or optionally surrounded by 1, 2 or more R groups. 5a The following groups are substituted: C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, C 1-6 Alkyl acyl, C 6-10 Aryl acyl, 5-10 membered heteroaryl acyl, 3-6 membered heterocyclic acyl, C 3-6 Cycloalkyl acyl; each R 5a They are the same or different, and are independently selected from halogens and C. 1-6alkyl, C 1-6 alkoxy; or, two R5and the atom to which they are attached form a C 3-6 cycloalkyl.

[0046] According to some embodiments, R5are the same or different, each independently selected from 0, 1, 2 or more of a methyl group, oxo (=0), a cyclopropyl group, a 2-fluoroethyl group, a 2-methoxyethyl group, an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a trifluoroacetyl group, an isonicotinoyl group, a nicotinoyl group, a cyclopropionyl group, a cyclobutyryl group, or two R5and the atom to which they are attached form a cyclopropyl group.

[0047] According to some embodiments, selected from

[0048] According to some embodiments, the compound of Formula I is selected from the structures shown below:

[0049]

[0050] wherein R1, R4, R5, A, B, R a , m have the definitions described herein.

[0051] According to some embodiments, the compound of Formula I is selected from the structures shown below:

[0052]

[0053] wherein R4, R5, A, B, R a , m have the definitions described herein.

[0054] According to some embodiments, the compound of Formula I is selected from the structures shown below:

[0055]

[0056] wherein R1, R2, R3, R4have the definitions described herein, and R6is selected from a C 6a alkyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-14 cycloalkyl; each R 6a are the same or different, each independently selected from deuterium, halogen, CN, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkyl, C 3-6cycloalkyl.

[0057] Preferably, R6is selected from the group consisting of unsubstituted or optionally substituted with one, two or more R 6a substituted C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, C 3-6 cycloalkyl; each R 6a are the same or different, independently of each other, selected from the group consisting of deuterium, halogen, CN, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl.

[0058] Preferably, R6is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, pyridyl, cyclopropyl, cyclobutyl.

[0059] According to some embodiments, the compound of formula I is selected from the group consisting of the following structures:

[0060]

[0061] wherein R6has the definition described herein.

[0062] According to some embodiments, the compound of formula I is selected from the group consisting of the following structures:

[0063]

[0064]

[0065]

[0066] The present application also provides a method for preparing a compound of formula I, comprising the following steps:

[0067]

[0068] wherein X, A, R1, R2, R3, R a , m have the definition described above; L is selected from leaving groups such as OH, Cl, Br.

[0069] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound of formula I, its racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, pharmaceutically acceptable salt or prodrug thereof.

[0070] According to embodiments of the present application, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0071] The excipients in the pharmaceutical compositions are "acceptable" in that they are compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject being treated. One or more pharmaceutical excipients can be used for delivery of the active compounds.

[0072] According to some embodiments of the application, the pharmaceutical composition can further comprise one or more additional therapeutic agents.

[0073] The present application further provides the use of a compound of Formula I, a racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, pharmaceutically acceptable salt, or prodrug thereof, or the pharmaceutical composition thereof, in the manufacture of a medicament.

[0074] According to some embodiments, the medicament is a medicament for the diagnosis, prevention and / or treatment of a LRRK2-mediated disease or disorder.

[0075] According to some embodiments, the medicament is a LRRK2 inhibitor.

[0076] According to some embodiments, the LRRK2-mediated disease or disorder is selected from Parkinson's disease, leprosy, IBD, Alzheimer's disease, L-dopa induced dyskinesia, dementia, amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myeloid leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

[0077] According to some embodiments, the compound of Formula I, a racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, pharmaceutically acceptable salt, or prodrug thereof, can be formulated into a variety of dosage forms for administration by any appropriate route using conventional methods and one or more pharmaceutically acceptable carriers. Thus, the compound of Formula I, a racemate, stereoisomer, tautomer, isotopically-labeled, solvate, polymorph, pharmaceutically acceptable salt, or prodrug thereof, can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous), inhalation or insufflation, including tablets, hard or soft gel capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrup.

[0078] The present application also provides a method for the diagnosis, prevention and / or treatment of a LRRK2-mediated disease or disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound or pharmaceutical composition of the present application, alone or, optionally, in combination with another compound of the present application and / or at least one other type of therapeutic agent.

[0079] According to some embodiments, the LRRK2-mediated disease or condition is selected from Parkinson, leprosy, IBD, Alzheimer's disease, L-dopa induced dyskinesia, dementia, amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myeloid leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.

[0080] In some embodiments, the patient is a mammal, preferably a human.

[0081] Beneficial effects

[0082] The compounds provided by the present application have good LRRK2 inhibitory effect, and can be used for treating or preventing LRRK2 related diseases and conditions, and preparing drugs for such diseases and conditions.

[0083] Definitions and explanations of terms

[0084] Unless otherwise indicated, the definitions of groups and terms recited in the specification and claims hereof, including definitions of examples, illustrative examples, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other in any manner. The group definitions and compound structures after such combination should be understood as within the scope recited in the specification and / or claims.

[0085] The term "optional" (or "optionally", "option") in the general formula definition of the present application means the case of being substituted by zero, one or more substituents, for example "optionally substituted by one, two or more R" means that it can not be substituted by R (no substitution) or can be optionally substituted by one, two or more R.

[0086] "More" means three or more, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0087] Unless otherwise indicated, the numerical ranges recited in the specification and claims hereof are meant to include each and every specific integer value within the stated range. For example, a range of "1 to 12" is intended to include each and every specific integer value, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, within the stated range.

[0088] The term "halogen" means fluorine, chlorine, bromine and iodine.

[0089] The term "C 1-10"Alkyl" denotes straight-chained and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 1-8 "Alkyl" denotes straight-chained and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C 1-6 "Alkyl" denotes straight-chained and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, "C

[0090] The term "C 2-10 "Alkenyl" is to be understood as preferably denoting straight-chained or branched univalent hydrocarbon radicals, which contain one or more double bonds and have 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-8 "Alkenyl" is to be understood as preferably denoting straight-chained or branched univalent hydrocarbon radicals, which contain one or more double bonds and have 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-10 "Alkenyl" is to be understood as preferably denoting straight-chained or branched univalent hydrocarbon radicals, which contain one or more double bonds and have 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-6 "Alkenyl" is to be understood as preferably denoting straight-chained or branched univalent hydrocarbon radicals, which contain one or more double bonds and have 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably "C 2-3Alkynyl" is understood to preferably mean a straight-chain or branched univalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C2-C8-alkynyl"), 2, 3, 4, 5 or 6 carbon atoms (i.e. "C2-C6-alkynyl"), 2 or 3 carbon atoms ("C2-C3-alkynyl"). Alkynyl groups are, in particular, C2-C6-alkynyl. Examples are acetylenyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,1-dimethyl- prop-2-ynyl, 1-ethylprop-1-ynyl, 1-propylprop-1-ynyl, 1-isopropylprop-1-ynyl.

[0091] The term "C 2-10 Alkynyl" is understood to preferably mean a straight-chain or branched univalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C2-C8-alkynyl"), 2, 3, 4, 5 or 6 carbon atoms (i.e. "C2-C6-alkynyl"), 2 or 3 carbon atoms ("C2-C3-alkynyl"). Alkynyl groups are, in particular, C2-C6-alkynyl. Examples are acetylenyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,1-dimethyl- prop-2-ynyl, 1-ethylprop-1-ynyl, 1-propylprop-1-ynyl, 1-isopropylprop-1-ynyl. 2-8 Alkynyl" is understood to preferably mean a straight-chain or branched univalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C2-C8-alkynyl"), 2, 3, 4, 5 or 6 carbon atoms (i.e. "C2-C6-alkynyl"), 2 or 3 carbon atoms ("C2-C3-alkynyl"). Alkynyl groups are, in particular, C2-C6-alkynyl. Examples are acetylenyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,1-dimethyl- prop-2-ynyl, 1-ethylprop-1-ynyl, 1-propylprop-1-ynyl, 1-isopropylprop-1-ynyl. 2-6 Alkynyl" is understood to preferably mean a straight-chain or branched univalent hydrocarbon group, which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, e.g. 2, 3, 4, 5, 6, 7 or 8 carbon atoms (i.e. "C2-C8-alkynyl"), 2, 3, 4, 5 or 6 carbon atoms (i.e. "C2-C6-alkynyl"), 2 or 3 carbon atoms ("C2-C3-alkynyl"). Alkynyl groups are, in particular, C2-C6-alkynyl. Examples are acetylenyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,1-dimethyl- prop-2-ynyl, 1-ethylprop-1-ynyl, 1-propylprop-1-ynyl, 1-isopropylprop-1-ynyl. 2-3"alkynyl"). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0092] The term "carbocyclo" or "carbocyclyl" means any stable 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12- or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which can be saturated, partially unsaturated, unsaturated, or aromatic. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthryl, and tetrahydronaphthyl (tetrahydronaphthalene). Bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, and tetrahydronaphthyl, unless otherwise specified. When the term "carbocycle" is used, it is intended to include "aryl". A bridge is created when one or more, preferably one to three, carbon atoms link two non-adjacent carbon atoms. Preferably, the bridge is one or two carbon atoms. It should be noted that a bridge always converts a monocycle into a tricycle. When a ring is bridged, the substituents described for the ring can also be present on the bridge.

[0093] The term "C 3-14 "Cycloalkyl" is to be understood as meaning a saturated, monovalent, monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic hydrocarbon ring or alkane having 3 to 14 carbon atoms, preferably "C 3-10 "Cycloalkyl", more preferably "C3-8 Cycloalkyl". The term "C 3-10 Cycloalkyl" is to be understood as meaning saturated, monovalent, monocyclic, bicyclic (e.g. bridged, spirocyclic) or tricyclic hydrocarbon rings having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Said C 3-10 Cycloalkyl" is to be understood as meaning saturated, monovalent, monocyclic, bicyclic (e.g. bridged, spirocyclic) or tricyclic hydrocarbon rings having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Said C

[0094] The term "heterocyclyl or heterocycle" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, the term "3-14 membered heterocyclyl or heterocycle" is a 3-, 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic (e.g., fused, bridged, spirocyclic) or 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more, heteroatoms selected from O, S and N, wherein N and S can also be optionally oxidized to various oxidation states to form nitroso, -S(O)- or -S(O)2- states. Preferably, the heterocyclyl can be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl can be attached to the rest of the molecule by any of the carbon atoms or the nitrogen atom, if present. The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. In particular, the heterocyclyl can include, but is not limited to: 4-membered rings such as azetidinyl, oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings such as diazepanyl. Optionally, the heterocyclyl can be benzo-fused. The heterocyclyl can be bicyclic, for example, but not limited to 5,5 membered rings such as hexahydrocyclopenta[c]pyrrol-2(lH)-yl ring, or 5,6 membered bicyclic rings such as hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl ring. The heterocyclyl can be partially unsaturated, i.e. it can contain one or more double bonds, for example, but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-lH-pyrrolyl, 4H-[l,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[l,4]thiazinyl, or it can be benzo-fused, for example, but not limited to dihydroisoquinolinyl. When the 3-20 membered heterocyclyl is attached to other groups to form a compound of the invention, it can be attached to the other groups via a carbon atom of the 3-20 membered heterocyclyl or it can be attached to the other groups via a heteroatom of the 3-20 membered heterocyclyl ring. For example, when the 3-20 membered heterocyclyl is selected from piperazinyl, it can be attached to the other groups via a nitrogen atom of the piperazinyl. Or when the 3-20 membered heterocyclyl is selected from piperidinyl, it can be attached to the other groups via a nitrogen atom and the carbon atom in para position of the piperidinyl ring.

[0095] The term "C 6-14 The term "aryl" is to be understood as preferably meaning a monovalent aromatic or partially aromatic monocyclic, bicyclic (e.g., fused, bridged, spirocyclic) or tricyclic hydrocarbon ring having 6 to 14 carbon atoms, which can be a single aromatic ring or multiple aromatic rings that are fused together. The term "C6-14 Aryl" is to be understood as preferably denoting a monovalent aromatic or partially aromatic, monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 Aryl") having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular a ring having 6 carbon atoms ("C6-aryl"), such as, for example, a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms ("C9-aryl"), such as, for example, an indanyl or indenyl group, or a ring having 10 carbon atoms ("C 10 Aryl") such as, for example, a tetrahydronaphthyl, dihydronaphthyl or naphthyl group, or a ring having 13 carbon atoms ("C 13 Aryl") such as, for example, a fluorenyl group, or a ring having 14 carbon atoms ("C 14 Aryl") such as, for example, an anthryl group. When the C 6-20 Aryl" is substituted, it can be mono- or polysubstituted. Also, there is no restriction on the substitution sites, for example, it can be ortho, para or meta substitution.

[0096] The term "5-14 membered heteroaryl or heteroaromatic ring" is to be understood as including monovalent monocyclic, bicyclic (e.g. fused, bridged, spirocyclic) or tricyclic aromatic ring systems having 5 to 14 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S. The term "5-14 membered heteroaryl" is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and comprising 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S and, in addition, in each case can be benzo-fused. Examples of monocyclic "heteroaryl" groups include, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazinyl, oxazinyl, triazinyl, thiodiazinyl or oxadiazinyl and the like. "Heteroaryl" also refers to groups in which the heteroaromatic ring is fused with one or more aryl, alicyclic or heterocyclyl rings, where the point of attachment is on the heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolizyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-oxazinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenoxazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-ortho-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-4H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophenyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-20 membered heteroaryl is attached to other groups to form a compound of the invention, it can be attached to a carbon atom or a heteroatom of the 5-20 membered heteroaryl ring. When the 5-20 membered heteroaryl is substituted, it can be mono- or poly-substituted. Also, there is no limitation on the substitution site, for example, the hydrogen attached to a carbon atom of the heteroaryl ring can be substituted, or the hydrogen attached to a heteroatom of the heteroaryl ring can be substituted.

[0097] The term "spirocyclic" refers to a ring system in which two rings share one ring atom.

[0098] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0099] The term "bridged ring" refers to a ring system in which two rings share 3 or more ring-forming atoms.

[0100] Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylenyl includes all possible isomeric forms thereof, e.g., positional isomers. Thus, for some illustrative, non-limiting examples, forms substituted or bonded at one, two or more positions in its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) can be included, including pyridin-2-yl, pyridin-2- ylenyl, pyridin-3-yl, pyridin-3-yl enyl, pyridin-4-yl and pyridin-4-yl enyl; thienyl or thienylenyl includes thien-2-yl, thien-2-yl enyl, thien-3-yl and thien-3-yl enyl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0101] The term "oxo" refers to an oxy substituent (=O) formed by oxidation of a carbon atom, nitrogen atom or sulfur atom in a substituent.

[0102] The term "alkylamino" refers to -NH-(alkyl) or -N-(alkyl)2, where alkyl is as defined above. Non-limiting examples of alkylamino groups include: methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, methylethylamino, diethylamino, dipropylamino, methylpropylamino, diisopropylamino, dibutylamino, and the like.

[0103] The term "alkyloxy" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples of alkyloxy groups include: methoxy, ethoxy, propyloxy, butyloxy. The alkyloxy group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy or heterocycloalkyloxy.

[0104] The terms "alkyleneoxy" and "oxyalkylene" refer to -alkylene-O- or -O-alkylene-, where alkylene represents a straight-chained or branched saturated divalent hydrocarbon radical. The definition of the number of carbon atoms for "alkylene" applies mutatis mutandis to the definition of "alkyl" above. It will be understood by those skilled in the art that the alkyleneoxy or oxyalkylene group can be attached in either direction to the remainder of the molecule of which it is a part, i.e., they can be used interchangeably.

[0105] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens.

[0106] In the present application, the compounds involved also include isotopically-labeled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes of atoms that can be incorporated into compounds of the application include isotopes of H, C, N, O, S, F, and CI, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present application, prodrugs thereof, or pharmaceutically acceptable salts of said compounds or of said prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes such as 3 H, and 14 C) are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H or D, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, therefore, can be preferred in some circumstances. Compounds of the present application as claimed in the claims can be particularly defined with respect to substitution by deuterium or tritium. Moreover, the presence of deuterium or tritium in a substituent not individually listed as a term in the specification is not to be construed as excluding deuterium or tritium, but rather as also encompassing deuterium or tritium.

[0107] It will be appreciated by one skilled in the art that the compounds of Formula (I) can exist in various pharmaceutically acceptable salt forms. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., carboxyl) and a basic center (e.g., amino), they can also form inner salts.

[0108] The compounds of the present application can exist in the form of solvates (e.g., hydrates), wherein the compound of the present application contains as an element of the crystal lattice of the compound a polar solvent, in particular, for example, water, methanol or ethanol. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0109] Depending on its molecular structure, a compound of the application can be chiral and therefore can exist as various enantiomeric forms. The compounds can thus exist in racemic or optically active forms. The compounds of the application encompass the isomers of each chiral carbon in the R or S configuration or mixtures thereof, racemates. The compounds of the application or intermediates thereto can be separated into the enantiomeric compounds by chemical or physical methods known to those of ordinary skill in the art, or be synthesized in such form. In the case of racemic amines, the diastereomeric forms are prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, binaphthyl-tartric acid, mandelic acid, malic acid, lactic acid, the appropriate N-protected amino acid, for example N-benzoyl proline or N-benzenesulfonyl proline, or the various optically active camphorsulfonic acids. Chromatographic enantiomeric resolution can also be advantageously performed with optically active, derivatizing agents, for example, dinitrobenzoyl phenylglycine, cellulose or other carbohydrate derivatives, or chiral derivatizing reagents of the hoben-reiland type. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0110] The corresponding stable isomers can be isolated according to known methods, for example by extraction, filtration or column chromatography.

[0111] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine; cattle, goats, horses, or primates, most preferably humans.

[0112] The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes one or more of the following: (1) preventing the disease: for example, preventing a disease, disorder or condition from occurring in an individual that is predisposed or susceptible to the disease, but has not yet experienced or displayed pathogenesis or symptoms of the disease.(2) inhibiting the disease: for example, arresting the development of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease (i.e., stopping the pathology and / or symptoms from advancing).(3) relieving the disease: for example, causing the regression of a disease, disorder or condition in an individual that is experiencing or displaying the pathology or symptoms of the disease (i.e., reversing the pathology and / or symptoms). DETAILED DESCRIPTION

[0113] The technical solutions of the present application will be further described in detail below in conjunction with specific examples. It should be understood that the following examples are only illustratively described and explained, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is encompassed within the scope intended to be protected by the present application.

[0114] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0115] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0116] LC-MS was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18150 × 4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C18150 × 4.6 mm column).

[0117] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15mm to 0.20mm, while the standard size for separating and purifying products using TLC is 0.4mm to 0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0118] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0119] Example 1

[0120] (N 4 -Methyl-N 2 -(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)-5-(trifluoromethyl)pyrimidin-2,4-diamine

[0121]

[0122] first step

[0123] Preparation of tert-butyl 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (Cpd-01B)

[0124] 2-Bromo-6,7-dihydrothiopheno[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Cpd-01A, 400 mg, 1.2 mmol) was added to 1,4-dioxane (5 mL), followed by the addition of N... 4 The reaction mixture consisted of methyl-5-(trifluoromethyl)pyrimidin-2,4-diamine (290 mg, 1.5 mmol), cesium carbonate (2.4 g, 7.4 mmol), methanesulfonic acid (dicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-(1,1′-biphenyl)-2-yl)phosphonane)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) (115 mg, 0.12 mmol) and dicyclohexyl(3-isopropoxy-2′,4′,6′-triisopropyl-(1,1′-biphenyl)-2-yl)phosphonane (134 mg, 0.24 mmol), purged with nitrogen three times. The reaction solution was reacted at 110 °C for 4 hours. After the reaction was complete, the reaction solution was filtered, and the solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give tert-butyl 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (Cpd-01B, 100 mg), yield: 88%.

[0125] MS m / z(ESI): 430[M+1] + .

[0126] Step 2

[0127] N 4 -Methyl-N 2 Preparation of -(4,5,6,7-tetrahydrothiopheno[3,2-c]pyridin-2-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Cpd-01)

[0128] Compound Cpd-01B (50 mg, 0.12 mmol) was dissolved in dioxane (1 mL), and dioxane hydrochloride (1 mL, 4 mol / L) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, purified, and dried under vacuum to obtain N. 4 -Methyl-N 2 -(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (Cpd-01, 30 mg), yield: 60%.

[0129] MS m / z(ESI): 330[M+1] + .

[0130] 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.30 (s, 2H), 8.20 (s, 1H), 7.53 (s, 1H), 6.49 (s, 1H), 4.08 (s, 2H), 3.37 (d, J = 5.3 Hz, 2H), 3.04 - 2.89 (m, 5H).

[0131] Example 2

[0132] N 4 - methyl-N 2 - (5-methyl-4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

[0133]

[0134] First Step

[0135] N 4 - methyl-N 2 Preparation of (5-methyl-4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (Cpd-02)

[0136] Compound Cpd-01 (20 mg, 0.06 mmol) was dissolved in methanol (5 mL), to which triethylamine (30 mg, 0.30 mmol) and paraformaldehyde (19 mg, 0.61 mmol) were added, and stirred at room temperature for 1 hour. Sodium cyanoborohydride (38 mg, 0.61 mmol) was added to the reaction solution, and stirred at room temperature for 16 hours. The reaction solution was concentrated, and the crude product was purified by a preparative plate (petroleum ether / ethyl acetate = 1 / 1) to obtain N 4 - methyl-N 2 (5-methyl-4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-2-yl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (Cpd-02, 10 mg) at a yield of 48%.

[0137] MS m / z (ESI): 344 [M+1]+.

[0138] 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.15 (s, 1H), 7.24 (s, 1H), 6.36 (s, 1H), 3.41 (s, 2H), 3.03 (s, 2H), 2.71 (d, J = 23.1 Hz, 3H), 2.41 (s, 2H).

[0139] Example 3

[0140] N 2 -(3-chloro-5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-N 4 5-Methyl-5-(trifluoromethyl)pyrimidin-2,4-diamine

[0141]

[0142] first step

[0143] Preparation of tert-butyl 3-chloro-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (Cpd-03A)

[0144] Compound Cpd-01B (100 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL). N-chlorosuccinimide (62 mg, 0.46 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The reactants were directly purified by preparative chromatography (petroleum ether / ethyl acetate = 1 / 1) to give tert-butyl 3-chloro-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (Cpd-03A, 26 mg), yield: 23%.

[0145] MS m / z(ESI): 464[M+1] + .

[0146] Step 2

[0147] N 2 -(3-chloro-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-N 4 Preparation of methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Cpd-03B)

[0148] Compound Cpd-03A (26 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, purified, and dried under vacuum to obtain N. 2 -(3-chloro-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-N 4 2-Methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Cpd-03B, 20 mg), yield: 89%.

[0149] MS m / z(ESI): 364[M+1] + .

[0150] Step 3

[0151] N 2 - methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Cpd-03) was prepared 4 - methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Cpd-03) was prepared

[0152] Compound Cpd-03B (20 mg, 0.06 mmol) was dissolved in methanol (5 mL), to which triethylamine (30 mg, 0.30 mmol) and paraformaldehyde (19 mg, 0.61 mmol) were added, and stirred at room temperature for 1 hour. Sodium cyanoborohydride (38 mg, 0.61 mmol) was added to the reaction solution, and stirred at room temperature for 16 hours. The reaction solution was concentrated, and the crude product was purified by a preparative plate (petroleum ether / ethyl acetate = 1 / 1) to obtain N 2 - methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Cpd-03) was prepared 4 - methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (Cpd-03, 13 mg), yield: 62%.

[0153] MS m / z (ESI): 378 [M+1] + .

[0154] 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (br, 1H), 8.16 (s, 1H), 7.25 (s, 1H), 3.24 (s, 2H), 2.94 (d, J = 4.4 Hz, 3H), 2.71 (d, J = 4.9 Hz, 2H), 2.65 (t, J = 5.2 Hz, 2H), 2.38 (s, 3H).

[0155] Example 4

[0156] 6-acetyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carbonitrile

[0157]

[0158] First step

[0159] Preparation of tert-butyl 2-amino-3-cyano-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate (Cpd-27B)

[0160] A mixture of tert-butyl 4-oxopiperidine-1-carboxylate Cpd-27A (5.0 g, 25.10 mmol), malononitrile (3.3 g, 50.20 mmol), sulfur powder (1.2 g, 4.72 mmol) and L-proline (0.6 g, 5.02 mol) was added to N,N-dimethylformamide (100 mL) and heated at 60 °C for 60 min under nitrogen atmosphere. After completion of the reaction, the mixture was diluted with water (1 L). The residue was extracted with ethyl acetate (800 mL x 3). The organic phase was washed with saturated brine (800 mL), dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (dichloromethane / methanol = 15 / 1) to give tert-butyl 2-amino-3-cyano-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate Cpd-27B (6.75 g) in 96% yield.

[0161] MS m / z (ESI): 224 [M+1-56] + .

[0162] Second Step

[0163] Preparation of tert-butyl 2-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyano-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (Cpd-27C)

[0164] A mixture of tert-butyl 2-amino-3-cyano-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate Cpd-27B (5.0 g, 17.83 mmol), 2,4-dichloro-5-trifluoromethylpyrimidine (3.9 g, 17.83 mmol), tris(dibenzylideneacetone)dipalladium (1.6 g, 1.78 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.1 g, 3.56 mmol) and cesium carbonate (11.6 g, 35.60 mmol) was added to toluene (250 mL) and stirred at 80 °C for 2 h under nitrogen atmosphere. After completion of the reaction, the mixture was diluted with water (500 mL), extracted with ethyl acetate (1 L x 3), dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give tert-butyl 2-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-cyano-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate Cpd-27C (4.28 g) in 52% yield.

[0165] MS m / z (ESI): 460 [M+1] + .

[0166] Third Step

[0167] Preparation of tert-butyl 3-cyano-2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate (Cpd-27D)

[0168] tert-Butyl 3-cyano-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate Cpd-27D (2.0 g, 4.40 mmol) was dissolved in dichloromethane (20 mL), to which was added hydrochloric acid dioxane solution (4 M, 20 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain 2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 3-carbonitrile Cpd-27E (1.56 g) in a yield of 100%.

[0169] MS m / z (ESI): 455 [M+1] + .

[0170] Fourth step

[0171] Preparation of 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile (Cpd-27E)

[0172] tert-Butyl 3-cyano-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2- yl)amino)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate Cpd-27D (2.0 g, 4.40 mmol) was dissolved in dichloromethane (20 mL), to which was added hydrochloric acid dioxane solution (4 M, 20 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain 2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 3-carbonitrile Cpd-27E (1.56 g) in a yield of 100%.

[0173] MS m / z (ESI): 455 [M+1] + .

[0174] Fifth step

[0175] 6-acetyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile (Cpd-27)

[0176] To a solution of 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-27E (100 mg, 0.28 mmol) in dichloromethane (5 mL) was added N,N diisopropyl ethyl amine (109 mg, 0.84 mmol) and the reaction was cooled to 0 °C. To this was added drop wise acetyl chloride (33 mg, 0.42 mmol). After completion of the addition, the reaction was continued at room temperature for 1 h. After completion of the reaction, it was concentrated and purified by reverse phase preparative purification to get 6-acetyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-27 (15 mg). Yield: 4%.

[0177] MS m / z (ESI): 397 [M+1] + .

[0178] 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.21 (s, 1H), 7.53 (s, 1H), 4.58-4.53 (m, 2H), 3.71 (t, J = 5.7 Hz, 2H), 3.01 (d, J = 3.8 Hz, 3H), 2.66 (s, 1H), 2.52 (s, 1H), 2.10-2.07 (m, 3H).

[0179] Example 5

[0180] 6-acetyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile

[0181]

[0182] To a solution of 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-27E (100 mg, 0.28 mmol) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (109 mg, 0.84 mmol). The reaction was cooled to 0 °C and to this reaction was added dropwise propionyl chloride (33 mg, 0.42 mmol) followed by stirring at room temperature for 1 h. After completion of the reaction, it was concentrated and the crude obtained was purified by preparative plate to get 6-propionyl-2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-28 (30 mg) in 7% yield.

[0183] MS m / z (ESI): 411 [M+1] + .

[0184] 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.22 (s, 1H), 7.57 (s, 1H), 4.59 - 4.55 (m, 2H), 3.75 - 3.72 (m, 2H), 3.02 (d, J = 3.9 Hz, 3H), 2.66 (d, J = 6.0 Hz, 1H), 2.54 (s, 1H), 2.46 - 2.35 (m, 2H), 1.00 (t, J = 7.7 Hz, 3H).

[0185] Example 6

[0186] 6-Propionyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carbonitrile

[0187]

[0188] To a solution of 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-27E (100 mg, 0.25 mmol) and N,N-diisopropyl ethylamine (99 mg, 0.76 mmol) in N,N-dimethylformamide (1 mL) was added 2-methylpropanoyl chloride (40 mg, 0.38 mmol) dropwise at 0 °C. Then stirred at room temperature for 2 hours. After the reaction was completed, N,N-dimethylformamide was removed by freeze-drying, and the crude product was purified by a preparative plate (dichloromethane / methanol = 15 / 1) to give 6-isobutyryl-2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-29 (15 mg), yield: 13%.

[0189] MS m / z (ESI): 425 [M+1] + .

[0190] 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.22 (s, 1H), 7.55 (s, 1H), 4.66 - 4.54 (m, 2H), 3.84 - 3.71 (m, 2H), 3.01 (t, J = 5.7 Hz, 3H), 2.99 - 2.88 (m, 1H), 2.66 - 2.51 (m, 2H), 1.05 - 0.98 (m, 6H).

[0191] Example 7

[0192] 6-isobutyryl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carbonitrile

[0193]

[0194] To a solution of 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-27E (50 mg, 0.14 mmol) and triethylamine (28 mg, 0.28 mmol) in dichloromethane (5 mL) was added pivalic anhydride (39 mg, 0.21 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated to give a residue which was purified by a preparative plate (dichloromethane / methanol = 30 / 1) to give 6-pivaloyl-2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-30 (15 mg) in 24% yield.

[0195] MS m / z (ESI): 439 [M+1] + .

[0196] 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.21 (s, 1H), 7.50 (s, 1H), 4.60 (s, 2H), 3.83 (t, J = 5.6 Hz, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.60 (s, 2H), 1.22 (s, 9H).

[0197] Example 8

[0198] 6-pivaloyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carbonitrile

[0199]

[0200] To a solution of 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-27E (50 mg, 0.14 mmol) and triethylamine (28 mg, 0.28 mmol) in dichloromethane (5 mL) was added trifluoroacetic anhydride (29 mg, 0.14 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated to give a residue which was purified by a preparative plate (dichloromethane / methanol = 30 / 1) to give 6-trifluoroacetyl-2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-31 (3 mg) in 4.7% yield.

[0201] MS m / z (ESI): 451 [M+1] +

[0202] 1 H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.21 (s, 1H), 7.57 (s, 1H), 4.70 (s, 2H), 4.19 - 3.72 (m, 2H), 3.02 (d, J = 4.0 Hz, 3H), 2.79 - 2.58 (m, 2H).

[0203] Example 9

[0204] 6-Isonicotinoyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile

[0205]

[0206] Isonicotinoyl chloride (30 mg, 0.22 mmol), 2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carbonitrile Cpd-27E (70 mg, 0.19 mmol) and triethylamine (40 mg, 0.39 mmol) were added into dichloromethane (5 mL), stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the crude product was separated and purified by a preparative plate (dichloromethane / methanol = 10 / 1) to obtain 6-isonicotinoyl-2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-32 (10 mg), yield: 10%.

[0207] MS m / z (ESI): 460 [M+1] + .

[0208] 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.68 (s, 2H), 8.22 (s, 1H), 7.92 (s, 1H), 7.53 - 7.49 (m, 2H), 4.73 - 4.54 (m, 2H), 3.94 - 3.59 (m, 2H), 3.04 - 2.95 (m, 3H), 2.69 (s, 2H).

[0209] Example 10

[0210] 6-nicotinoyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4, 5, 6, 7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile

[0211]

[0212] Nicotinoyl chloride (30 mg, 0.22 mmol), 2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carbonitrile Cpd-27E (70 mg, 0.19 mmol) and triethylamine (40 mg, 0.39 mmol) were added into dichloromethane (5 mL) and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the crude product was separated and purified by a preparative plate (dichloromethane / methanol = 10 / 1) to obtain 6-nicotinoyl-2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-33 (25 mg), yield: 26%.

[0213] MS m / z (ESI): 460 [M+1] + .

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.79 - 8.57 (m, 2H), 8.31 - 8.10 (m, 1H), 7.75 - 7.36 (m, 3H), 4.85 - 4.32 (m, 2H), 4.03 - 3.44 (m, 2H), 3.10 - 2.86 (m, 3H), 2.78 - 2.58 (m, 2H).

[0215] Example 11

[0216] 6-nicotinoyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4, 5, 6, 7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile

[0217]

[0218] To a solution of 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-27E (100 mg, 0.28 mmol), cyclopropanecarbonyl chloride (35 mg, 0.33 mmol) and triethylamine (57 mg, 0.56 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the filtrate was concentrated to get the crude product, which was separated and purified by preparative plate (dichloromethane / methanol = 10 / 1) to give 6-cyclopropanecarbonyl-2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-34 (10 mg), yield: 8%.

[0219] MS m / z (ESI): 423 [M+1] + .

[0220] 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.22 (s, 1H), 7.56 (s, 1H), 4.96 - 4.41 (m, 2H), 4.09 - 3.66 (m, 2H), 3.02 (s, 3H), 2.72 - 2.53 (m, 2H), 2.16 - 1.93 (m, 1H), 0.84 - 0.68 (m, 4H).

[0221] Example 12

[0222] 6-cyclopropanecarbonyl-2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile

[0223]

[0224] To a solution of 2-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-27E (100 mg, 0.28 mmol), cyclobutanecarbonyl chloride (37 mg, 0.31 mmol) and triethylamine (57 mg, 0.56 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 hour. After the reaction was completed, the filtrate was concentrated to get the crude product, which was separated and purified by preparative plate (dichloromethane / methanol = 10 / 1) to give 6-(cyclobutanecarbonyl)-2-((4-(methylamino)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carbonitrile Cpd-35 (25 mg), yield: 19%.

[0225] MS m / z (ESI): 437 [M+1] + .

[0226] 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.22 (s, 1H), 7.55 (s, 1H), 4.63 - 4.36 (m, 2H), 3.79 - 3.54 (m, 2H), 3.50 - 3.37 (m, 1H), 3.08 - 2.97 (m, 3H), 2.65 - 2.52 (m, 2H), 2.24 - 2.05 (m, 4H), 2.00 - 1.83 (m, 1H), 1.81 - 1.66 (m, 1H).

[0227] Biological evaluation

[0228] Test 1, Determination of the inhibitory activity of the compounds of the application on recombinant human LRRK2 kinase

[0229] (I) Biochemical assay of the compounds

[0230] • Purpose of the experiment:

[0231] The energy signal transfer (520nM / 485nM fluorescence signal ratio) resulting from the binding of the phosphoryl group of the phosphorylated Fluorescein-ERM (LRRKtide) polypeptide to the LanthaScreen.Tb-pERM (pLRRKtide) antibody is detected by homogeneous time-resolved fluorescence. The LRRK2 kinase inhibition IC50value of the compound under test is calculated.

[0232] • Experimental material:

[0233] 1. Reaction solution:

[0234] LRRK2: Invitrogen - PR8604B

[0235] Fluorescein-ERM (LRRKtide) polypeptide: Invitrogen - PV4901

[0236] ATP: Sigma - A7699

[0237] Tb-anti-pLRRKtide antibody: Invitrogen - PV4900

[0238] 2. Final concentration of LRRK2

[0239] LRRK2: 2 nM

[0240] Fluorescein-ERM (LRRKtide) polypeptide: 400 nM

[0241] ATP: 38 μM

[0242] Tb-anti-pLRRKtide antibody: 0.25 nM

[0243] • Experimental procedure:

[0244] 1. Compound dilutions were performed using Echo, final concentrations ranging from 10 μM to 0.17 nM;

[0245] 2. 5 μL of protease and peptide mix were added to the assay plate wells (containing compound);

[0246] 3. Centrifuge at 1000 rpm for 15 seconds, incubate at 23 °C for 15 minutes;

[0247] 4. Start the reaction by adding 5 μL / well of ATP solution;

[0248] 5. Centrifuge the assay plate at 1000 rpm for approximately 15 seconds and seal with an adhesive film;

[0249] 6. Incubate at 23 °C for 120 minutes;

[0250] 7. Stop the reaction by adding 10 μL / well of antibody detection solution;

[0251] 8. Centrifuge the assay plate at 1000 rpm for approximately 15 seconds, incubate at 23 °C for 60 minutes;

[0252] 9. Read the assay plate on an Envision.

[0253] 10. Calculate the relative inhibition of enzyme activity relative to DMSO blanks by signal ratio, and calculate IC50values using software XLfit 5 to fit curves.

[0254] • Experimental results:

[0255] Table 1. Results of LRRK2 kinase inhibition activity test of compounds of the present application

[0256]

[0257]

[0258] The experimental results show that the compounds of the present application have good LRRK2 kinase inhibition activity.

[0259] The above has exemplarily described the embodiments of the technical scheme of the present application. It should be understood that the protection scope of the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A compound of formula II-2, its isotopic label, or a pharmaceutically acceptable salt thereof: in, R4 is selected from H, F, Cl, and CN; Selected from 2. A compound of formula III-1, its isotopic label, or a pharmaceutically acceptable salt thereof. in, R6 is selected from methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, pyridyl, cyclopropyl, and cyclobutyl.

3. The compound according to claim 1, its isotopic label, or a pharmaceutically acceptable salt, characterized in that, The compound is selected from the structures shown below:

4. A pharmaceutical composition comprising at least one of the compounds of any one of claims 1-3, their isotopic labels, or pharmaceutically acceptable salts.

5. The use of at least one of the compounds, isotopic markers thereof, or pharmaceutically acceptable salts of any one of claims 1-3, or the pharmaceutical composition of claim 4, in the preparation of a medicament for the prevention and / or treatment of LRRK2-mediated diseases or conditions.

6. The application according to claim 5, characterized in that, The LRRK2-mediated diseases or symptoms are selected from Parkinson's disease, leprosy, IBD, Alzheimer's disease, L-DOPA-induced dyskinesia, dementia, amyotrophic lateral sclerosis (ALS), kidney cancer, breast cancer, prostate cancer, papillary carcinoma, lung cancer, acute myeloid leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, ALS, rheumatoid arthritis, or ankylosing spondylitis.

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