Pyrimidine derivatives useful as LRRK2 kinase inhibitors

Abstract

Compounds having activity as inhibitors of LRRK2 kinase are provided. The compounds have the structure (I): TIFF2024512024000197.tif2659(I) or a pharma- ceutical acceptable salt, stereoisomer or prodrug thereof, wherein A, B, R 1a , R 1b , R 2 and L is as defined herein. Methods for making and using the compounds, pharmaceutical compositions containing the compounds and methods for modulating the activity of LRRK2 kinase are also provided.

Description

[Technical Field]

[0001] Embodiments of the present disclosure relate generally to compounds and methods for their preparation and use as therapeutic or prophylactic agents, for example, for the treatment of neurodegenerative diseases, central nervous system (CNS) disorders, cancer, and inflammatory diseases. [Background technology]

[0002] Neurodegenerative diseases such as Parkinson's disease, Lewy body dementia, and Huntington's disease affect millions of people. Parkinson's disease is a chronic, progressive motor system disorder that affects approximately 1 in 1,000 people, with hereditary Parkinson's disease accounting for 5-10% of all cases. Parkinson's disease is caused by the progressive loss of midbrain dopamine neurons, impairing patients' ability to direct and control their movements. The main symptoms of Parkinson's disease are tremor, rigidity, bradykinesia, and impaired balance.

[0003] The gene encoding leucine-rich repeat kinase 2 protein (LRRK2) has been identified as being associated with hereditary Parkinson's disease (see, e.g., Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, pp. 595-600; Zimprich et al., Neuron, Vol. 44(4), 2004, pp. 601-607). In vitro studies have shown that Parkinson's disease-associated mutations result in increased LRRK2 kinase activity and a decreased GTP hydrolysis rate compared to the wild-type (Guo et al., Experimental Cell Research, Vol. 313(16), 2007, pp. 3658-3670). Anti-LRRK2 antibodies have been used to detect brainstem Lewy bodies associated with Parkinson's disease and cortical Lewy body dementia, suggesting that LRRK2 may play an important role in the formation and pathogenesis of Lewy bodies associated with these diseases (Zhou et al., Molecular Degeneration, 2006, 1:17 doi:10.1186 / 1750-1326-1-17). LRRK2 has also been identified as a gene potentially associated with increased susceptibility to Crohn's disease and leprosy (Zhang et al., New England J. Med. Vol. 361 (2009) pp. 2609-2618).

[0004] LRRK2 has been implicated in L-DOPA-induced dyskinesia (Hurley et al., Eur. J. Neurosci., Vol. 26, 2007, pp. 171-177); CNS disorders associated with the differentiation of neural progenitor cells (Milosevic et al., Neurodegen., Vol. 4, 2009, p. 25); cancers such as kidney, breast, prostate, blood, and lung cancers, as well as acute myeloid leukemia (see, e.g., PCT Publication WO 2011 / 038572); papillary renal carcinoma and thyroid carcinoma (Looyenga et al., www.pnas.org / cgi / doi / 10.1073 / pnas.1012500108); multiple myeloma (Chapman et al., Nature Vol. 471, 2011, pp. 467-472); amyotrophic lateral sclerosis (Shtilbans et al., Amyotrophic Lateral Sclerosis Early Online 2011, pp. 1-7); rheumatoid arthritis (Nakamura et al., DNA Res. Vol. 13(4), 2006, pp. 169-183); and ankylosing spondylitis (Danoy et al., PLoS Genetics, Vol. 6(12), 2010, e1001195, pp. 1-5).

[0005] Thus, compounds and compositions effective in modulating LRRK2 kinase activity may provide treatment for neurodegenerative diseases, such as Parkinson's disease and Lewy body dementia, CNS disorders, such as Alzheimer's disease and L-DOPA-induced dyskinesia, cancers, such as kidney, breast, prostate, hematological, papillary, and lung cancers, acute myeloid leukemia, and multiple myeloma, and inflammatory diseases, such as leprosy, Crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis. Embodiments of the present disclosure fulfill this need and further provide related advantages. Summary of the Invention

[0006] Briefly, embodiments of the present disclosure provide compounds, including pharmaceutically acceptable salts, stereoisomers and prodrugs thereof, that are capable of modulating the kinase activity of LRRK2.

[0007] In one aspect, the present disclosure provides a compound of structure (I): [ka] (I) and a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein A, B, R 1a , R 1b , R 2 and L are each as described below.

[0008] In another embodiment, pharmaceutical compositions comprising the compounds of the present disclosure and methods of use thereof for the treatment of neurodegenerative diseases, central nervous system (CNS) disorders, cancer, inflammatory diseases, and combinations thereof are also provided. DETAILED DESCRIPTION OF THE INVENTION

[0009] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details.

[0010] Unless the context indicates otherwise, throughout this specification and claims, the term "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in their open and inclusive sense, i.e., "including but not limited to."

[0011] As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range, and fractions thereof (e.g., tenths and hundredths of integers), where appropriate, unless otherwise specified. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure, unless otherwise specified. As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the listed components. The use of alternatives (e.g., "or") should be understood to mean either one, both, or any combination of the alternatives.

[0012] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0014] "Amino" refers to the group -NH2.

[0015] "Carboxy" or "carboxyl" refers to the group -CO2H, which can also exist as a -CO2- group depending on conditions (e.g., pH, counter ions, etc.).

[0016] "Cyano" refers to the radical -CN.

[0017] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0018] "Alkyl" refers to a saturated, straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, having from 1 to 12 carbon atoms (C1-C 12 alkyl), 1 to 8 carbon atoms (C1-C8 alkyl), or 1 to 6 carbon atoms (C1-C6 alkyl), or any value within these ranges, such as C4-C6 alkyl, and is attached to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. The carbon numbers referenced refer to the carbon backbone and carbon branches, but do not include carbon atoms belonging to any substituents. Unless specifically stated otherwise in this specification, alkyl groups are optionally substituted.

[0019] "Alkoxy" means a group of the formula -OR a refers to a group, wherein R a is a group of 1 to 12 carbon atoms (C1-C 12 and alkyl groups as defined above containing 1 to 8 carbon atoms (C1-C8 alkoxy), 1 to 8 carbon atoms (C1-C8 alkoxy), or 1 to 6 carbon atoms (C1-C6 alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.

[0020] "Aminyl" is a group of the formula -NR a R b refers to a group, wherein R a and R b are each independently H or C1-C6 alkyl as defined above. a and R b When both are H, the "aminyl" group is the same as the "amino" group defined above. Unless otherwise specified, the C1-C6 alkyl portion of the aminyl group is optionally substituted.

[0021] "Aromatic ring" refers to a cyclic, planar molecule or portion of a molecule (i.e., group) having a resonance-bonded ring that exhibits enhanced stability compared to other bonding arrangements with the same set of atoms. Generally, an aromatic ring comprises a set of covalently bonded, coplanar atoms and contains an even, but not a multiple of four, number of π electrons (e.g., alternating double and single bonds) (i.e., 4n+2 π electrons, n=0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, and pyrimidonyl. Unless specifically stated otherwise in this specification, "aromatic ring" includes all groups that are optionally substituted.

[0022] "Aryl" refers to an alkyl group having 6 to 18 carbon atoms, e.g., 6 to 10 carbon atoms (C6-C 10 The term "aryl" refers to a carbocyclic ring system containing at least one carbocyclic aromatic ring. For purposes of the present disclosure, an aryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated herein, an aryl group is optionally substituted.

[0023] As used herein, "arylene" refers to a divalent or polyvalent aryl group (i.e., as defined above) that links a portion of a molecule to one group, two or more groups, or a first molecule to a portion of a second molecule. Arylene groups include, but are not limited to, phenylene. Unless specifically stated otherwise, arylene is optionally substituted.

[0024] "Carbocyclic" or "carbocycle" refers to a ring system in which each of the ring atoms is carbon.

[0025] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic carbocyclic group, consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, and which has from 3 to 15 ring carbon atoms (C3-C4). 15 Cycloalkyl), 3 to 10 ring carbon atoms (C3-C 10 Cycloalkyl groups have from 3 to 8 ring carbon atoms (C-C cycloalkyl), or from 3 to 8 ring carbon atoms (C-C cycloalkyl), or any value within these ranges, e.g., from 3 to 4 carbon atoms (C-C cycloalkyl), and are saturated or partially unsaturated, and are bonded to the remainder of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, (1S,2S,3S,4S,6S,7S)-cubanyl, and the like. Unless specifically stated otherwise in the specification, cycloalkyl groups are optionally substituted.

[0026] "Fused" refers to any ring structure having two or more rings, where at least two rings share two adjacent atoms. For example, in some embodiments, a fused ring group has the following structure: [ka] It has one of the following. Unless stated otherwise specifically in the specification, fused ring groups are optionally substituted.

[0027] "Bridged" refers to any ring structure described herein having two or more joined rings that share three or more atoms and can be carbocyclic (i.e., all ring atoms are carbon) or heterocyclic (i.e., the ring contains carbon and one or more heteroatoms). For example, in some embodiments, the bridged ring group has the following structure: [ka] It has one of the following. Unless stated otherwise specifically in the specification, fused ring groups are optionally substituted.

[0028] "Spiro" refers to any ring structure described herein having at least two rings with only one common atom. In some embodiments, the spiro ring group has the following structure: [ka] It has one of the following. Unless stated otherwise specifically in the specification, a spirocycle group is optionally substituted.

[0029] "Halo" refers to bromo, chloro, fluoro or iodo.

[0030] "Haloalkyl" refers to an alkyl group, as defined above, that is substituted with one or more halo groups, as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.

[0031] "Halocycloalkyl" refers to a cycloalkyl group, as defined above, that is substituted with one or more halo groups, as defined above, e.g., trifluorocyclopropyl, difluorocyclobutyl, trichlorocyclopentyl, 2,2,2-trifluorocyclohexyl, 1,2-difluorocyclopropyl, 3-bromo-2-fluorocyclopropyl, 1,2-dibromocyclopentyl, etc. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.

[0032] "Hydroxylalkyl" refers to an alkyl group, as defined above, substituted with one or more hydroxyl groups. The hydroxyalkyl group is attached to the backbone via an alkyl carbon atom. Unless otherwise specifically stated herein, the hydroxylalkyl group is optionally substituted.

[0033] "Alkylaminyl" refers to a group of the formula -NHR a or -NR a R a group, where each R a are independently an alkyl group, as defined above, containing 1 to 12 carbon atoms. A "haloalkylaminyl" group is an alkylaminyl group containing at least one halo substituent on the alkyl group. A "hydroxylalkylaminyl" group is an alkylaminyl group containing at least one hydroxyl substituent on the alkyl group. An "amidinylalkylaminyl" group is an alkylaminyl group containing at least one amidinyl substituent on the alkyl group. Unless specifically stated otherwise in the specification, alkylaminyl groups, haloalkylaminyl groups, hydroxylalkylaminyl groups and / or amidinylalkylaminyl groups are optionally substituted.

[0034] "Alkylaminylalkyl" refers to an alkyl group that contains at least one alkylaminyl substituent. The alkylaminyl substituent may be on a tertiary, secondary, or primary carbon. Unless otherwise specifically stated in the specification, alkylaminylalkyl groups are optionally substituted.

[0035] "Alkylcarbonyl" is a group of the formula -C(=O)R a refers to a group, wherein R a is an alkyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkylcarbonyl group is optionally substituted.

[0036] "Haloalkylcarbonyl" refers to a group of the formula -C(=O)R a refers to a group, wherein R a is a haloalkyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a haloalkylcarbonyl group is optionally substituted.

[0037] "Cycloalkylcarbonyl" refers to a group of the formula -C(=O)R a refers to a group, wherein R ais cycloalkyl as defined above. Unless stated otherwise specifically in the specification, a cycloalkylcarbonyl group is optionally substituted.

[0038] A "halocycloalkylaminyl" is a group of the formula -NR a R b refers to a group, wherein R a and R b are each independently H or C-C alkyl, and the others comprise halocycloalkyl groups as defined above. Unless otherwise specified, the C-C alkyl and / or halocycloalkyl portions of a halocycloalkylaminyl group are optionally substituted.

[0039] "Alkylcarbonylaminyl" refers to a group of the formula -NR a R b refers to a group, wherein R a is H or C1-C6 alkyl, and R b is an alkylcarbonyl group as defined above. Unless otherwise specified, the C1-C6 alkyl and / or alkylcarbonyl portion of the alkylcarbonylaminyl group is optionally substituted. In some embodiments, the alkylcarbonylaminyl has the following structure: [ka] It has one of the following.

[0040] "Haloalkylcarbonylaminyl" refers to a group of the formula -NR a R b refers to a group, wherein R a is H or C1-C6 alkyl, and R b is a haloalkylcarbonyl group as defined above. Unless otherwise specified, the C1-C6 alkyl and / or haloalkylcarbonyl portion of the haloalkylcarbonylaminyl group is optionally substituted.

[0041] "Cycloalkylcarbonylaminyl" refers to a group of the formula -NR a R b refers to a group, wherein R ais H or C1-C6 alkyl, and R b is a cycloalkylcarbonyl group as defined above. Unless otherwise specified, the C1-C6 alkyl and / or cycloalkylcarbonyl portion of a cycloalkylcarbonylaminyl group is optionally substituted.

[0042] "Heterocyclyl" refers to a 3- to 18-membered, e.g., 3- to 10-membered or 3- to 8-membered, non-aromatic ring group having 1 to 10 ring carbon atoms (e.g., 2 to 10) and 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless specifically stated otherwise in the specification, a heterocyclyl group is partially or fully saturated and can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can contain fused, spiro, and / or bridged rings. The nitrogen and sulfur atoms in the heterocyclyl group are optionally oxidized, and the nitrogen atom(s) can be optionally quaternized. Examples of such heterocyclyl groups include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro-1H-pyrrolidine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidin ... Heterocyclyl groups include, but are not limited to, azolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 2-oxaspiro[3.3]heptanyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, heterocyclyl groups are optionally substituted.

[0043] "Heterocyclylalkyl" refers to an alkyl group that contains at least one heterocyclyl substituent. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group is optionally substituted.

[0044] "Heteroaryl" refers to a 5- to 18-membered, e.g., 5- or 6-membered, ring group having 1 to 13 ring carbon atoms, 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. The heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may contain fused or bridged rings; the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; and the nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoi "Heteroarylene" refers to a divalent or polyvalent heteroaryl group, including, but not limited to, indolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). "Heteroarylene" refers to a divalent or polyvalent heteroaryl group. Unless stated otherwise specifically in the specification, heteroaryl and heteroarylene groups are optionally substituted.

[0045] As used herein, the term "substituted" refers to any of the above groups (e.g., alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxylalkyl) in which at least one hydrogen atom (e.g., 1, 2, 3, or all hydrogen atoms) has been replaced by a bond to a non-hydrogen substituent. Examples of non-hydrogen substituents include, but are not limited to, amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and / or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.

[0046] In some specific embodiments, the optional substituents are independently selected from the group consisting of halo, C-C alkyl, and C-C alkoxy. In other embodiments, the optional substituents are independently selected from the group consisting of amino, halo, hydroxyl, oxo, cyano, C-C alkyl, C-C haloalkyl, C-C hydroxylalkyl, C-C aminoalkyl, C-C alkylaminylalkyl, C-C alkoxy; C-C haloalkoxy, C-C alkylcarbonyl, C-C haloalkylcarbonyl, C-C alkylaminyl, C-C haloalkylaminyl, C-C alkylcarbonylaminyl, C-C haloalkylcarbonylaminyl, C-C cycloalkyl, C-C cycloalkylcarbonyl, C-C halocycloalkylaminyl, and C-C cycloalkylcarbonylaminyl. In some more specific embodiments, the optional substituents are independently selected from the group consisting of halo, cyano, C1-C6 alkyl, and C1-C6 haloalkyl.

[0047] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to achieve its intended use, including but not limited to, disease treatment as defined below. A therapeutically effective amount may vary depending on the intended treatment use (in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a specific response in target cells, such as a decrease in platelet adhesion and / or cell migration. Specific doses will vary depending on the particular compound selected, the administration regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system used.

[0048] As used herein, "treatment" or "treating" refers to an approach to obtain beneficial or desired results for a disease, disorder, or medical condition, including, but not limited to, therapeutic and / or preventive effects. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. Therapeutic benefit is also achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, even though the subject may still be suffering from the underlying disorder. A preventive effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof. In certain embodiments, for preventive benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject who reports one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0049] As used herein, the terms "co-administration," "administered in combination with," and grammatical equivalents include administering two or more agents to an animal, including a human, such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0050] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0051] A "pharmaceutically acceptable acid addition salt" refers to a salt that retains the biological effectiveness of the free base and is biologically acceptable or biologically suitable for administration to a subject. See generally SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition salts are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response. Pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as those derived from acids such as, for example, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, and glutaric acid. , 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.

[0052] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness of the free acid and is biologically acceptable or biologically suitable for administration to a subject. See generally SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable acid addition bases are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic reaction. Pharmaceutically acceptable base addition salts are prepared by adding the free acid to an inorganic or organic base. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0053] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (eg, methyl bromide).

[0054] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function of a target protein by inhibiting the activity or expression of a protein such as LRRK2. Thus, the terms "antagonist" and "inhibitor" are defined in relation to the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target, but compounds that inhibit the biological activity of a target protein by interacting with other members of a signal transduction pathway in which the target protein is a member are also specifically included within this definition. Preferred biological activities inhibited by antagonists are associated with tumor development, growth, or spread.

[0055] "Subject" refers to an animal, e.g., a mammal, e.g., a human. The methods described herein can be useful for both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

[0056] "Mammal" includes humans and both domestic animals, such as laboratory animals and pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals.

[0057] "Prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein (e.g., a compound of structure (I)). Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A description of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 (both of which are incorporated herein by reference in their entireties). The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved to the parent active compound by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy group, an amino group, or a thiol group is bonded to any group that is cleaved to form a free hydroxy group, a free amino group, or a free sulfhydryl group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of hydroxy functional groups, or acetamide, formamide and benzamide derivatives of amine functional groups in the active compounds.

[0058] The term "in vivo" refers to events that take place inside a subject's body.

[0059] The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of structure (I).

[0060] Certain embodiments are also meant to encompass in vivo metabolic products of the compounds of the present disclosure. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the present disclosure to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0061] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0062] In many cases, crystallization produces solvates of the compounds disclosed herein.As used herein, the term "solvate" refers to an aggregate comprising one or more compounds of the present disclosure and one or more solvent molecules.In some embodiments, the solvent is water, and in this case, the solvate is a hydrate.Alternatively, in other embodiments, the solvent is an organic solvent.Therefore, the compounds of the present disclosure can exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as corresponding solvated forms.In some embodiments, the compounds of the present disclosure are true solvates, while in other cases, the compounds of the present disclosure simply retain adventitious water or are a mixture of water and some adventitious solvent.

[0063] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted and unsubstituted aryl groups.

[0064] A "pharmaceutical composition" refers to a formulation of a compound of the present disclosure and a vehicle generally accepted in the art for delivering the compound of the present disclosure to a mammal, such as a human. Such a vehicle includes any pharmaceutically acceptable carrier, diluent, or excipient.

[0065] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, additive, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier.

[0066] "Stereoisomers" refer to compounds in which the same atoms are bonded by the same bonds but which have different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0067] The compounds of the present disclosure (i.e., compounds of structure (I)) or pharmaceutically acceptable salts thereof may contain one or more centers of geometric asymmetry and thus give rise to stereoisomers, e.g., enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- of amino acids. Accordingly, embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other center of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0068] Embodiments of the present disclosure include all types of rotamers and conformationally restricted states of the disclosed compounds. Atropisomers are stereoisomers that arise due to hindered rotation about a single bond and are included when the energy difference due to steric strain or other factors creates a sufficiently high barrier to rotation to allow isolation of individual conformers. As an example, certain compounds of the present disclosure may exist as a mixture of atropisomers or may be purified or enriched with respect to the presence of a single atropisomer.

[0069] In some embodiments, the compound of structure (I) is a mixture of enantiomers or diastereomers. In other embodiments, the compound of structure (I) is substantially one enantiomer or diastereomer.

[0070] "Tautomer" refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. Thus, embodiments include tautomers of the compounds of the present disclosure.

[0071] The chemical naming procedures and structural diagrams used herein are a modified form of the IUPAC nomenclature system, using the ACD / Name version 9.07 software program and / or the ChemDraw Professional version 17.0.0.206 software naming program (CambridgeSoft). For complex chemical names used herein, a substituent is typically named before the group to which it is attached. For example, cyclopropylethyl contains an ethyl backbone with a cyclopropyl substituent. Except as noted below, all bonds are identified in the chemical structural diagrams herein, except for all bonds on some carbon atoms, and are considered to be connected to sufficient hydrogen atoms to complete valence.

[0072] (compound) The present disclosure provides compounds, including pharmaceutically acceptable salts, stereoisomers and prodrugs thereof, that are capable of inhibiting LRRK2 kinase.

[0073] Thus, one embodiment is a compound having the following structure (I): [ka] (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: A is phenylene or 5- or 6-membered heteroarylene, each of which is optionally substituted with one or more substituents selected from halo, C1-C6 alkyl, and C1-C6 alkoxy; B is C3-C8 monocyclic cycloalkyl, C6-C 10 Spirocyclic cycloalkyl, C6-C 10 Fused Polycyclic Cycloalkyl, C6-C 10a bridged polycyclic cycloalkyl, a 3- to 8-membered monocyclic heterocyclyl, a 3- to 8-membered monocyclic heterocyclylalkyl, a 6- to 10-membered spirocyclic heterocyclyl, a 6- to 10-membered fused polycyclic heterocyclyl, or a 6- to 10-membered bridged polycyclic heterocyclyl, each of which is amino, halo, hydroxyl, oxo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxylalkyl, C1-C6 aminoalkyl, C1-C6 alkylaminylalkyl, C1-C6 alkoxy; or C1-C6 haloalkoxy optionally substituted with one or more substituents selected from C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, C1-C6 alkylaminyl, C1-C6 haloalkylaminyl, C1-C6 alkylcarbonylaminyl, C1-C6 haloalkylcarbonylaminyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylaminyl and C3-C8 cycloalkylcarbonylaminyl; L is a direct bond, CH or C=O; R 1a and R 1b are each independently H, halo, cyano, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C cycloalkyl; and R 2 is C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered spirocyclic heterocyclyl, 6- to 10-membered fused polycyclic heterocyclyl, or 6- to 10-membered bridged polycyclic heterocyclyl, each of which is optionally substituted with one or more substituents selected from halo, cyano, C1-C6 alkyl, and C1-C6 haloalkyl.

[0074] One embodiment has the following structure (I): [ka] (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: A is phenylene or 5- or 6-membered heteroarylene, each of which is optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl), and C-C alkoxy; B is C3-C8 monocyclic cycloalkyl, C6-C 10 Spirocyclic cycloalkyl, C6-C 10 Fused Polycyclic Cycloalkyl, C6-C 10 a bridged polycyclic cycloalkyl, a 3- to 8-membered monocyclic heterocyclyl, a 3- to 8-membered monocyclic heterocyclylalkyl, a 6- to 10-membered spirocyclic heterocyclyl, a 6- to 10-membered fused polycyclic heterocyclyl, or a 6- to 10-membered bridged polycyclic heterocyclyl, each of which is amino, halo, hydroxyl, oxo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxylalkyl, C1-C6 aminoalkyl, C1-C6 alkylaminylalkyl, C1-C6 alkoxy; or C1-C6 haloalkoxy optionally substituted with one or more substituents selected from C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, C1-C6 alkylaminyl, C1-C6 haloalkylaminyl, C1-C6 alkylcarbonylaminyl, C1-C6 haloalkylcarbonylaminyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylaminyl and C3-C8 cycloalkylcarbonylaminyl; L is a direct bond or C(R a R b ), where R a and R b are each independently hydrogen, C1-C6 alkyl (e.g., methyl), or R a and R b can be joined together with the carbons to which they are attached to form a C1-C6 cycloalkyl (e.g., cyclopropyl or cyclobutyl); R 1a and R 1bare each independently H, halo, cyano, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C cycloalkyl; and R 2 is C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered spirocyclic heterocyclyl, 6- to 10-membered fused polycyclic heterocyclyl, or 6- to 10-membered bridged polycyclic heterocyclyl, each of which is optionally substituted with one or more substituents selected from halo, cyano, C1-C6 alkyl, and C1-C6 haloalkyl.

[0075] One embodiment has the following structure (I): [ka] (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein: A is phenylene or 5- or 6-membered heteroarylene, each of which is optionally substituted with one or more substituents selected from halo, C-C alkyl, C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl), and C-C alkoxy; B is C3-C8 monocyclic cycloalkyl, C6-C 10 Spirocyclic cycloalkyl, C6-C 10 Fused Polycyclic Cycloalkyl, C6-C 10a bridged polycyclic cycloalkyl, a 3- to 8-membered monocyclic heterocyclyl, a 3- to 8-membered monocyclic heterocyclylalkyl, a 6- to 10-membered spirocyclic heterocyclyl, a 6- to 10-membered fused polycyclic heterocyclyl, or a 6- to 10-membered bridged polycyclic heterocyclyl, each of which is amino, halo, hydroxyl, oxo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxylalkyl, C1-C6 aminoalkyl, C1-C6 alkylaminylalkyl, C1-C6 alkoxy; or C1-C6 haloalkoxy optionally substituted with one or more substituents selected from C1-C6 alkylcarbonyl, C1-C6 haloalkylcarbonyl, C1-C6 alkylaminyl, C1-C6 haloalkylaminyl, C1-C6 alkylcarbonylaminyl, C1-C6 haloalkylcarbonylaminyl, C3-C8 cycloalkyl, C3-C8 cycloalkylcarbonyl, C3-C8 halocycloalkylaminyl and C3-C8 cycloalkylcarbonylaminyl; L is a direct bond or C(R a R b ), where R a and R b are each independently hydrogen, C1-C6 alkyl (e.g., methyl), or R a and R b can be joined together with the carbons to which they are attached to form a C3-C8 cycloalkyl (e.g., cyclopropyl or cyclobutyl); R 1a and R 1b are each independently H, halo, cyano, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C cycloalkyl; and R 2 is C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered spirocyclic heterocyclyl, 6- to 10-membered fused polycyclic heterocyclyl, or 6- to 10-membered bridged polycyclic heterocyclyl, each of which is optionally substituted with one or more substituents selected from halo, cyano, C1-C6 alkyl, hydroxyl, alkoxy, and C1-C6 haloalkyl.

[0076] In certain embodiments, A is phenylene. In some more specific embodiments, A is substituted phenylene. In certain more specific embodiments, A is phenylene substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkoxy, and combinations thereof. In some embodiments, A is phenylene substituted with one or more substituents selected from the group consisting of halo and C1-C6 alkoxy. In some embodiments, A is unsubstituted phenylene.

[0077] In other embodiments, A is a 5- or 6-membered heteroarylene. In more specific embodiments, A is pyridinylene or pyrazolylene. In certain embodiments, A is substituted with one or more substituents selected from halo, C-C alkyl, and C-C alkoxy. In some embodiments, A is monocyclic. In some embodiments, A is substituted with one or more substituents selected from halo, C-C alkyl, C-C cycloalkyl, and C-C alkoxy.

[0078] In some embodiments, B is a C3-C8 monocyclic cycloalkyl. In some embodiments, B is a 3-8 membered monocyclic heterocyclyl. In some embodiments, B is a 3-8 membered spirocyclic heterocyclyl. In some embodiments, B is a C3-C8 fused polycyclic cycloalkyl. In certain specific embodiments, B is a 3-8 membered monocyclic heterocyclylalkyl. In some embodiments, B is a C6-C 10 It is a spirocyclic cycloalkyl.

[0079] In further embodiments, B is substituted. In more specific embodiments, B is substituted with one or more substituents selected from the group consisting of amino, halo, hydroxyl, oxo, cyano, C-C alkyl, C-C haloalkyl, C-C hydroxylalkyl, C-C aminoalkyl, C-C alkylaminylalkyl, C-C alkoxy, C-C haloalkylcarbonyl, C-C alkylaminyl, C-C haloalkylaminyl, C-C alkylcarbonylaminyl, C-C haloalkylcarbonylaminyl, C-C cycloalkylcarbonylaminyl, C-C halocycloalkylaminyl, and combinations thereof. In some specific embodiments, B is unsubstituted.

[0080] In further embodiments, B is substituted. In more specific embodiments, B is substituted with one or more substituents selected from the group consisting of amino, halo, hydroxyl, oxo, cyano, C-C alkyl, C-C haloalkyl, C-C hydroxylalkyl, C-C aminoalkyl, C-C alkylaminylalkyl, C-C alkoxy, C-C haloalkylcarbonyl, C-C alkylaminyl, C-C haloalkylaminyl, C-C alkylcarbonylaminyl, C-C haloalkylcarbonylaminyl, C-C cycloalkylcarbonylaminyl, and C-C halocycloalkylaminyl.

[0081] In some more specific embodiments, B has the following structure: [ka] [ka] It has one of the following.

[0082] In some embodiments, B has the following structure: [ka] [ka] It has one of the following.

[0083] In some more specific embodiments, B has the following structure: [ka] [ka] It has one of the following.

[0084] In some embodiments, B has the following structure: [ka] [ka] It has one of the following.

[0085] In some embodiments, L is a direct bond. In certain other embodiments, L is CH. In some other embodiments, L is C=O.

[0086] In some embodiments, R 1a Or R 1b or both are selected from the group consisting of H, methyl, fluoro, chloro, cyano, methoxy, trifluoromethyl, and cyclopropyl. 1b is H and R 1a is fluoro or chloro. In some specific embodiments, R 1b is H and R 1a is cyclopropyl. In certain specific embodiments, R 1b is H and R 1a is methyl. In some more specific embodiments, R 1b is H and R 1a is cyano. In certain more specific embodiments, R1b is H and R 1a is H. In some specific embodiments, R 1b is H and R 1a is methoxy. In certain embodiments, R 1b is H and R 1a is trifluoromethyl. In some embodiments, R 1b is methyl and R 1a is fluoro or chloro. In certain embodiments, R 1b is chloro or fluoro, and R 1a is fluoro or chloro.

[0087] In some embodiments, R 2 is C1-C6 alkyl. In certain embodiments, R 2 is C-C cycloalkyl. In some specific embodiments, R 2 is a 3- to 8-membered heterocyclyl. In some embodiments, R 2 is a 6-10 membered spirocyclic heterocyclyl. In certain more specific embodiments, R 2 is a 6-10 membered fused polycyclic heterocyclyl. In some specific embodiments, R 2 is a 6- to 10-membered bridged polycyclic heterocyclyl.

[0088] In certain specific embodiments, R 2 is substituted. In some more specific embodiments, R 2 is substituted with one or more substituents selected from the group consisting of methyl, ethyl, iso-propyl, fluoro, trifluoromethyl, and cyano. In certain more specific embodiments, R 2 is non-substituted.

[0089] In some embodiments, [ka] has the following structure: [ka] It has one of the following.

[0090] In some embodiments, [ka] has the following structure: [ka] [ka] It has one of the following.

[0091] In certain embodiments, [ka] has the following structure: [ka] It has one of the following.

[0092] In certain embodiments, [ka] has the following structure: [ka] [ka] It has one of the following.

[0093] In various different embodiments, the compound has one of the structures shown in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. The compounds of Table 1 are prepared as described in the Examples or according to methods known in the art and analyzed by mass spectrometry and / or 1 It was analyzed by 1 H NMR spectroscopy.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

[0094] It is understood that combinations of substituents and / or variables of the depicted formulae herein are permissible only if such combinations result in stable compounds.

[0095] In further embodiments, various compounds of the present disclosure that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of the present disclosure can be converted to their free base or acid form by standard techniques.

[0096] Methods for preparing the compounds described herein are provided in the Examples below. Generally, starting materials may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or may be synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or may be prepared as described herein.

[0097] (Pharmaceutical composition) Other embodiments relate to pharmaceutical compositions. The pharmaceutical compositions comprise any one (or more) of the compounds described above and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In further embodiments, the pharmaceutical compositions comprise a compound disclosed herein and an additional therapeutic agent (e.g., an anti-cancer agent). Non-limiting examples of therapeutic agents are described below.

[0098] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration, and, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0099] In certain embodiments, the compounds described herein are administered locally rather than systemically, for example, by direct injection of the compound into organs, often in depot or sustained-release formulations.In certain embodiments, long-acting formulations are administered by implantation (for example, subcutaneously or intramuscularly) or intramuscular injection.In addition, in other embodiments, the compounds are delivered in targeted drug delivery systems, for example, liposomes coated with organ-specific antibodies.In such embodiments, the liposomes are targeted to organs and selectively taken up by organs.In still other embodiments, the compounds described herein are provided in the form of rapid-release formulations, sustained-release formulations, or intermediate-release formulations.In still other embodiments, the compounds described herein are administered locally.

[0100] In the treatment methods according to embodiments of the present disclosure, an effective amount of at least one compound of structure (I) is administered to a subject suffering from or diagnosed with such a disease, disorder, or medical condition. The effective amount or dose can be determined by methods such as modeling, dose escalation studies, or clinical trials, for example, by considering the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing treatments, the subject's health status and response to the drug, and the judgment of the treating physician.

[0101] The compounds of the present disclosure are effective over a wide dosage range. For example, for adult treatment, dosages of 10-5000 mg per day, 10 ...

[0102] In some embodiments, the compound of the present disclosure is administered in a single dose.Typically, such administration is carried out by injection, for example, intravenous injection, in order to rapidly introduce the drug.However, other routes can be used as needed.A single dose of the compound of the present disclosure can also be used to treat acute conditions.

[0103] In some embodiments, the compound of the present disclosure is administered in multiple doses. In some embodiments, administration is approximately once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is approximately once a month, once every two weeks, once a week, or once every two days. In another embodiment, the compound of the present disclosure and another agent (e.g., an anticancer agent) are administered together from about once a day to about six times a day. In another embodiment, administration of the compound of the present disclosure and the agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some instances, continuous administration is achieved and maintained as long as necessary.

[0104] The administration of the compound of the present disclosure can be continued as long as necessary. In some embodiments, the compound of the present disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compound of the present disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compound of the present disclosure is administered continuously and chronically, for example, to treat chronic effects.

[0105] In some embodiments, the compounds of the present disclosure are administered in individual dosage forms. It is known in the art that due to subject-to-subject variability in the pharmacokinetics of compounds, individualization of dosing regimens is necessary for proper treatment.

[0106] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions.In certain embodiments, pharmaceutical compositions are formulated by conventional methods using one or more physiologically acceptable carriers, including additives and auxiliary agents that facilitate the compound of the present disclosure to be processed into pharmaceutical preparations.Suitable formulations depend on the selected route of administration.Any pharmaceutically acceptable technology, carrier and additive can be used as suitable for formulating pharmaceutical compositions described herein:Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995);Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980;and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins1999).

[0107] Pharmaceutical compositions are provided that include one or more compounds of structure (I) and a pharmaceutically acceptable carrier.

[0108] Provided is a pharmaceutical composition comprising one or more compounds selected from the compound of structure (I) and pharmaceutically acceptable diluents, additives and carriers.In certain embodiments, the compound described herein is administered as a pharmaceutical composition, in which one or more compounds selected from the compound of structure (I) are mixed with other active ingredients, as in combination therapy.All combinations of active substances described in the following combination therapy section and throughout this disclosure are encompassed herein.In certain embodiments, the pharmaceutical composition comprises one or more compounds of structure (I).

[0109] In certain embodiments, pharmaceutical compositions of compounds of structure (I) inhibit LRRK2 kinase when administered to a patient or biological sample.

[0110] As used herein, a pharmaceutical composition refers to a mixture of one or more compounds selected from the compounds of structure (I) with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or additives. In certain embodiments, the pharmaceutical composition facilitates the administration of the compound to an organism. In some embodiments, a therapeutically effective amount of one or more compounds selected from the compounds of structure (I) provided herein is administered as a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In certain embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

[0111] In one embodiment, one or more compounds selected from the compounds of structure (I) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more compounds selected from the compounds of structure (I) are formulated for transdermal mucosal administration. In certain embodiments, transdermal mucosal formulations contain a penetrant suitable for penetrating the barrier. In yet other embodiments, when the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions contain physiologically compatible buffers and / or additives.

[0112] In another embodiment, the compound described herein is formulated for oral administration.The compound described herein is formulated by combining active compound with, for example, pharmaceutically acceptable carrier or additive.In various embodiments, the compound described herein is formulated as oral dosage form, including, for example, tablet, powder, pill, dragee, capsule, liquid, gel, syrup, elixir, slurry, suspension etc.

[0113] In certain embodiments, the pharmaceutical preparation for oral use is prepared by mixing one or more solid additives with one or more compounds as described herein, optionally grinding the mixture obtained, and then adding suitable auxiliary agent as needed, and then processing the mixture of granules to obtain tablet or dragee core.Suitable additives are, in particular, excipients, for example, sugars including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example: corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, crystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, for example: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.In certain embodiments, disintegrant is optionally added.Disintegrant includes, for example, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salt, for example, sodium alginate, for example.

[0114] In one embodiment, dosage forms such as sugar-coated tablet cores and tablets are provided with one or more suitable coatings.In certain embodiments, concentrated sugar solution is used to coat dosage forms.Sugar solution optionally contains additional components such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvent or solvent mixture, for example.Dyes and / or pigments are also optionally added to coating for identification purposes.Dyes and / or pigments are also optionally used to characterize the dosage of different combinations of active compounds.

[0115] In certain embodiments, a therapeutically effective amount of at least one compound described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In certain embodiments, the push-fit capsules contain the active ingredient mixed with one or more excipients. Excipients include, by way of example only, lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Stabilizers are also optionally added.

[0116] In yet other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In certain embodiments, the injection formulations are provided in unit dosage form (e.g., ampoules) or multi-dose containers. Preservatives are optionally added. In yet other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally contain formulating agents, such as suspending agents, stabilizers, and / or dispersing agents. In certain embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of water-soluble active compounds. In further embodiments, suspensions of one or more compounds selected from the compounds of structure (I) are prepared as suitable oily injection suspensions. Lipophilic solvents or vehicles suitable for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran.Optionally, the suspension contains suitable stabilizers or substances that increase the solubility of the compound, allowing the preparation of highly concentrated solutions.Alternatively, in other embodiments, the active ingredient is in powder form, which is to be reconstituted with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0117] Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and one or more compounds selected from the compounds of structure (I) described herein as an active ingredient. The active ingredient may be in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. The methods and pharmaceutical compositions described herein also encompass the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds described herein. The compounds described herein also encompass unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Solvated forms of the compounds described herein are also considered to be disclosed herein. Pharmaceutical compositions also optionally contain other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, solubility enhancers, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0118] Methods for preparing compositions containing the compounds described herein include combining the compounds with one or more inert pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid forms. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein may take the form of liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to use, or emulsions. These compositions may also optionally contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

[0119] In some embodiments, the pharmaceutical composition comprising one or more compounds selected from the compound of structure (I) is in the form of a liquid, for example, the drug is present in solution, suspension, or both.Typically, when the composition is administered as a suspension, the first part of the drug is present in solution, and the second part of the drug is present in the form of particles suspended in a liquid matrix.In some embodiments, the liquid composition comprises a gel formulation.In other embodiments, the liquid composition is aqueous.

[0120] In certain embodiments, aqueous suspension comprises one or more polymers as suspending agent.Polymer comprises water-soluble polymer, for example, cellulose polymer, for example, hydroxypropylmethylcellulose, and water-insoluble polymer, for example, cross-linked carboxyl-containing polymer.Some pharmaceutical compositions described herein comprise mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0121] The pharmaceutical composition also optionally includes a solubilizing agent to aid in the dissolution of one or more compounds selected from the compounds of structure (I). The term "solubilizing agent" generally includes substances that result in the formation of a micellar or true solution of the substance. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0122] In addition, the pharmaceutical composition optionally contains one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are present in amounts necessary to maintain the pH of the composition within an acceptable range.

[0123] The composition also optionally contains one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0124] Other pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0125] The composition may contain one or more surfactants to enhance physical stability or for other purposes.Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10 and octoxynol 40.

[0126] The compositions may optionally include one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium bisulfite.

[0127] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case a preservative is typically included in the composition.

[0128] In another embodiment, other delivery systems for hydrophobic pharmaceutical compounds are used.Liposomes and emulsions are examples of delivery vehicles or carriers useful herein.In certain embodiments, organic solvents, such as N-methylpyrrolidone, are also used.In further embodiments, the compounds described herein are delivered using sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agents.Various sustained-release materials are useful in the present invention.In some embodiments, sustained-release capsules release compounds for several weeks to up to more than 100 days.Depending on the chemical nature and biological stability of therapeutic agents, additional strategies for protein stabilization are adopted.

[0129] In certain embodiments, the formulations described herein contain one or more antioxidants, metal chelators, thiol-containing compounds, and / or other common stabilizers. Examples of stabilizers include: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v (g) 0.001% w / v to about 0.05% w / v of polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations, such as magnesium and zinc; or (n) combinations thereof.

[0130] In some embodiments, the concentration of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17 ... 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9 %,8.75%,8.50%,8.25%,8%,7.75%,7.50%,7.25%,7%,6.75%,6.50%,6.25%,6%,5.75%,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,125%,1%,0.5%,0.4%,0.3%,0.2%,0.1%, More than 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001%.

[0131] In some embodiments, the concentration of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about The ranges are 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, and about 1% to about 10%.

[0132] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical composition of the present disclosure is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, and is equal to or less than 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g.

[0133] In some embodiments, the amount of one or more compounds selected from the compounds of structure (I) provided in the pharmaceutical compositions of the present disclosure is within the range of 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0134] Packaging materials for use in packaging the pharmaceutical compositions described herein include, for example, those described in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. For example, a container contains one or more compounds described herein, optionally in a composition or in combination with another substance disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic injection needle). Such kits optionally contain the compound together with an identifying description or label or instructions for its use in the methods described herein.

[0135] For example, a kit typically includes one or more additional containers, each containing one or more of various materials (e.g., reagents, optionally in concentrated form, and / or devices) that are commercially and user-desirable for the use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels for carriers, packaging, containers, vials, and / or tubes that describe the contents and / or instructions for use, and package inserts containing instructions for use. Typically, a set of instructions is included. The label is optionally on or associated with the container. For example, a label is on the container when letters, numbers, or other characters forming the label are attached, molded, or engraved on the container itself, while a label is associated with the container when the label is present in a receptacle or carrier that holds the container, for example, as a package insert. The label is also used to indicate that the contents are to be used for a specific therapeutic application. Furthermore, the label indicates instructions for using the contents, for example, the methods described herein. In certain embodiments, the pharmaceutical composition is provided in a pack or dispenser device containing one or more unit dosage forms containing the compounds described herein. The pack may, for example, comprise metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device may be provided with instructions for administration. Alternatively, the pack or dispenser may be provided with a notice associated with the container in a format prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, and this notice reflects the approval by the agency of the drug form for administration to humans or animals. Such notice may, for example, be the prescription drug label approved by the U.S. Food and Drug Administration, or the approved product insert. In some embodiments, a composition comprising the compound provided herein formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for the treatment of a given condition.

[0136] (method) Embodiments of the present disclosure are useful as inhibitors of LRRK2 in a host species. The host or patient may belong to any mammalian species, such as a primate species, particularly humans; rodents, including mice, rats, and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are the subject of experimental studies and provide treatment models for human diseases.

[0137] Accordingly, some embodiments include methods of treating, preventing, or managing symptoms of a disease or disorder, wherein the disease or disorder is selected from a neurodegenerative disease, a central nervous system (CNS) disorder, cancer, an inflammatory disease, and combinations thereof.

[0138] In some embodiments, the disease or disorder is a neurodegenerative disease. For example, in some more specific embodiments, the neurodegenerative disease is Parkinson's disease or Lewy body dementia. In certain embodiments, the disease or disorder is a CNS disorder (e.g., Alzheimer's disease or L-DOPA-induced dyskinesia). In certain embodiments, the disease or disorder is cancer. In certain more specific embodiments, the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary carcinoma, lung cancer, acute myeloid leukemia or multiple myeloma. In some embodiments, the disease or disorder is an inflammatory disease. In some more specific embodiments, the inflammatory disease is leprosy, Crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.

[0139] Embodiments of the present disclosure also relate to the use of a compound according to structure (I) and / or a physiologically acceptable salt thereof for the prophylactic or therapeutic treatment and / or monitoring of a disease caused, mediated, and / or modulated by LRRK2 kinase activity. Furthermore, embodiments of the present disclosure relate to the use of a compound according to structure (I) and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the prophylactic or therapeutic treatment and / or monitoring of a disease caused, mediated, and / or modulated by LRRK2 kinase activity. In certain embodiments, the present disclosure provides the use of a compound according to structure I or a physiologically acceptable salt thereof for the manufacture of a medicament for the prophylactic or therapeutic treatment of an LRRK2-mediated disorder.

[0140] In another embodiment, the present disclosure relates to a method of treating an inflammatory disease or condition mediated by LRRK2 by administering to a patient in need thereof a therapeutically effective amount of a compound of structure (I).

[0141] Also included herein are methods of treatment in which at least one compound of structure (I) is administered in combination with an anti-inflammatory or therapeutic agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, nonspecific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants, and methotrexate. Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium, and hydroxychloroquine.

[0142] Examples of NSAIDs also include COX-2 specific inhibitors, such as celecoxib, valdecoxib, lumiracoxib and / or etoricoxib.

[0143] In some embodiments, the anti-inflammatory agent is a salicylate, including but not limited to acetylsalicylic acid or aspirin, sodium salicylate, choline salicylate, and magnesium salicylate.

[0144] The anti-inflammatory agent can also be a corticosteroid, for example, cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

[0145] In a further embodiment, the anti-inflammatory agent is a gold compound, such as gold sodium thiomalate or auranofin.

[0146] The present disclosure also includes embodiments in which the anti-inflammatory agent is a metabolic inhibitor, for example, a dihydrofolate reductase inhibitor such as methotrexate, or a dihydroorotate dehydrogenase inhibitor such as leflunomide.

[0147] Therapeutic agents also include drugs for pain or inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by biotransformation of selective hydrolysis products of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory drugs, analgesics, inhibitors of prostaglandin and thromboxane synthesis, inhibitors of inducible cyclooxygenase, and the like. These may include selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, beta-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0148] Other embodiments of the present disclosure relate to combinations in which at least one anti-inflammatory compound is an anti-monoclonal antibody (e.g., eculizumab or pexelizumab), a TNF antagonist (e.g., entanercept), or the anti-TNFα monoclonal antibody infliximab.

[0149] Yet other embodiments of the present disclosure relate to combinations wherein at least one active agent is an immunosuppressant compound, such as an immunosuppressant compound selected from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

[0150] In some embodiments, the pharmaceutical agent administered in combination with a compound described herein is any suitable drug that can be effectively delivered by inhalation, for example, an analgesic such as codeine, dihydromorphine, ergotamine, fentanyl, or morphine; an angina medication such as diltiazem; an antiallergic such as cromoglycate, ketotifen, or nedocromil; an anti-infective such as a cephalosporin, penicillin, streptomycin, sulfonamide, tetracycline, or pentamidine; an antihistamine such as methapyrilene; an anti-inflammatory such as beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone; an antitussive such as noscapine; a bronchodilator such as ephedrine, adrenaline, fenoterol, formoterol. , isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics such as amiloride; anticholinergics such as ipratropium, atropine or oxitropium; hormones such as cortisone, hydrocortisone or prednisolone; xanthines such as aminophylline, choline theophylline, lysine theophylline or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. It will be apparent to those skilled in the art that, where appropriate, drugs may be used in the form of a salt (e.g., as an alkali metal or amine salt, or as an acid addition salt) or ester (e.g., a lower alkyl ester) or solvate (e.g., a hydrate) to optimize the activity and / or stability of the drug.

[0151] The drugs disclosed herein or other suitable drugs are administered according to the condition to be treated.Therefore, in some embodiments, one or more compounds of the present disclosure are co-administered with the other drugs described above.When used in combination therapy, the compounds described herein are administered simultaneously with the second drug or separately.This combined administration can include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration.That is, the compounds described herein and any of the drugs described above can be formulated together in the same dosage form and administered simultaneously.Alternatively, the compounds disclosed herein and any of the drugs described above can be administered simultaneously, in which case both drugs are in separate formulations.In another option, the compounds disclosed herein can be administered immediately after any of the drugs described above, or vice versa.In some embodiments of separate administration protocols, the compounds disclosed herein and any of the drugs described above are administered within minutes, hours, or days.

[0152] In some embodiments, a compound of structure (I) is administered as a monotherapy.

[0153] The methods of the presently disclosed embodiments can be carried out either in vitro or in vivo. The sensitivity of a particular cell to treatment with a compound of structure (I) can be particularly determined by in vitro testing, either in the course of research or clinical application. Typically, a culture of cells is combined with various concentrations of the compound for a period of time sufficient for the active agent to inhibit LRRK2 kinase activity, usually from about 1 hour to 1 week. In vitro treatment can be performed using cultured cells from a biopsy sample or a cell line. In some embodiments, the IC of a compound of structure (I) to inhibit LRRK2 kinase is determined. 50 was determined by the concentration of compound required to inhibit 50% of LRRK2 activity.

[0154] The following examples and preparations further describe and illustrate the compounds of the present disclosure, and methods for preparing and testing such compounds. It should be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples and throughout the specification and claims, molecules with a single stereocenter exist as a racemic mixture unless otherwise specified. Those molecules with two or more stereocenters exist as a racemic mixture of diastereomers unless otherwise specified. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art. [Example]

[0155] The following examples are presented for illustrative purposes. For examples leading to compounds of structure (I), general synthetic schemes 1-12 are generally employed unless otherwise indicated.

[0156] The following general reaction scheme illustrates the reaction of a compound of structure (I): [ka] (I) 1 illustrates an exemplary method for preparing a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein A, B, R 1a , R 1b , R 2 and L are each as defined herein.

[0157] Any of the reaction schemes may be modified at any step to add and / or modify substituents as needed during any stage of the overall synthesis of the desired compound.

[0158] Those skilled in the art will also recognize that in the preparation of compounds described herein, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters. Protecting groups are known to those skilled in the art and are added or removed, as desired, according to standard techniques described herein. The use of protecting groups is explained in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As will be appreciated by those skilled in the art, the protecting group can be a polymer resin, such as a Wang resin, a Rink resin, or a 2-chlorotrityl-chloride resin.

[0159] It will also be understood by those skilled in the art that such protected derivatives of the disclosed compounds may not themselves have pharmacological activity, but may be administered to a mammal and then metabolized in the body to form a pharmacologically active compound of the disclosed compounds. Such derivatives may therefore be described as "prodrugs." Prodrugs of the disclosed compounds are included within the scope of embodiments of the present disclosure.

[0160] (General Procedure) All proton NMR experiments were recorded at 400 MHz on a Bruker NEO spectrometer equipped with a BBFO probe. Deuterated solvents contained less than 0.05% v / v of tetramethylsilane, which was used as the reference signal (set at 0.00 ppm). When the deuterated solvent did not contain tetramethylsilane, the peak of the remaining non-deuterated solvent was used as the reference signal according to published guidelines (J. Org. Chem. 1997, 62(21), 7512-7515). Chemical shifts are expressed in parts per million (ppm, δ units).

[0161] Coupling constants are in hertz (Hz). Splitting patterns describe the apparent multiplicity and are designated as broad singlet (bs), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), qt (quinplet), or brs (broad singlet).

[0162] LC / MS analysis was performed on an Agilent Technologies UHPLC 1290 Infinity II equipped with a G6125 MS detector.

[0163] Microwave reactions were carried out on a Monowave 300 from Anton Paar GmbH using standard protocols.

[0164] (abbreviation) °C (degrees Celsius); 1H NMR (proton nuclear magnetic resonance); ACN (acetonitrile); AcOH (acetic acid); BINAP (2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl); DCE (dichloroethane); DCM (dichloromethane); DFAA (difluoroacetic anhydride); DIPEA (N,N-diisopropylethylamine); DPPA (diphenylphosphoryl azide); EDC·HCl (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride); DMF (N,N-dimethylformamide); DMSO-d6 (deuterated dimethyl sulfoxide); eq (equivalent); EtOAc (ethyl acetate); g (gram); h (hour); HPLC (high performance liquid chromatography); LC-MS (liquid chromatography-mass spectrometry); MeOH (methanol); mg (milligram); min (minute); mL (milliliter); mmol (millimol); MsCl (methanesulfonyl chloride); Pd(dppf)Cl₂·DCM ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane); Pd(OAc)₂ (palladium(II) acetate); SFC (supercritical fluid chromatography); tBu (tert-butyl ether); tBuOH (tert-butanol); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); TLC (thin layer chromatography); TTIP (titanium(IV) isopropoxide).

[0165] (Production of synthetic intermediates)

[0166] [Table 2]

[0167] All dichloropyrimidine intermediates A are commercially available.

[0168] [Table 3-1] [Table 3-2]

[0169] All alcohol intermediates B are commercially available, with the following exceptions: Intermediate B5 was prepared as shown in PCT Publication WO2020 / 087024A1. Intermediate B8 was prepared as shown in PCT Publication WO2016 / 191312A1. Intermediate B9 was prepared as shown in PCT Publication WO2019 / 232053A1. Intermediate B12 was prepared as shown in J. Org. Chem. 2010, 75, 3, 929-932. Intermediate B13 was prepared as shown in PCT Publication WO2018 / 227067A1. Intermediate B15 was prepared as shown in PCT Publication WO2018 / 112382A1. Intermediate B36 was prepared as shown in PCT Publication US2016 / 0122318A1. Intermediate B43 was prepared as shown in Bioorg. Med. Chem. Lett. 2009, 19, 209-213. Intermediate B44 was prepared as shown in Bioorg. Med. Chem. Lett. 2010, 20, 1830-1833. Intermediate B47 was prepared as shown in PCT Publication WO2014 / 154794A1. Intermediates B16, B17, B18, B41, B45, B46, B48 and B49 were prepared as follows:

[0170] Intermediate B16 tert-Butyl (4-(hydroxymethyl)cuban-1-yl)carbamate

[0171] Step 1: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)cubane-1-carboxylate [ka] Triethylamine (0.572 g, 5.65 mol) and DPPA (0.960 g, 3.49 mmol) were added to a solution of 4-(methoxycarbonyl)cubane-1-carboxylic acid (0.600 g, 2.91 mmol) in tBuOH (4 mL), and the resulting mixture was stirred at 25 °C for 1 h and then heated to reflux for 16 h. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give a residue that was dissolved in EtOAc (15 mL), washed with saturated NaHCO (5 mL) and brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was purified by Isolera (silica gel 60-120 mesh, eluted with 20% EtOAc in petroleum ether) to give the title compound as a white solid (0.25 g, 29% yield). 1 H NMR (400 MHz, CDCl3)δ = 5.10(bs, 1H), 4.11-4.18(m, 6H), 3.73(s, 3H), 1.47(s, 9H). LCMS:222.1 [M+H-tBu].

[0172] Step 2: Synthesis of 4-((tert-butoxycarbonyl)amino)cubane-1-carboxylic acid [ka] A solution of NaOH (0.04 g, 0.992 mmol) in MeOH (3.4 mL) was added to a solution of methyl 4-((tert-butoxycarbonyl)amino)cubane-1-carboxylate (B17a, 0.25 g, 0.901 mmol) in THF (2.5 mL) at 0° C., and the resulting mixture was stirred at 55° C. for 4 h. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give a residue, which was taken up in ice water (5 mL), acidified (pH 3.0) with citric acid, and extracted with DCM (2×5 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound as an off-white solid (0.15 g, 62% yield). 1H NMR (400 MHz, DMSO-d6) δ = 12.18(bs, 1H), 7.72(bs, 1H), 3.94-3.97(m, 6H), 1.39(s, 9H). LCMS:208.1 [M+H-tBu].

[0173] Step 3: Synthesis of tert-butyl (4-(hydroxymethyl)cuban-1-yl)carbamate [ka] Borane-tetrahydrofuran complex (0.712 mL, 1.139 mmol) was added to a solution of 4-((tert-butoxycarbonyl)amino)cubane-1-carboxylic acid (0.150 g, 0.570 mmol) in THF (2.5 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to 0 °C, quenched with ice-water (5 mL), and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the title compound as an off-white solid (0.13 g, 91% yield). LCMS: 194.1 [M+H-tBu].

[0174] Intermediate B17 tert-Butyl (4-(hydroxymethyl)cycloheptyl)carbamate [ka] Borane-tetrahydrofuran complex (1 M in THF, 1.943 ml, 1.943 mmol) was added dropwise to a solution of 4-((tert-butoxycarbonyl)amino)cycloheptane-1-carboxylic acid (0.250 g, 0.972 mmol) in THF (4 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was quenched with methanol (10 mL), diluted with ice-water (15 mL), and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 45% EtOAc in petroleum ether) to give the title compound as a gum (0.20 g, 85% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 6.71(bs, 1H), 4.42(bs, 1H), 3.14(bs, 2H), 0.86-1.79(m, 21H). LCMS:188.1 [M+H-tBu].

[0175] Intermediate B18 tert-Butyl (4-(hydroxymethyl)-4-methylcyclohexyl)carbamate [ka] Borane-tetrahydrofuran complex (1 M in THF, 2.332 ml, 2.332 mmol) was added dropwise to a solution of 4-((tert-butoxycarbonyl)amino)-1-methylcyclohexane-1-carboxylic acid (0.30 g, 1.166 mmol) in THF (2.5 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was quenched with saturated NaHCO (10 mL) and extracted with EtOAc (2 × 25 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 50% EtOAc in petroleum ether) to give the title compound (0.18 g) as an off-white solid, which was used without further purification. LCMS: 144.2 [M+H-Boc].

[0176] Intermediate B41 4-(hydroxymethyl)cycloheptan-1-ol [ka] Lithium aluminum hydride (1 M in THF, 3.201 mL, 3.20 mmol) was added to a solution of 4-oxocycloheptane-1-carboxylic acid (0.500 g, 3.20 mmol) in THF (5 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to 0 °C, quenched with ice water (5 mL), and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the title compound as an off-white solid (0.07 g, 15% yield). LCMS: 145.1 [M+H].

[0177] Intermediate B45 (4-(trifluoromethoxy)cyclohexyl)methanol [ka] Borane-tetrahydrofuran complex (1 M in THF, 0.943 mL, 0.943 mmol) was added to a solution of 4-(trifluoromethoxy)cyclohexane-1-carboxylic acid (0.100 g, 0.471 mmol) in THF (3 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to 0 °C, quenched with ice water (5 mL), and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 20% EtOAc in petroleum ether) to give the title compound as a colorless gum (0.08 g, 86% yield). LCMS: 199.1 [M+H].

[0178] Intermediate B46 trans 4-(difluoromethoxy)cyclohexyl)methanol [ka] Borane-tetrahydrofuran complex (1 M in THF, 0.515 mL, 0.515 mmol) was added to a solution of (1R,4R)-4-(difluoromethoxy)cyclohexane-1-carboxylic acid (0.100 g, 0.515 mmol) in THF (3 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to 0 °C, quenched with ice water (5 mL), and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 15% EtOAc in petroleum ether) to give the title compound as a colorless gum (0.079 g, 85% yield). LCMS: 181.1 [M+H].

[0179] Intermediate B48 3-(Hydroxymethyl)thietane 1,1-dioxide [ka] OXONE®, a monopersulfated compound (0.590 g, 1.920 mmol), was added to a solution of thietan-3-ylmethanol (0.200 g, 1.920 mmol) in a 1:1 mixture of MeOH and water (2 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 16 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to 0° C., quenched with ice-water (5 mL), and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a colorless gum (0.060 g, 23% yield), which was used without further purification. LCMS: 137.1 [M+H].

[0180] Intermediate B49 3-(Hydroxymethyl)thietane 1,1-dioxide

[0181] Step 1: Synthesis of (1S,3R,4R)-3-fluoro-4-hydroxycyclohexane-1-carboxylic acid [ka] Lithium hydroxide monohydrate (0.106 g, 4.420 mmol) was added to a solution of ethyl (1S,3R,4R)-3-fluoro-4-hydroxycyclohexane-1-carboxylate (0.700 g, 3.680 mmol) in EtOH (7 mL) and water (1 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 3 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was evaporated under reduced pressure to give a residue, which was acidified to pH 2 with 1.5 N HCl and then extracted with EtOAc (2 × 5 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound as a colorless gum (0.370 g, 60% yield), which was used without further purification. LCMS: 184.3 [M+Na].

[0182] Step 2: Synthesis of (1R,2R,4S)-2-fluoro-4-(hydroxymethyl)cyclohexan-1-ol [ka] Borane-tetrahydrofuran complex (1 M in THF, 2.282 mL, 2.282 mmol) was added to a solution of (1S,3R,4R)-3-fluoro-4-hydroxycyclohexane-1-carboxylic acid (0.370 g, 2.282 mmol) in THF (6 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was cooled to 0 °C, quenched with ice water (5 mL), and extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound as a colorless gum (0.180 g, 43% yield), which was used without further purification. LCMS: 149.1 [M+H].

[0183] [Table 4-1] [Table 4-2]

[0184] All amine intermediates C are commercially available, with the following exceptions: Intermediate C5 was prepared as shown in PCT Publication WO2017 / 087905A1. Intermediate C8 was prepared as shown in PCT Publication WO2006 / 064189A1. Intermediate C10 was prepared as shown in J. Med. Chem. 2012, 55, 22, 9416-9433. Intermediate C19 was prepared as shown in PCT Publication WO2012 / 062783A1. Intermediates C22 and C24 were prepared as shown in PCT Publication WO2020 / 088390A1. Intermediate C26 was prepared as shown in PCT Publication WO2020 / 216371A1. Intermediate C28 was prepared as shown in J. Med. Chem. 2012, 55(22), 9416-9433. Intermediate C29 was prepared as shown in PCT Publication WO2020 / 070331A1. Intermediate C30 was prepared as shown in PCT Publication WO2019 / 121691A1. Intermediates C33 and C34 were prepared as shown in PCT Publication WO2019 / 112269A1. Intermediate C41 was prepared as shown in PCT publication CN110467615A1. Intermediate C45 was prepared as shown in PCT Publication WO2016 / 049211A1. Intermediate C47 was prepared as shown in PCT Publication WO2021 / 005222A1. Intermediates C6 and C7 were prepared according to the following synthetic scheme: [ka]

[0185] Intermediate C6 3-(4-amino-3-methyl-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

[0186] Step 1: Synthesis of methyl 3-((methylsulfonyl)oxy)cyclobutane-1-carboxylate: DIPEA (10.43 g, 81.0 mmol) and MsCl (5.03 ml, 64.5 mmol) were added to a solution of methyl 3-hydroxycyclobutane-1-carboxylate (7.00 g, 53.8 mmol) in DCM (70 mL) at 0° C., and the resulting mixture was stirred for 3 h at 25° C. After completion of the reaction (as indicated by TLC), the reaction mixture was diluted with DCM (100 mL), washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound as a brown solid (10.5 g, 94% yield), which was used without further purification. 1H NMR(400 MHz, CDCl3)δ = 4.91-4.98(m, 1H), 3.72(s, 3H), 3.02(s, 3H), 2.69-2.77(m, 2H), 2.55-2.64(m, 2H).

[0187] Step 2: Synthesis of methyl 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carboxylate Methyl 3-((methylsulfonyl)oxy)cyclobutane-1-carboxylate (11.80 g, 56.6 mmol) and CsCO (23.07 g, 70.8 mmol) were added to a solution of 3-methyl-4-nitro-1H-pyrazole (6.00 g, 47.2 mmol) in DMF (60 mL) at 25° C., and the resulting mixture was stirred at 80° C. for 16 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was poured onto crushed ice (500 g) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with water (3 × 100 mL) and brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material, which was purified by Isolera (silica gel 230-400 mesh, eluted with 40% EtOAc in petroleum ether) to give the title compound as an off-white solid (mixture of regioisomers, 6.5 g, 54% yield). 1 H NMR(400 MHz, CDCl3)δ = 8.14(s, 1H), 4.96-5.00(m, 1H), 3.74-3.78(m, 3H), 3.22-3.26(m, 1H), 2.87-3.02(m, 2H), 2.64-2.80(m, 2H), 2.55-2.57(m, 3H). LCMS:240.1 [M+H].

[0188] Step 3: Synthesis of 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid Lithium hydroxide monohydrate (1.301 g, 54.3 mmol) was added to a solution of methyl 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carboxylate (6.500 g, 27.2 mmol) in MeOH:water:THF (1:1:1, 150 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 16 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water (50 mL) and acidified to pH 2 with HCl (1.5 N). The resulting precipitate was filtered, washed with water (2×10 mL), and dried to give the title compound as an off-white solid (mixture of regioisomers, yield 4.2 g, 68%). 1 H NMR(400 MHz, DMSO-d6)δ = 12.45(bs, 1H), 8.91(s, 1H), 5.01-5.05(m, 1H), 3.07-3.14(m, 1H), 2.72-2.80(m, 2H), 2.46-2.69(m, 5H). LCMS:224.1 [MH].

[0189] Step 4: Synthesis of 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carboxamide Oxalyl chloride (1.127 ml, 12.88 mmol) and DMF (0.583 mL, 7.49 mmol) were slowly added to a stirred solution of 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid (2.900 g, 12.88 mmol) in DCM (35 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure to give a residue, which was taken up in THF (46.7 mL). Aqueous ammonia (25% in water, 58.5 mL, 2678 mmol) was slowly added at 0° C., and the resulting mixture was stirred at 25° C. for 16 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give a residue, which was cooled to 0° C. The resulting precipitate was filtered, washed with water (2 x 5 mL) and dried to give the title compound as an off-white solid (mixture of regioisomers, 2.7 g, 91% yield). LCMS: 225.1 [M+H].

[0190] Step 5: Synthesis of 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (C6a) and 3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (C7a) Phosphoryl chloride (13.90 mL, 149.0 mmol) was added to a solution of 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carboxamide (6.70 g, 29.9 mmol) in DCE (40 mL), and the resulting mixture was heated to reflux for 30 min. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give a residue which was slowly poured onto crushed ice and then neutralized with NaHCO. 、 Extraction with DCM (3 × 100 mL) was performed. The combined organic extracts were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material, which was purified by Isolera (silica gel 230-400 mesh, eluted with 20% EtOAc in petroleum ether) to give the title product as an off-white solid (mixture of regioisomers C7a and C8a, 5.4 g, 87% yield). 1 H NMR(400 MHz, CDCl3)δ = 8.15-8.16(m, 1H), 4.97-5.09(m, 1H), 3.36-3.42(m, 1H), 3.05-3.19(m, 2H), 2.87-2.96(m, 2H), 2.58-2.67(m, 3H). LCMS:207.1 [M+H].

[0191] 0.90 g of the mixture of regioisomers was purified by SFC (Chiralpak AS-H column, elution with 0.5% isopropylamine in IPA: 30% CO) to give 0.65 g of the major isomer (second eluting peak) and 0.25 g of the minor isomer (first eluting peak). 1 Based on the H NMR data (WO2017 / 218843A1), the first eluting peak was attributed to C7a and the second eluting peak to C6a. 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (C6a):1 H NMR(400 MHz, CDCl3)δ = 8.14(s, 1H), 4.98-5.03(m, 1H), 3.34-3.42(m, 1H), 3.04-3.14(m, 2H), 2.88-2.96(m, 2H), 2.58(s, 3H). LCMS:207.1 [M+H]. 3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (C7a): 1 H NMR(400 MHz, CDCl3)δ = 8.16(s, 1H), 5.06-5.08(m, 1H), 3.36-3.37(m, 1H), 3.10-3.13(m, 2H), 2.87-2.90(m, 2H), 2.67(s, 3H). LCMS:207.1 [M+H].

[0192] Step 6: Synthesis of 3-(4-amino-3-methyl-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile Iron powder (1.600 g, 29.10 mmol) and ammonium chloride (0.156 g, 2.91 mmol) were added to a suspension of 3-(3-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (C6a, 0.600 g, 2.91 mmol) in a mixture of ethanol (8 mL) and water (2 mL), and the resulting suspension was stirred at 90 °C for 3 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite (i.e., diatomaceous earth), which was then rinsed with EtOAc (10 mL). The combined filtrate was concentrated under reduced pressure to give the crude material, which was taken up in DCM (20 mL), washed with brine (2 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound (0.48 g), which was used without further purification. LCMS: 177.1 [M+H].

[0193] Intermediate C7 3-(4-amino-5-methyl-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile

[0194] Step 7: Synthesis of 3-(4-amino-3-methyl-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile Iron powder (0.680 g, 12.120 mmol) and ammonium chloride (0.065 g, 1.212 mmol) were added to a suspension of 3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (C7a, 0.250 g, 1.212 mmol) in a mixture of ethanol (4 mL) and water (1 mL), and the resulting suspension was stirred at 90 °C for 3 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite (i.e., diatomaceous earth), which was then rinsed with EtOAc (5 mL). The combined filtrate was concentrated under reduced pressure to give the crude material, which was taken up in DCM (10 mL), washed with brine (2 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound (0.16 g), which was used without further purification. LCMS: 177.1 [M+H].

[0195] Intermediate C35 1-Cyclopropyl-3-methyl-1H-pyrazol-4-amine

[0196] Step 1: Synthesis of 1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole [ka] Copper(II) acetate (0.286 g, 1.574 mmol), 2,2'-dipyridine (0.256 g, 1.574 mmol), and NaHCO (0.334 g, 3.15 mmol) were added to a stirred solution of 3-methyl-4-nitro-1H-pyrazole (0.200 g, 1.574 mmol) and cyclopropylboronic acid (0.270 g, 3.150 mmol) in dichloroethane (10 mL). The resulting mixture was stirred at 70 °C under an oxygen atmosphere for 12 h. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite (i.e., diatomaceous earth), which was then rinsed with DCM (2 × 20 mL). The combined filtrate was washed with water (20 mL) and brine (25 mL), and the organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 20% EtOAc in petroleum ether) to give the title compound as a colorless liquid (0.180 g, 68% yield). LCMS: 168.1 [M+H].

[0197] Step 2: Synthesis of 1-cyclopropyl-3-methyl-1H-pyrazol-4-amine [ka] Iron powder (0.334 g, 5.98 mmol) and NH4Cl (0.032 g, 0.598 mmol) were added to a suspension of 1-cyclopropyl-3-methyl-4-nitro-1H-pyrazole (0.100 g, 0.598 mmol) in a mixture of ethanol (4 mL) and water (1 mL), and the resulting suspension was stirred at 90 °C for 3 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite® (i.e., diatomaceous earth), which was then rinsed with EtOAc (5 mL). The combined filtrate was concentrated under reduced pressure to give a crude material, which was taken up in DCM (10 mL), washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.045 g), which was used without further purification. LCMS: 138.2 [M+H].

[0198] Intermediate C36 1-Cyclopropyl-3-methoxy-1H-pyrazol-4-amine

[0199] Step 1: Synthesis of 1-cyclopropyl-3-methoxy-4-nitro-1H-pyrazole [ka] Copper(II) acetate (0.508 g, 2.80 mmol), 2,2'-dipyridine (0.437 g, 2.80 mmol), and NaHCO (0.444 g, 4.19 mmol) were added to a stirred solution of 3-methoxy-4-nitro-1H-pyrazole (0.400 g, 2.80 mmol) and cyclopropylboronic acid (0.480 g, 5.59 mmol) in dichloroethane (20 mL). The resulting mixture was stirred at 70 °C under an oxygen atmosphere for 12 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite (i.e., diatomaceous earth), which was then rinsed with DCM (2 × 20 mL). The combined filtrate was washed with water (20 mL) and brine (25 mL), and the organic layer was separated, dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 20% EtOAc in petroleum ether) to give the title compound as a pale yellow solid (0.30 g, 58% yield). 1 H NMR(400 MHz, CDCl3)δ = 8.06(s, 1H), 4.06(s, 3H), 3.53-3.56(m, 1H), 1.10-1.18(m, 4H). LCMS:184.1 [M+H].

[0200] Step 2: Synthesis of 1-cyclopropyl-3-methoxy-1H-pyrazol-4-amine [ka] Iron powder (0.457 g, 8.190 mmol) and NH4Cl (0.438 g, 8.190 mmol) were added to a suspension of 1-cyclopropyl-3-methoxy-4-nitro-1H-pyrazole (0.300 g, 1.638 mmol) in a mixture of ethanol (4 mL) and water (1 mL), and the resulting suspension was stirred for 2 hours at 80° C. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite® (i.e., diatomaceous earth), which was then rinsed with EtOAc (5 mL). The combined filtrate was concentrated under reduced pressure to give a crude material which was taken up in DCM (10 mL), washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 50% EtOAc in petroleum ether) to give the title compound as a brown gum (0.170 g, 62% yield). LCMS: 154.2 [M+H].

[0201] Intermediate C43 4-(6-oxa-2-azaspiro[3.4]octan-2-yl)aniline

[0202] Step 1: Synthesis of 2-(4-nitrophenyl)-6-oxa-2-azaspiro[3.4]octane [ka] K2CO3 (0.366 g, 2.65 mmol) was added to a solution of 6-oxa-2-azaspiro[3.4]octane (0.200 g, 1.767 mmol) and 1-fluoro-4-nitrobenzene (0.188 mL, 1.767 mmol) in dry DMF (1 mL) at 25 °C, and the resulting mixture was subjected to microwave irradiation at 80 °C for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was poured into crushed ice (10 g) and extracted with EtOAc (5 mL × 3). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 15% EtOAc in petroleum ether) to give the title compound as a yellow solid (0.260 g, 63% yield). 1 H NMR (400 MHz, DMSO-d6)δ = 8.06(s, 1H), 4.06(s, 3H), 3.53-3.56(m, 1H), 1.10-1.18(m, 4H). LCMS:235.1 [M+H].

[0203] Step 2: Synthesis of 4-(6-oxa-2-azaspiro[3.4]octan-2-yl)aniline [ka] Pd / C (10% w / w, 0.020 g) was added to a solution of 2-(4-nitrophenyl)-6-oxa-2-azaspiro[3.4]octane (0.200 g, 0.854 mmol) in methanol (4 mL), and the resulting mixture was stirred at 25 °C under a H atmosphere (bag pressure) for 4 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite (i.e., diatomaceous earth), which was then rinsed with MeOH (5 mL). The combined filtrate was concentrated under reduced pressure to give the title compound (0.150 g, 86% yield), which was used without further purification. LCMS: 205.1 [M+H].

[0204] Intermediate C46 (R)-4-(3-methylmorpholino)aniline

[0205] Step 1: Synthesis of (R)-3-methyl-4-(4-nitrophenyl)morpholine [ka] K2CO3 (1.025 g, 7.41 mmol) was added to a solution of (R)-3-methylmorpholine (0.400 g, 4.94 mmol) and 1-fluoro-4-nitrobenzene (1.046, 7.41 mmol) in dry DMF (5 mL) at 25 °C, and the reaction mixture was subjected to microwave irradiation at 80 °C for 2 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was poured into crushed ice (50 g) and extracted with EtOAc (15 mL × 3). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was triturated with n-hexane (15 mL). The resulting solid was filtered, washed with n-hexane (2 × 5 mL), and dried under reduced pressure to give the title compound as a yellow solid (0.800 g, 60% yield). LCMS: 223.1 [M+H].

[0206] Step 2: Synthesis of (R)-4-(3-methylmorpholino)aniline [ka] Iron powder (0.503 g, 9.00 mmol) and NH4Cl (0.048 g, 0.900 mmol) were added to a suspension of (R)-3-methyl-4-(4-nitrophenyl)morpholine (0.200 g, 0.900 mmol) in a mixture of ethanol (8 mL) and water (2 mL), and the resulting suspension was stirred at 80°C for 2 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite® (i.e., diatomaceous earth), which was then rinsed with EtOAc (5 mL). The combined filtrates were concentrated under reduced pressure to give a residue that was taken up in DCM (10 mL), washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the title compound as an off-white solid (0.110 g, 64% yield). LCMS: 193.2 [M+H].

[0207] Intermediate C48 4-(2-(trifluoromethyl)morpholino)aniline

[0208] Step 1: Synthesis of 4-(4-nitrophenyl)-2-(trifluoromethyl)morpholine [ka] DIPEA (1.360 ml, 7.79 mmol) was added to a solution of 2-(trifluoromethyl)morpholine (0.400 g, 2.60 mmol) and 1-fluoro-4-nitrobenzene (0.366 g, 2.60 mmol) in dry DMF (4 mL) at 25° C., and the resulting mixture was stirred at 100° C. for 16 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was poured onto crushed ice (40 g). The resulting precipitate was filtered, washed with water (2×10 mL), and dried under reduced pressure to give the title compound as a yellow solid (0.500 g, 64% yield). LCMS: 277.1 [M+H]

[0209] Step 2: Synthesis of 4-(2-(trifluoromethyl)morpholino)aniline [ka] Pd / C (10% w / w, 0.025 g) was added to a solution of 4-(4-nitrophenyl)-2-(trifluoromethyl)morpholine (0.250 g, 0.905 mmol) in methanol (3 mL), and the resulting suspension was stirred at 25 °C under a H atmosphere (bag pressure) for 2 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite (i.e., diatomaceous earth), which was then rinsed with MeOH (5 mL). The combined filtrate was concentrated under reduced pressure to give the title compound (0.130 g, 59% yield), which was used without further purification. LCMS: 247.2 [M+H].

[0210] Intermediate C49 2-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile

[0211] Step 1: Synthesis of 2-methyl-2-(5-methyl-4-nitro-1H-pyrazol-1-yl)propanamide [ka] K2CO3 (1.086 g, 7.86 mmol) and 2-bromo-2-methylpropanamide (0.653 g, 3.93 mmol) were added to a stirred solution of 5-methyl-4-nitro-1H-pyrazole (0.500 g, 3.93 mmol) in dry DMF (5 mL), and the reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction (as indicated by TLC), the reaction mixture was poured onto crushed ice (50 g) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the title compound as a yellow gum (0.600 g, 50% yield). LCMS: 213.2 [M+H].

[0212] Step 2: Synthesis of 2-methyl-2-(5-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile POCl (3.11 mL, 33.400 mmol) was added to 2-methyl-2-(5-methyl-4-nitro-1H-pyrazol-1-yl)propanamide (0.50 g, 2.356 mmol) at 0 °C, and the resulting solution was stirred at 110 °C for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was concentrated under reduced pressure to give a crude material, which was taken up in EtOAc (10 mL) and neutralized with aqueous NaHCO (10%). The resulting aqueous layer was extracted with EtOAc (2 × 5 mL), and the combined organic extracts were dried over NaSO, filtered, and concentrated under reduced pressure to give a crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 15% EtOAc in petroleum ether) to give the title compound as a pale yellow gum (0.300 g, 66% yield). 1 H NMR(400 MHz, CD3OD)δ = 8.79(s, 1H), 2.55(s, 3H), 2.03(s, 6H). LCMS:195.1 [M+H].

[0213] Step 3: Synthesis of 2-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropanenitrile Iron powder (0.575 g, 10.30 mmol) and NH4Cl (0.551 g, 10.30 mmol) were added to a suspension of 2-methyl-2-(5-methyl-4-nitro-1H-pyrazol-1-yl)propanenitrile (0.200 g, 1.030 mmol) in a mixture of ethanol (4 mL) and water (1 mL), and the resulting suspension was stirred for 2 hours at 75° C. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite® (i.e., diatomaceous earth), which was then rinsed with EtOAc (5 mL). The combined filtrate was concentrated under reduced pressure to give the crude material, which was taken up in DCM (10 mL), washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the title compound as an off-white solid (0.084 g, 46% yield). 1 H NMR (400 MHz, CD3OD)δ = 7.34(s, 1H), 2.19(s, 3H), 1.93(s, 6H). LCMS:165.2 [M+H].

[0214] (Production of Examples)

[0215] General synthetic scheme 1 for synthesizing Examples 1-16: [ka] In the formula, R 1a , R 1b , R 2 , A and L are each as defined herein, and n is 0 or 1.

[0216] Step 1: General procedure GP1 for the synthesis of intermediate D: A solution of alcohol intermediate B (1.0 eq) in DMF was added to a stirred suspension of NaH (60% in mineral oil, 1.2 eq) in DMF at 0° C., and the resulting mixture was stirred at 25° C. for 10 minutes. A solution of dichloropyrimidine intermediate A (1.0 eq) in DMF was then added, and the resulting mixture was stirred at 25° C. until the reaction was complete (as indicated by TLC). The reaction mixture was then quenched with saturated NH4Cl and diluted with EtOAc. The layers were separated, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography to give the desired intermediate D.

[0217] Step 2: General procedure GP2 for the synthesis of intermediate E (Buchwald-Hartwig coupling): CsCO (2.0 eq) was added to a stirred solution of Intermediate D (1.0 eq) and amine Intermediate C (1.0 eq) in dioxane, and the resulting mixture was purged with N for 10 minutes. BINAP (0.2 eq) and Pd(OAc) (0.1 eq) were then added, and the reaction mixture was subjected to microwave irradiation at 100 °C for 2 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite (i.e., diatomaceous earth), and the filtrate was concentrated under reduced pressure to give the crude material, which was purified by flash chromatography to give the desired Intermediate E.

[0218] Step 3: General procedure GP3 for the synthesis of Examples 1-16 (Boc deprotection): TFA (5 vol) was added to a solution of Intermediate E (1 eq) in dry DCM at 0° C., and the resulting mixture was stirred at 25° C. until completion (as indicated by TLC). The reaction mixture was then concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give the desired Examples 1-16.

[0219] The following examples were synthesized according to general synthetic scheme 1: [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0220] General synthetic scheme 2 for synthesizing Examples 17-30, 95-96 and 163-177: [ka] In the formula, R P is C(O)OtBu (Examples 17-28, 163-171) or C(O)CF3 (Examples 29-30) or C(O)CH3 (Examples 95-96, 172-177).

[0221] Step 1: Synthesis of intermediate F: Intermediate F was synthesized according to general procedure GP1 above.

[0222] Step 2: Synthesis of Intermediate G (including Examples 95-96 and 172-177): Intermediate G (including Examples 95-96 and 172-177, wherein R p is C(O)CH3) were synthesized according to general procedure GP2 above. For examples 95-96 and 172-177, the crude material was purified by preparative HPLC.

[0223] Step 3: Synthesis of Examples 17-28 and 163-171: Examples 17-28 and 163-171 were synthesized according to general procedure GP3 above.

[0224] Step 4: Synthesis of Examples 29-30: Examples 29 to 30 (wherein R p is C(O)CF3) were synthesized according to general procedure GP2 described above. The trifluoroacetamide protecting group was found to be unstable under Buchwald-Hartwig coupling conditions, and the desired examples 29-30 (which were purified by preparative HPLC) were obtained without a dedicated deprotection step.

[0225] The following examples were synthesized according to general synthetic scheme 2: [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8]

[0226] General Synthetic Scheme 3 for the Synthesis of Examples 31-55 [ka] In the formula, n is 0 or 1.

[0227] Step 1: Synthesis of intermediate H: A solution of the Boc-protected amine (Intermediate D, 1.0 eq) in DMF was added to a stirred suspension of NaH (60% in mineral oil, 2.0 eq) in DMF at 0° C., and the resulting mixture was stirred at 25° C. for 10 minutes. Iodomethane (2.0 eq) was then added, and the resulting mixture was stirred at 25° C. until the reaction was complete (as indicated by TLC). The reaction mixture was then quenched with saturated NH4Cl and diluted with EtOAc. The layers were separated, and the organic layer was washed with water and brine. The layers were separated, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography to give the desired Intermediate H.

[0228] Step 2: Synthesis of Intermediate I: Intermediate I was synthesized according to general procedure GP2 above.

[0229] Step 3: Synthesis of Examples 31-54: Examples 31-54 were synthesized according to general procedure GP3 above.

[0230] Step 4: Synthesis of Example 55: Formaldehyde (37% in water, 2.0 eq), AcOH (0.2 eq), and MP-cyanoborohydride resin (2.5 eq) were added to a solution of 5-methoxy-4-(((1R,4R)-4-(methylamino)cyclohexyl)methoxy)-N-(4-morpholinophenyl)pyrimidin-2-amine (Example 35, 1.0 eq) in MeOH at 0° C., and the resulting mixture was stirred at 25° C. for 16 h. After completion of the reaction (as indicated by LCMS), the reaction mixture was filtered through a pad of Celite® (i.e., diatomaceous earth), which was rinsed with MeOH (2×5 mL). The combined filtrates were concentrated under reduced pressure to give the crude material, which was purified by preparative HPLC to give Example 55 as an off-white solid.

[0231] The following examples were synthesized according to general synthetic scheme 3: [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8]

[0232] General Synthetic Scheme 4 for the Synthesis of Examples 56-70 [ka]

[0233] Step 1: Synthesis of Intermediate J Intermediate J was synthesized according to general procedure GP3 above. The crude material was purified by flash chromatography.

[0234] Step 2: Synthesis of Examples 56 to 70 Formaldehyde (37% in water, 2.0 eq), AcOH (0.2 eq), and NaBH (1.5 eq) were added to a solution of amine intermediate J (1.0 eq) in DCM at 0° C., and the resulting mixture was stirred at 45° C. until reaction completion (as indicated by LCMS). The reaction mixture was then cooled to 0° C., quenched with ice-water, and extracted with DCM (2×50). The combined organic extracts were dried over NaSO, filtered, and concentrated under reduced pressure to give crude material, which was purified by preparative HPLC to give the desired Examples 56–70.

[0235] The following examples were synthesized according to general synthetic scheme 4: [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0236] General Synthetic Scheme 5 for the Synthesis of Examples 71-94 and 178-208 [ka] where R is C(cPr)(Me).

[0237] Step 1: Synthesis of Intermediate E: Intermediate E was synthesized according to general procedure GP2 above.

[0238] Step 2: Synthesis of Example 71 Boc deprotection of tert-butyl ((1R,4R)-4-(((2-((4-morpholinophenyl)amino)pyrimidin-4-yl)oxy)methyl)cyclohexyl)carbamate was carried out according to general procedure GP3 above to give 4-(((1R,4R)-4-aminocyclohexyl)methoxy)-N-(4-morpholinophenyl)pyrimidin-2-amine (Example 2, 1.0 eq), which was dissolved in DCM (10 volumes) containing 1-methylcyclopropane-1-carboxylic acid (1.0 eq). HOBt (1.2 eq) and EDC·HCl (1.5 eq) were added, and the resulting mixture was stirred at 25 °C for 16 h. After completion of the reaction (as indicated by LCMS), the reaction mixture was diluted with DCM (10 mL), washed with aqueous NaHCO (2 mL) and brine (2 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was purified by preparative HPLC to afford Example 71 as a pale yellow solid.

[0239] Step 3: Synthesis of intermediate K: Intermediate K was synthesized according to general procedure GP3 above. The crude material was purified by flash chromatography.

[0240] Step 4: General procedure GP4 for the synthesis of intermediate L (acetamide formation): Triethylamine (3.0 eq) and acetic anhydride (1.5 eq) were added to a solution of amine intermediate K (1.0 eq) in DCM (10 vol) at 0°C, and the resulting mixture was stirred at 0°C for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was quenched with ice water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh) to give the desired intermediate L.

[0241] Step 5: Synthesis of Examples 72-89 and 178-208: Examples 72-89 and 178-208 were synthesized according to general procedure GP2 above; the crude material was purified by preparative HPLC.

[0242] The following examples were synthesized according to general synthetic scheme 5: [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10] [Table 9-11] [Table 9-12] [Table 9-13] [Table 9-14] [Table 9-15]

[0243] Synthetic Scheme 6 for the Synthesis of Example 97 [ka]

[0244] Step 1: Synthesis of intermediate M: Intermediate M was synthesized according to general procedure GP1 above.

[0245] Step 2: Synthesis of intermediate N: Intermediate N was synthesized according to general procedure GP3 above. The crude material was purified by flash chromatography.

[0246] Step 3: Synthesis of intermediate O: Intermediate O was synthesized according to general procedure GP4 above.

[0247] Step 4: Synthesis of Example 97 1-(6-(((2-((4-((2S,6R)-2,6-dimethylmorpholino)phenyl)amino)-5-fluoropyrimidin-4-yl)oxy)methyl)-2-azaspiro[3.3]heptan-2-yl)ethan-1-one (Example 97) was synthesized according to general procedure GP2 above and purified by preparative HPLC. 1 H NMR(400 MHz, CD3OD)δ = δ 8.11(d, J = 2.0 Hz, 1H), 7.72(d, J = 8.8 Hz, 2H), 7.34-7.37(m, 2H), 4.43-4.44(m, 2H), 4.25(s, 1H), 4.17(s, 1H), 3.93-4.01(m, 4H), 3.56-3.59(m, 2H), 2.88-2.95(m, 2H), 2.72-2.75(m, 1H), 2.42-2.47(m, 2H), 2.14-2.40(m, 2H), 1.85-1.86(m, 3H), 1.24-1.29(m, 6H). LCMS:470.2 [M+H]

[0248] General synthetic scheme 7 for synthesizing examples 98-108 and 209-213: [ka] In the formula, R F is CF3 or CHF2.

[0249] Step 1: Synthesis of intermediate P: Intermediate P is reacted with acetic anhydride and trifluoroacetic anhydride (R F is CF3) or difluoroacetic anhydride (R F The compound was synthesized according to the modified general procedure GP4 above, where CHF2 was substituted.

[0250] Step 2: Synthesis of Intermediate Q (including Examples 98-102 and 209-213): Intermediate Q (including Examples 98-102 and 209-213) was synthesized according to general procedure GP2 described above. For Examples 98-102 and 209-213, the crude material was purified by preparative HPLC.

[0251] Step 3: General procedure GP5 (amide reduction) for the synthesis of examples 103-108: Borane-tetrahydrofuran complex (1 M in THF, 1.0 eq) was added dropwise to a solution of the amide (Examples 98-102, 1.0 eq) in THF (10 volumes) at 0° C., and the resulting mixture was stirred at 25° C. for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was quenched with saturated NH4Cl and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude materials, which were purified by preparative HPLC to give Examples 99-106.

[0252] The following examples were synthesized according to general synthetic scheme 7: [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5]

[0253] General Synthetic Scheme 8 for the Synthesis of Examples 109-114 [ka] In the formula, R F is CF3 or CHF2.

[0254] Step 1: Synthesis of intermediate R: Intermediate R was synthesized according to general procedure GP3 above. The crude material was purified by flash chromatography.

[0255] Step 2: Synthesis of intermediate S: Intermediate S was synthesized according to a modified general procedure GP4 above, where acetic anhydride was replaced with trifluoroacetic anhydride (R F is CF3) or difluoroacetic anhydride (R F is CHF2).

[0256] Step 3: Synthesis of Examples 109-112: Examples 109-112 were synthesized according to general procedure GP2 above. The crude material was purified by preparative HPLC.

[0257] Step 4: Synthesis of Examples 113-114: Examples 113-114 were synthesized according to general procedure GP5 above.

[0258] The following examples were synthesized according to general synthetic scheme 8: [Table 11-1] [Table 11-2]

[0259] General Synthetic Scheme 9 for the Synthesis of Examples 115-116 [ka]

[0260] Step 1: Synthesis of Examples 115 and 116: 1,1,1-Trifluoropropan-2-one (1.5 eq) was added to a solution of the amine (Examples 2 and 10, 1.0 eq) in MeOH (10 volumes), and the resulting mixture was stirred at 25° C. for 2 hours. MP-cyanoborohydride resin (1.0 eq) was then added, and the reaction mixture was stirred at 60° C. for 48 hours. After completion of the reaction (as indicated by LCMS), the reaction mixture was filtered through a pad of Celite® (i.e., diatomaceous earth), which was then washed with MeOH (2×5 mL). The combined filtrate was concentrated under reduced pressure to give crude material, which was purified by preparative HPLC to give Examples 115-116 as pale yellow solids.

[0261] The following examples were synthesized according to general synthetic scheme 9: [Table 12]

[0262] General synthetic scheme 10 for synthesizing examples 117-144 and 214-264: [ka] In the formula, R a is H or CH3, and R b is CF3 or a bridged alkyl linking two carbons of the ring, and n is 0 or 1.

[0263] Step 1: General procedure GP6 for the synthesis of intermediate T: Alcohol intermediate B (1.2 eq) and K2CO3 (2.0 eq) were added to a solution of dichloropyrimidine intermediate A (1.0 eq) in ACN (10 vol), and the resulting mixture was stirred at 85 °C for 18 h. After completion of the reaction (as indicated by TLC), the reaction mixture was quenched with ice-water and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 15% EtOAc in petroleum) to give the desired intermediate T.

[0264] Step 2: General procedure GP7 for the synthesis of intermediate U: NaBH (1.5 eq) was added portionwise to a solution of intermediate T (1.0 eq) in MeOH (5 vol) at 0 °C, and the mixture was stirred at 25 °C for 2 h. After completion of the reaction (as indicated by TLC), the reaction mixture was quenched with saturated NH Cl and extracted twice with DCM. The combined organic extracts were dried over Na SO , filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 30% EtOAc in petroleum ether) to give the desired intermediate U.

[0265] Step 3: Synthesis of Examples 117-134 and 214-250: Examples 117-134 and 214-250 were synthesized according to general procedure GP2 above. The crude material was purified by preparative HPLC.

[0266] Step 4: Synthesis of 4-(((2,5-dichloropyrimidin-4-yl)oxy)methyl)-1-methylcyclohexan-1-ol (Intermediate V): Methylmagnesium chloride (3 M in THF, 1.56 mL, 4.68 mmol) was slowly added to a solution of 4-(((2,5-dichloropyrimidin-4-yl)oxy)methyl)cyclohexan-1-one (0.20 g, 0.73 mmol) in tetrahydrofuran (5 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 2 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was quenched with water (2 mL), filtered to remove insoluble material, and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material, which was purified by flash chromatography (silica gel 230-400 mesh, eluted with 25% EtOAc in petroleum ether) to give the title compound (Intermediate V, 100 mg, 50% yield) as a colorless gum. LCMS: 277.2 [M+H].

[0267] Step 5: Synthesis of Examples 135 and 251-253 Examples 135 and 251-253 were synthesized according to general procedure GP2 above and purified by preparative HPLC.

[0268] Step 6: Synthesis of intermediate W: Intermediate W was synthesized according to general procedure GP1 above.

[0269] Step 7: Synthesis of Examples 136-144 and 254-264: Examples 136-144 and 254-264 were synthesized according to general procedure GP2 above. The crude material was purified by preparative HPLC.

[0270] The following examples were synthesized according to general synthetic scheme 10: [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8] [Table 13-9] [Table 13-10] [Table 13-11] [Table 13-12] [Table 13-13] [Table 13-14] [Table 13-15] [Table 13-16] [Table 13-17] [Table 13-18] [Table 13-19] [Table 13-20] [Table 13-21]

[0271] General synthetic scheme 11 for synthesizing Examples 265-267: [ka]

[0272] Step 1: Synthesis of intermediate X: Intermediate X was synthesized according to general procedure GP2 above.

[0273] Step 2: Synthesis of intermediate Y: Cs2CO3 (3.0 eq) was added to a stirred solution of intermediate X (1.0 eq) and trimethylboroxine (50% in THF, 2.0 eq) in THF, and the resulting mixture was purged with N2 for 10 minutes. Pd(dppf)Cl2·DCM (0.1 eq) was then added, and the resulting mixture was stirred in a sealed tube at 70 °C for 7 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite® (i.e., diatomaceous earth), which was then rinsed with THF. The combined filtrate was concentrated under reduced pressure to give the crude material, which was purified by flash chromatography to give the desired intermediate Y.

[0274] Step 1: Synthesis of Examples 265-267: Examples 265-267 were synthesized according to general procedure GP7 above; the crude material was purified by preparative HPLC.

[0275] The following examples were synthesized according to general synthetic scheme 11: [Table 14]

[0276] General synthetic scheme 12 for synthesizing Examples 145-146: [ka]

[0277] Step 1: Synthesis of 4-(((2,5-dichloropyrimidin-4-yl)oxy)methyl)-N-(3,3-difluorocyclobutyl)cyclohexan-1-amine: Titanium(IV) isopropoxide (TTIP, 0.639 mL, 2.181 mmol) was added to a suspension of 4-(((2,5-dichloropyrimidin-4-yl)oxy)methyl)cyclohexan-1-one (Intermediate T, 0.150 g, 0.545 mmol) and 3,3-difluorocyclobutan-1-amine (0.070 g, 0.654 mmol) in a mixture of THF (10 mL), DCM (3 mL), and DMF (1 mL), and the resulting mixture was stirred at 25° C. for 16 hours and heated at 55° C. for 16 hours. The reaction mixture was then cooled to 0° C., and sodium cyanoborohydride (0.051 g, 0.818 mmol) was added at 0° C., and the reaction mixture was stirred at 25° C. for an additional 16 hours. After completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of Celite® (i.e., diatomaceous earth), which was then washed with EtOAc (15 mL). The combined filtrate was concentrated under reduced pressure to give a residue, which was dissolved in DCM (20 mL), washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material, which was used without further purification. LCMS: 365.9 [M+H].

[0278] Step 2: Synthesis of Examples 145-146 Examples 145-146 were synthesized according to general procedure GP2 above. The crude material was purified by preparative HPLC.

[0279] The following examples were synthesized according to general synthetic scheme 12: [Table 15]

[0280] General Synthetic Scheme 13 for the Synthesis of Examples 147-162 [ka] In the formula, B 1 is the subset of B consisting of cycloalkyl and heterocycloalkyl groups.

[0281] Step 1: Synthesis of intermediate Z: Intermediate Z was synthesized according to general procedure GP1 above.

[0282] Step 2: Synthesis of Examples 147-162 and 268-291: Examples 147-162 and 268-291 were synthesized according to general procedure GP2 above. The crude material was purified by preparative HPLC.

[0283] The following examples were synthesized according to general synthetic scheme 13: [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5] [Table 16-6] [Table 16-7] [Table 16-8] [Table 16-9] [Table 16-10] [Table 16-11] [Table 16-12]

[0284] (Enzyme Assay) LRRK2 enzyme assay LRRKtide substrate (peptide sequence RLGRDKYKTLRQIRQ, derived from human ezrin [amino acids 561-573], moesin [amino acids 539-553], and radixin [amino acids 558-570], obtained from Signal Chem, catalog number L10-58, reconstituted in 20 mM Tris-HCl, pH 7.5, to a final concentration of 1 mg / mL, assay concentration 20 μM) and recombinant human LRRK2 (catalytic domain only [amino acids 970-2527], GST-tagged, expressed in insect cells, obtained from Thermo Fisher Scientific, catalog number PV4874, 0.35 mg / mL, assay concentration 30 nM) were diluted in assay buffer (20 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg / mL BSA, 0.1 mM Na3VO4, 2 mM The compounds of interest (serial 3-fold dilutions from 10 μM to 0.5 nM in DMSO) or control (1% DMSO) were dispensed into the kinase reaction mixture using Acoustic technology (Echo550; nanoliter range). After 20 minutes of incubation at room temperature, the kinase reaction was [ 32 The reaction was initiated by the addition of [P]-ATP (specific activity 10 μCi / μl), and the mixture was incubated for 2 hours at room temperature. The reaction was then stopped by spotting the reaction mixture onto a strip of phosphocellulose P81 paper. After washing, the radioactivity of the P81 paper was measured, and kinase activity data were expressed as a percentage of the remaining kinase activity in the test sample compared to the vehicle (dimethyl sulfoxide) reaction. IC 50 Values ​​and curve fits were obtained using Prism (GraphPad Software). [Table 17-1] [Table 17-2]

[0285] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referenced herein and / or listed in Application Data Sheets, including U.S. Provisional Patent Application No. 63 / 164,804, filed March 23, 2021, are incorporated herein by reference in their entirety. Aspects of the embodiments can be modified, as necessary, to employ concepts from various patents, applications, and publications to provide further embodiments.

[0286] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by this disclosure.

Claims

1. The following structure (I): 【Chemistry 1】 (I) [In the formula, A is phenylene or 5- or 6-membered heteroarylene, each of which is halo, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl and C 1 -C 6 optionally substituted with one or more substituents selected from alkoxy; B is C 3 -C 8 Monocyclic cycloalkyl, C 6 -C 10 Spirocyclic cycloalkyl, C 6 -C 10 Fused polycyclic cycloalkyl, C 6 -C 10 bridged polycyclic cycloalkyl, 3- to 8-membered monocyclic heterocyclyl, 3- to 8-membered monocyclic heterocyclylalkyl, 6- to 10-membered spirocyclic heterocyclyl, 6- to 10-membered fused polycyclic heterocyclyl or 6- to 10-membered bridged polycyclic heterocyclyl, each of which is selected from the group consisting of amino, halo, hydroxyl, oxo, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyl alkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Alkylaminylalkyl, C 1 -C 6 Alkoxy; C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkyl carbonyl, C 1 -C 6 Haloalkylcarbonyl, C 1 -C 6 Alkylaminyl, C 1 -C 6 Haloalkylaminyl, C 1 -C 6 Alkylcarbonylaminyl, C 1 -C 6 Haloalkylcarbonylaminyl, C 3 -C 8 Cycloalkyl, C 3 -C 8 Cycloalkylcarbonyl, C 3 -C 8 Halocycloalkylaminyl and C 3 -C 8 optionally substituted with one or more substituents selected from cycloalkylcarbonylaminyl; L is a direct bond, CH 2 or C=O; R 1a and R 1b are each independently H, halo, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or C 3 -C 8 is cycloalkyl; and R 2 is C 1 -C 6 Alkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered spirocyclic heterocyclyl, 6- to 10-membered fused polycyclic heterocyclyl, or 6- to 10-membered bridged polycyclic heterocyclyl, each of which is selected from the group consisting of halo, cyano, C 1 -C 6 Alkyl, hydroxyl, alkoxy and C 1 -C 6 haloalkyl; or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof.

2. A is halo and C 1 -C 6 2. The compound of claim 1, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein the phenylene is substituted with one or more substituents selected from the group consisting of alkoxy.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, stereoisomer, or prodrug thereof, wherein A is unsubstituted phenylene.

4. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein A is a 5- or 6-membered heteroarylene.

5. 5. The compound of claim 1 or 4, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein A is pyridinylene or pyrazolylene.

6. A is halo, C is 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl and C 1 -C 6 6. The compound of claim 1, 4 or 5, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, substituted with one or more substituents selected from alkoxy.

7. B is C 3 -C 8 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, which is a monocyclic cycloalkyl.

8. 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein B is 3-8 membered monocyclic heterocyclyl.

9. 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein B is a 3-8 membered spirocyclic heterocyclyl.

10. B is C 3 -C 8 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, which is a fused polycyclic cycloalkyl.

11. 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein B is a 3-8 membered monocyclic heterocyclylalkyl.

12. B is C 6 -C 10 7. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, which is a spirocyclic cycloalkyl.

13. B is amino, halo, hydroxyl, oxo, cyano, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyl alkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Alkylaminylalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkyl carbonyl, C 1 -C 6 Haloalkylcarbonyl, C 1 -C 6 Alkylaminyl, C 1 -C 6 Haloalkylaminyl, C 1 -C 6 Alkylcarbonylaminyl, C 1 -C 6 Haloalkylcarbonylaminyl, C 3 -C 8 Cycloalkylcarbonylaminyl and C 3 -C 8 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, substituted with one or more substituents selected from the group consisting of halocycloalkylaminyl.

14. 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein B is unsubstituted.

15. B has the following structure: 【Chemistry 2-1】 【Chemistry 2-2】 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, having one of:

16. R 1a , R 1b or both are selected from the group consisting of H, methyl, fluoro, chloro, cyano, methoxy, trifluoromethyl and cyclopropyl, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof.

17. R 2 But, C 1 -C 6 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein:

18. R 2 But, C 3 -C 8 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, which is cycloalkyl.

19. R 2 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein is 3-8 membered heterocyclyl.

20. R 2 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein is 6-10 membered spirocyclic heterocyclyl.

21. R 2 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein is 6-10 membered fused polycyclic heterocyclyl.

22. R 2 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein is 6-10 membered bridged polycyclic heterocyclyl.

23. R 2 is substituted with one or more substituents selected from the group consisting of methyl, ethyl, iso-propyl, fluoro, trifluoromethyl and cyano, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof.

24. R 2 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, wherein:

25. 【Chemical 3】 has the following structure: 【Chemistry 4-1】 【Chemistry 4-2】 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, having one of:

26. The compound has the following structure: 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 【Chemistry 5-5】 【Chemistry 5-6】 【Chemistry 5-7】 【Chemistry 5-8】 【Chemistry 5-9】 【Chemistry 5-10】 【Chemistry 5-11】 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, having one of:

27. 27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof, and a pharma- ceutically acceptable carrier, diluent or excipient.

28. A pharmaceutical for treating an LRRK2-mediated disease or disorder, comprising a compound according to any one of claims 1 to 26 or a pharma- ceutically acceptable salt, stereoisomer or prodrug thereof.

29. 29. The pharmaceutical of claim 28, wherein the disease or disorder is selected from a neurodegenerative disease, a central nervous system (CNS) disorder, cancer, an inflammatory disease, and combinations thereof.

30. a) the neurodegenerative disease is Parkinson's disease or Lewy body dementia; b) the CNS disease is Alzheimer's disease or L-DOPA-induced dyskinesia; c) the cancer is renal cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myeloid leukemia or multiple myeloma; or d) the inflammatory disease is leprosy, Crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis; The pharmaceutical composition according to claim 29.

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