LRRK2 inhibitor

Abstract

The present invention relates to an imidazo[4,5-c]quinoline compound of formula (I) and a pharmaceutically acceptable salt thereof. The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), and the use of said compound in the treatment of LRRK2-related diseases, such as neurodegenerative diseases including Parkinson's disease or Alzheimer's disease, or inflammatory bowel diseases such as Crohn's disease.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Application No. 63 / 341,065, filed May 12, 2022, the entire contents of which are incorporated herein by reference for all purposes.

Background Art

[0002] LRRK2 is a 286 kDa protein of the ROCO protein family with a complex multi - domain structure. Established protein motifs in LRRK2 include an armadillo - like (ARM) domain, ankyrin - like (ANK) domain, leucine - rich repeat (LRR) domain, Ras (renin - angiotensin system) complex (ROC) domain, C - terminal of ROC (COR) domain, kinase domain, and C - terminal WD40 domain. The ROC domain binds guanosine triphosphate (GTP), and the COR domain may be a regulator of the GTPase activity of the ROC domain. The kinase domain has structural homology with mitogen - activated protein kinase kinase kinase (MAPKKK) and has been shown to phosphorylate many cellular proteins in vitro, but the endogenous substrates have not yet been determined. LRRK2 has been found in various regions of the brain and in several peripheral tissues including the heart, lungs, spleen, and kidneys.

[0003] LRRK2 can play a complex role in multiple cellular processes as a result of its multi - domain construct, each of which is associated with putative protein - protein interactions, guanosine triphosphatase (GTPase) activity, and kinase activity. For example, LRRRK2 has been associated with NFAT inhibition in the immune system, vesicular transport, presynaptic homeostasis, mammalian target of rapamycin (mTOR) signaling, receptor tyrosine kinase MET - mediated signaling in papillary renal cell carcinoma and thyroid cancer, cytoskeletal dynamics, mitogen - activated protein kinase (MAPK) pathway, tumor necrosis factor - α (TNF - α) pathway, Wnt pathway, and autophagy. Genome - wide association (GWA) gene studies have implicated LRRRK2 in the etiology of various human diseases such as Parkinson's disease (PD) and inflammatory bowel disease (such as Crohn's disease) (Lewis, P.A. and Manzoni, C. Science Signaling 2012, 5(207), pe2).

[0004] Parkinson's disease (PD) is a relatively common age-related neurodegenerative disorder caused by the progressive loss of dopamine-producing neurons, affecting up to 4% of the population over 80 years old. PD is characterized by both motor symptoms such as resting tremor, rigidity, akinesia, and postural instability, as well as non-motor symptoms such as cognitive, sleep, and olfactory impairments. Genome-wide association (GWA) studies have linked LRRK2 to PD, and many patients with point mutations in LRRK2 exhibit symptoms indistinguishable from those of patients with idiopathic PD. More than 20 LRRK2 mutations have been associated with autosomal dominant parkinsonism, and the missense mutations R1441C, R1441G, R1441H, Y1699C, G2019S, I2020T, and N1437H are considered pathogenic. The LRRK2 R1441G mutation has been shown to increase the release of inflammatory cytokines (higher levels of TNF-α, IL-12, and lower levels of IL-10) in microglial cells derived from transgenic mice, and thus may cause direct toxicity to neurons (Gillardon, F. et al. Neuroscience 2012, 208, 41-48). In a mouse model of neuroinflammation, induction of LRRK2 in microglia was observed, and inhibition of LRRK2 kinase activity by a small molecule LRRK2 inhibitor (LRRK2-IN-1 or sunitinib) or LRRK2 knockout resulted in attenuation of TNF-α secretion and inducible nitric oxide synthase (iNOS) induction (Moehle, M. et al. J. Neurosci. 2012, 32(5), 1602-1611). The most common LRRK2 mutation, G2019S, is present in over 85% of PD patients with LRRK2 mutations. This mutation, which is located in the LRRK2 kinase domain, results in enhanced LRRK2 kinase activity. In the human brain, LRRK2 expression is highest in the same brain regions affected by PD, and LRRK2 is found in Lewy bodies, a hallmark feature of PD. Recent studies have shown that potent and selective brain-penetrant kinase inhibitors of LRRK2 may be a therapeutic treatment for PD.

[0005] Dementia results from a variety of specific pathological processes. The most common pathological processes that cause dementia are Alzheimer's disease (AD), cerebral amyloid angiopathy (CM), and prion-mediated diseases (e.g., Haan et al., Clin. Neurol. Neurosurg. 1990, 92(4): 305-310; Glenner et al., J. Neurol. Sci. 1989, 94: 1-28). AD is a progressive neurodegenerative disorder characterized by memory impairment and cognitive dysfunction. AD affects nearly half of all people over 85 years old, which is the fastest-growing segment of the US population. Therefore, the number of AD patients in the US is expected to increase from approximately 4 million to approximately 14 million by 2050. LRRK2 mutations have been associated with AD-like pathology, suggesting that there may be partial overlap between the neurodegenerative pathways in both AD and PD (Zpractich, A. et al. Neuron 2004, 44, 601-607). Furthermore, the LRRK2 R1628P variant (COR domain) has been associated with an increased incidence of AD in a specific population, probably due to increased apoptosis and cell death (Zhao, Y. et al.; Neurobiology of Aging 2011, 32, 1990-1993).

[0006] Inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease (CD), are complex diseases thought to result from an inappropriate immune response to the gut microbiota. Genome-wide association studies have recently identified LRRK2, particularly the M2397T polymorphism in the WD40 domain, as a major susceptibility gene for Crohn's disease (Liu, Z. et al. Nat. Immunol. 2011, 12, 1063-1070). LRRK2-deficient mice have been found to be more susceptible to dextran sulfate sodium-induced colitis than their wild-type counterparts, indicating that LRRK2 may play a role in the etiology of IBD (Liu, Z. and Lenardo, M.; Cell Research 2012, 1-3).

[0007] Both non-selective and selective small molecule compounds having LRRK2 inhibitory activity, such as staurosporine, sunitinib, LRRK2-IN-1, CZC-25146, TAE684, and those described in International Publication Nos. 2011 / 141756, 2012 / 028629, 2012 / 058193, 2017 / 046675, 2018 / 163030, 2018 / 163066, 2021 / 080929, and U.S. Patent Application Publication No. 20210002260, are described. It is desirable to provide compounds that are potent and selective inhibitors of LRRK2 and have favorable pharmacokinetic profiles and the ability to cross the blood-brain barrier. The present invention is directed to addressing these and other problems. SUMMARY OF THE INVENTION

[0008] In some embodiments, the present disclosure provides a compound of formula (I):

Chemical formula

[0009] In some embodiments, the disclosure provides a pharmaceutical composition of the invention comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In some embodiments, the present disclosure provides a method of inhibiting LRRK2 in a cell, the method comprising contacting the cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the present disclosure provides a method of treating an LRRK2-related disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] I. General The compounds of the present disclosure include compounds of formula (I), (Ia), (Ib), and (Ic), including the compounds of the examples. These compounds are useful for inhibiting LRRK2 and, without limitation thereto, for treating LRRK2-mediated diseases such as Parkinson's disease, Lewy body dementia, frontotemporal dementia, corticobasal dementia, progressive supranuclear palsy, Alzheimer's disease, tauopathy diseases, or α-synucleinopathy.

[0013] II. Definitions Unless otherwise specifically 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 invention belongs. Further, any methods or materials similar or equivalent to those described herein can be used in the practice of the present invention. For the purposes of the present invention, the following terms are defined.

[0014] "A", "an", or "the" refers to embodiments having one member as well as embodiments having two or more members. For example, the singular forms "a", "an", and "the" include plural referents unless the context indicates otherwise. Thus, for example, reference to "a cell" includes plural such cells, and reference to "the agent" includes reference to one or more agents known to those of ordinary skill in the art, and the like.

[0015] As used herein, "about" in reference to a value includes the recited value plus or minus 10% of the recited value. For example, about 50% includes the range from 45% to 55%, and about 20 molar equivalents includes the range from 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to plus or minus 10% of the recited value at each end of the range. For example, a ratio of about 1 to about 3 (weight / weight) includes the range from 0.9 to 3.3.

[0016] "Alkyl" means a straight-chain or branched saturated monovalent hydrocarbon. An alkyl group may have 1 to 18 carbon atoms (i.e., C 1~18 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4 alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 )2 )), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 )) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 )) 2 ), 2-methyl-2-butyl (-C(CH 3 )) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 )) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 )) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 ))), 2-methyl-2-pentyl (-C(CH 3 )) 2 CH 2CH 2 CH 3 )), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 )), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 )), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 )), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 )), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), and 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ). Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl. The alkyl group may or may not be substituted.

[0017] "Alkoxy" refers to an alkyl group: alkyl-O- having an oxygen atom connecting the alkyl group to the point of attachment. For the alkyl group, the alkoxy group may have any suitable number of carbon atoms such as C 1~6 . Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. The alkoxy group may be further substituted with various substituents described herein. The alkoxy group may or may not be substituted.

[0018] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

[0019] The "oxo" substituent refers to a divalent substituted "=O" present on a single atom. For example, an oxo substitution in combination with the carbon to which it is attached is a carbonyl (C=O).

[0020] As used herein, "haloalkyl" refers to an alkyl as defined herein in which one or more hydrogen atoms of the alkyl are independently replaced by halo substituents, which may be the same or different. For example, C 1~4 Haloalkyl is C 1~4 An alkyl in which one or more of the hydrogen atoms of the alkyl are replaced by halo substituents, C 1~4 Is an alkyl. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl. The haloalkyl group may or may not be substituted.

[0021] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. With respect to the alkyl group, the haloalkoxy group can have any suitable number of carbon atoms, such as C 1~6 And the like. The alkoxy group may be substituted with 1, 2, 3 or more halogens. When all of the hydrogens are replaced by halogen, for example, fluorine, the compound is oversubstituted, for example, perfluorinated. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like. The haloalkoxy group may or may not be substituted.

[0022] "Cycloalkyl" refers to a single saturated or partially unsaturated all-carbon ring having 3 to 20 ring carbon atoms, for example, 3 to 12 ring atoms, for example, 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 3 to 4 ring atoms (i.e., C 3~20 cycloalkyl). The term "cycloalkyl" also includes multiple fused, saturated and partially unsaturated all-carbon ring systems (e.g., ring systems containing 2, 3 or 4 carbocyclic rings). Thus, cycloalkyl includes bicyclic carbocyclic rings (e.g., bicyclic carbocyclic rings having 6 to 12 ring carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocyclic rings (e.g., tricyclic and tetracyclic carbocyclic rings having up to 20 ring carbon atoms). The rings of multiple fused ring systems can be connected to each other via condensation, spiro, and bridging bonds where permitted by valence requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl. The cycloalkyl group may or may not be substituted.

[0023] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, wherein the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above except that the alkyl component is at least divalent, i.e., an alkylene, and connects the cycloalkyl component and the point of attachment. The alkyl component is C 1~6 、C 1~2 、C 1~3 、C 1~4 、C 1~5 、C 2~3 、C 2~4 、C 2~5 、C 2~6 、C 3~4 、C 3~5 、C3~6 , C 4~5 , C 4~6 , and C 5~6 may contain any number of carbons such as, etc. The cycloalkyl component is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl. The alkyl-cycloalkyl group may or may not be substituted.

[0024] As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring having at least one heteroatom (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur) in the ring, or a polycyclic system, and the polycyclic system includes at least one non-aromatic ring containing at least one heteroatom. The polycyclic system can also include other aromatic and non-aromatic rings. Unless otherwise specified, the heterocyclyl group has 3 to 20 ring atoms, for example, 3 to 12 ring atoms, for example, 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Accordingly, this term includes a single saturated or partially unsaturated ring (e.g., 3-, 4-, 5-, 6-, or 7-membered ring) having 1 to 6 ring carbon atoms and 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The heteroatom is optionally oxidized to -N(-OH)-, =N(-O - )-, -S(=O)- or -S(=O) 2- can be formed. The rings of the plurality of condensed ring systems (e.g., bicyclic heterocyclyl) can be connected to each other via fusion, spiro, and cross-linking bonds when permitted by valence requirements. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, etc. The heterocycloalkyl group may or may not be substituted.

[0025] The heterocycloalkyl ring also includes 9- to 15-membered fused ring heterocycloalkyl having two, three, or more rings, where at least one ring is an aryl ring and at least one ring is a non-aromatic ring containing at least one heteroatom. Representative fused bicyclic heterocycloalkyls include, but are not limited to, indoline (dihydroindole), isoindoline (dihydroisoindole), indazole (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxole, dihydrobenz[b]dioxin, dihydrobenz[d]oxazole, dihydrobenz[b]thiophene, dihydroisobenz[c]thiophene, dihydrobenz[d]thiazole, dihydrobenz[c]isothiazole, and benzo[b][1,4]thiazine, as shown in the following structures:

Chemical Structure

Chemical formula

[0026] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, and the alkyl component connects the heterocycloalkyl component at the point of attachment. The alkyl component is at least divalent, an alkylene, and is as defined above except for connecting to the heterocycloalkyl component and the point of attachment. The alkyl component may contain any number of carbons such as C 1~6 、C 1~2 、C 1~3 、C 1~4 、C 1~5 、C 1~6 、C 2~3 、C 2~4 、C 2~5 、C 2~6 、C 3~4 、C 3~5 、C 3~6 、C 4~5 、C 4~6 、and C 5~6 . The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group may or may not be substituted. The alkyl-heterocycloalkyl group may or may not be substituted.

[0027] As used herein, "aryl" refers to a single all-carbon aromatic ring or a plurality of fused all-carbon ring systems in which at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also includes a plurality of fused ring systems having 9 to 20 carbon atoms, for example, 9 to 16 carbon atoms (e.g., a ring system containing 2, 3, or 4 rings), with at least one ring being aromatic and the other rings may or may not be aromatic (i.e., carbon rings). Such a plurality of fused ring systems is optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbon ring portion of the plurality of fused ring systems. The rings of the plurality of fused ring systems can be connected to each other via condensation, spiro, and bridging bonds when permitted by valence requirements. When referring to a particular range of ring members of aryl (e.g., 6- to 10-membered aryl), it should also be understood that the range of ring members is for all ring atoms of the aryl. For example, 6-membered aryl includes phenyl, and 10-membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, etc. An aryl group may or may not be substituted.

[0028] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, and the alkyl component connects the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene and connects the aryl component and the point of attachment. The alkyl component is C 1~6 、C 1~2 、C 1~3 、C 1~4 、C 1~5 、C 1~6 、C 2~3 、C 2~4 、C 2~5 、C 2~6 、C 3~4 、C 3~5 、C3~6 , C 4~5 , C 4~6 , and C 5~6 may contain any number of carbons such as. In some examples, the alkyl component may be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. The alkyl-aryl group may or may not be substituted.

[0029] As used herein, "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, and the atom is selected from the group consisting of oxygen, nitrogen, and sulfur. "Heteroaryl" also includes a plurality of fused ring systems having at least one such aromatic ring, and such a plurality of fused ring systems are further described below. Thus, "heteroaryl" includes a single aromatic ring having 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized forms if the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes a plurality of fused ring systems (e.g., ring systems containing 2, 3, or 4 rings), and the heteroaryl group defined above is fused with one or more rings selected from heteroaryl (e.g., forming 1,8-naphthyridinyl), heterocycle (e.g., forming 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., forming 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., forming indazolyl) to form a plurality of fused ring systems. Thus, heteroaryl (a single aromatic ring or a plurality of fused ring systems) has 1 to 20 carbon atoms and 1 to 6 heteroatoms within the heteroaryl ring. Such a plurality of fused ring systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic moiety of the fused ring. The rings of a plurality of fused ring systems can be connected to each other via fused, spiro, and bridging bonds when permitted by valence requirements. It should be understood that the individual rings of a plurality of fused ring systems can be connected to each other in any order. The point of attachment of heteroaryl or a plurality of fused ring systems of heteroaryl can be any suitable atom of heteroaryl or a plurality of fused ring systems of heteroaryl including carbon atoms and heteroatoms (e.g., nitrogen). When referring to heteroaryl having a specific range of ring members (e.g., 5- to 10-membered heteroaryl), the range of ring members is for all ring atoms of the heteroaryl, and it should also be understood to include carbon atoms and heteroatoms.For example, 5-membered heteroaryl includes thiazolyl, and 10-membered heteroaryl includes quinolinyl. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolin-4(3H)-one, and triazolyl. The heteroaryl group may or may not be substituted.

[0030] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, wherein the alkyl component links the heteroaryl component at the point of attachment. The alkyl component is at least divalent alkylene, and is as defined above except for linking to the heteroaryl component and the point of attachment. The alkyl component may contain any number of carbons, such as C 1~6 , C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6 . In some examples, the alkyl component may be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may or may not be substituted.

[0031] "The compounds of the present disclosure" include the compounds disclosed herein. For example, the compounds of the present disclosure include the compounds of the examples, and the compounds of formulas (I), (Ia), (Ib), and (Ic).

[0032] Pharmaceutically acceptable salts, tautomeric forms, and polymorphs of the compounds are also described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0033] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from appropriate bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX 4 + (wherein X is C 1 ~C 4 alkyl), etc. Base addition salts, such as sodium salts or potassium salts, are also included.

[0034] When the compounds are represented in their chiral forms, embodiments are understood to include, but are not limited to, specific diastereomerically or enantiomerically enriched forms. If chirality is not specified but present, embodiments are understood to be directed to either specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compounds. As used herein, "scalemic mixture" refers to a mixture of stereoisomers in a ratio other than 1:1.

[0035] "Racemate" refers to a mixture of enantiomers. The mixture can contain equal or unequal amounts of each enantiomer.

[0036] "Stereoisomers" refer to compounds in which the chirality of one or more stereocenters is different. Stereoisomers include enantiomers and diastereomers. A compound may exist in stereoisomeric forms if it has one or more asymmetric centers or a double bond with an asymmetric substitution, and thus can be produced as individual stereoisomers or as a mixture. Unless otherwise indicated, this description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0037] "Tautomers" refer to alternative forms of a compound in which the position of a proton is different, for example, enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to both ring-NH- and ring=N-, for example, pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0038] 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. Dashes at the beginning or end of a chemical group are for convenience. Chemical groups can be shown with or without one or more dashes without losing their normal meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group. A dashed line indicates an optional bond. Unless required chemically or structurally, the order in which a chemical group is written or the point at which it is attached to the rest of the molecule does not indicate or imply directionality. For example, the group "-SO 2 CH 2 -" is equivalent to "-CH 2 SO 2 -" and both can be connected in either direction. Similarly, an "arylalkyl" group can be attached to the rest of the molecule by either the aryl portion or the alkyl portion of the group. "C u~v " or (C u ~Cv )Prefixes such as indicate that the following radical has u to v carbon atoms. For example, "C" 1~6 "alkyl" or "C" 1 ~C 6 "alkyl" both indicate that the alkyl group has 1 to 6 carbon atoms.

[0039] As used herein, "composition" is intended to encompass a product containing specific components in specific amounts, and any product directly or indirectly resulting from a combination of specific amounts of specific components. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other components of the formulation and not harmful to its recipient.

[0040] "Pharmaceutically effective amount" refers to the amount of a compound of the present disclosure in a formulation or combination thereof that provides a desired therapeutic or pharmaceutical result.

[0041] As used herein, "pharmaceutical composition" refers to a product containing specific components in specific amounts, and any product directly or indirectly resulting from a combination of specific amounts of specific components. Pharmaceutical compositions are generally safe for biological use.

[0042] Examples of "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the US Food and Drug Administration as acceptable for use in humans or livestock.

[0043] As used herein, "inhibiting" or "inhibition of" LRRK2 refers to reducing the activity and / or function of the LRRK2 enzyme. The activity of the LRRK2 enzyme can be measured by any assay method known in the art, including the assays described in International Publication Nos. WO 2011 / 141756, WO 2012 / 028629, WO 2012 / 058193, WO 2017 / 046675, WO 2018 / 163030, WO 2018 / 163066, WO 2021 / 080929, or U.S. Patent Application Publication No. 20210002260, or assays found in the Examples, or assays described herein.

[0044] As used herein, "treatment" or "treating" or "treatment of" refers to an approach for obtaining a beneficial or desired result. For the purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms and / or reduction in the degree of symptoms and / or prevention of worsening of symptoms associated with a disease or condition. In some embodiments, "treatment" or "treatment of" includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the degree of the disease or condition), b) delaying or halting the onset of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition), c) alleviating the disease and / or condition, e.g., causing regression of clinical symptoms, improving the disease state, retarding the progression of the disease, enhancing the quality of life, and / or prolonging survival.

[0045] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount of a compound effective to elicit a desired biological or medical response, including an amount of the compound that is sufficient to achieve such treatment of a disease when administered to a subject for treating the disease. The effective amount can vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject being treated. The effective amount can include a range of amounts. As understood in the art, the effective amount can be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. "Effective amount" can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be administered in an effective amount if, alone or in combination with one or more other agents, a desired or beneficial result can be achieved or is achieved. The appropriate dose of any concurrently administered compound can optionally be reduced due to the combined action of the compounds (e.g., additive or synergistic effects).

[0046] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, to a subject. Administration can be carried out according to a schedule that specifies the frequency of administration, the dose administered, and other factors.

[0047] As used herein, "co-administration" refers to the administration of a unit dose of a compound disclosed herein before or after the administration of one or more additional therapeutic agents, for example, the administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by the administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by the administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by the administration of a unit dose of one or more additional therapeutic agents after several hours (e.g., 1 to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by the administration of a unit dose of a compound of the present disclosure after several hours (e.g., 1 to 12 hours). Co-administration of a compound disclosed herein and one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0048] "Subject" refers to an animal such as a mammal including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0049] "Disease" or "condition" refers to the condition or health state of a patient or subject that can be treated with a compound, pharmaceutical composition, or method provided herein.

[0050] III. Compounds The compounds of the present disclosure include compounds of formula (I), (Ia), (Ib), and (Ic), including the compounds of the examples.

[0051] In some embodiments, the compounds of the invention are compounds of formula (I):

Chemical formula

[0052] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein subscript n is 1 or 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein subscript n is 1

[0053] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein subscript m is 1, 2, 3, or 4. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein subscript m is 1 or 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein subscript m is 1

[0054] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein subscript p is 1, 2, 3, or 4. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein subscript p is 1 or 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein subscript p is 1

[0055] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is a 5- to 6-membered heterocycloalkyl having one heteroatom N, O or S, or a 5- to 6-membered heteroaryl having one or two heteroatoms each independently being N, O or S. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is a 5- to 6-membered heterocycloalkyl having one heteroatom N or O, or a 5- to 6-membered heteroaryl having one heteroatom N. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is pyrrolidinyl, piperidinyl, tetrahydropyranyl or pyridyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is tetrahydropyranyl.

[0056] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that each R 1 is independently C 1~6 alkyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that each R 1 is independently C 1~3 alkyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which each R 1 is methyl, ethyl, n-propyl or iso-propyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which each R 1 is Me.

[0057] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which R 3 is hydrogen or halogen. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which R 3 is halogen. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which R 3 is F or Cl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that R 3is a compound that is hydrogen.

[0058] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that each R 4 is independently a halogen or -CN. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that each R 4 is independently Cl or -CN. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that each R 4 is -CN.

[0059] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of Formula Ia:.

Chemical formula

[0060] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of Formula Ib:.

Chemical formula

[0061] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of Formula Ic:.

Chemical formula

[0062] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein ring B is a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms each independently being N, O or S. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein ring B is a 5- to 6-membered heteroaryl having 2 to 3 heteroatoms each independently being N, O or S. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein ring B is pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein ring B is pyrazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or pyridyl.

[0063] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound wherein the group is

Chemical formula

[0064] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is each R 2 is C 1~3 alkyl, =O, C(O)OR 2b , OC(O)R 2a , S(O) 2 R 2a , N(R 2b S(O) 2 R 2a , S(O) 2 N(R 2b (R 2c ), C 3~6 cycloalkyl, or a 3- to 6-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S, each alkyl or cycloalkyl is substituted with 1 to 2 R 2d groups, and each heterocycloalkyl is substituted with 1 to 2 R2e is optionally replaced at the base, each R 2b and R 2c is hydrogen or C 1~3 alkyl, each R 2d is independently C(O)R 2d1 or S(O) 2 R 2d1 is, each R 2e is independently C 1~3 alkyl, -OH, =O, C(O)R 2e1 or S(O) 2 R 2e1 is, each R 2a , R 2d1 and R 2e1 is independently C 1~3 alkyl, a compound.

[0065] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that each R 2 is independently =O, -COOH, -C(O)OMe, -SO 2 Me, -NHSO 2 Me, -CH 2 CH 2 SO 2 Me,

Chemical Structure

[0066] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which the group is

Chemical Structure

[0067] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of the compounds in Table 1.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

[0068] The compounds of the present disclosure described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as the free base. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compounds having the desired pharmacological activity. These salts can be derived from inorganic or organic acids or bases. Pharmaceutically acceptable salts of the compounds of formula (I) of the present disclosure include inorganic acid salts such as hydrochloride, sulfate, carbonate, and phosphate, and organic acid salts such as fumarate, maleate, methanesulfonate, and p-toluenesulfonate. Further, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as magnesium or calcium, salts with organic amines such as lower alkylamines or lower alcoholamines, salts with basic amino acids such as lysine, arginine, and ornithine, or ammonium salts are also included. For example, a compound containing basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate.A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, PA, 2006.

[0069] In some embodiments, the compounds, or pharmaceutically acceptable salts, isomers, or mixtures thereof, of the disclosure described herein may be compounds in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced with deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase resistance to metabolism and, thus, may be useful for increasing the half-life of the compounds, or pharmaceutically acceptable salts, isomers, or mixtures thereof, described herein when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced with deuterium.

[0070] Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125I can be mentioned. 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as N can be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by a process similar to that described in the examples shown below using appropriate isotope-labeled reagents in place of the unlabeled reagents previously used.

[0071] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more chiral centers and, therefore, can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- or (D)- or (L)- for amino acids with respect to absolute stereochemistry. The present disclosure means that it includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using a chiral synthon or chiral reagent or can be resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or a racemate of a salt or derivative), for example, using chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other center of geometric asymmetry, the compounds are intended to include both E and Z geometric isomers unless otherwise specified. Similarly, all tautomeric forms are intended to be included.

[0072] Activity against LRRK2 can be measured by any biochemical assay known in the art to be useful for evaluating LRRK2, such as commercially available assays like the LRRK2 ELISA kit (Aviva Systems, San Diego, CA USA) and the LRRK2 kinase enzyme system (Promega Corp.), the assays described in U.S. Patent Nos. 10,039,753 and 11,161,844, and the assays described herein. In some embodiments, the compounds of the disclosure have activity against LRRK2 and the IC 50 is less than about 30 μM, such as less than about 20 μM, less than about 10 μM, less than about 1 μM, less than about 0.1 μM, less than about 0.01 μM, less than about 0.001 μM, or less than about 0.0001 μM in a biochemical assay.

[0073] Activity against LRRK2 can also be measured by any cell assay known in the art to be useful for evaluating LRRK2, such as the phospho-LRRK2 (Ser935) cell kit (Cisbio Bioassays, France), as described in Hermanson, SB et al. PLOS ONE 7(8):e43580 and as described herein. In some embodiments, the compounds of the disclosure have activity against LRRK2 and the IC 50 is less than about 30 μM, such as less than about 20 μM, less than about 10 μM, less than about 1 μM, less than about 0.1 μM, less than about 0.01 μM, less than about 0.001 μM, or less than about 0.0001 μM in a cell assay.

[0074] In some forms, the compounds of the present disclosure are selective for LRRK2 over one or more of other kinases such as LRRK1, LIMK1, LIMK2, RIPK1, RIPK2, RIPK3, ANKRD3, SgK288, IRAK1, IRAK2, IRAK3, IRAK4, JAK1, JAK2, JAK3, TESK1, and / or TESK2. Selectivity can be measured by relative values in the corresponding biochemical assays, such as the activity of inhibiting LRRK2 over LRRK1, LIMK1, LIMK2, RIPK1, RIPK2, RIPK3, ANKRD3, SgK288, IRAK1, IRAK2, IRAK3, IRAK4, JAK1, JAK2, JAK3, TESK1, and / or TESK2.

[0075] In some embodiments, the compounds of the present disclosure have selectivity for LRRK2 over one or more of other kinases including LRRK1, LIMK1, LIMK2, RIPK1, RIPK2, RIPK3, ANKRD3, SgK288, IRAK1, IRAK2, IRAK3, IRAK4, JAK1, JAK2, JAK3, TESK1, and / or TESK2, for example, at least about 1.2-fold, about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 60-fold, about 70-fold, about 80-fold, about 90-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 1000-fold, about 2000-fold, about 3000-fold, about 4000-fold, about 5000-fold, or about 10000-fold or more over one or more of 2, 3, 4, 5, 6, 7, 8, or 9 or more of them.

[0076] IV. Pharmaceutical Compositions In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of a compound of formula (I), (Ia), (Ib), or (Ic), or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0077] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. Any suitable additional therapeutic agent or combination therapy, such as the agents and therapies described herein, can be used in combination with a compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (Ia), (Ib), or (Ic), and an additional therapeutic agent, wherein the additional therapeutic agent is an anti-Parkinson's disease agent.

[0079] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (Ia), (Ib), or (Ic), and an additional therapeutic agent, wherein the additional therapeutic agent is an anti-inflammatory bowel disease agent.

[0080] The compounds herein are formulated with conventional carriers and excipients. Tablets contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in a sterile form and are generally isotonic if delivery by means other than oral administration is intended. All formulations optionally contain excipients such as those described in "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents (e.g., EDTA), carbohydrates (e.g., dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.). The pH of the formulation ranges from about 3 to about 11, for example from about 7 to 10.

[0081] Although it is possible to administer the active ingredients alone, it may be preferable to provide them as pharmaceutical formulations. Formulations for both veterinary and human use comprise at least one active ingredient as defined above, together with one or more acceptable carriers and optionally other therapeutic components, particularly further therapeutic components as discussed herein. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to its recipient.

[0082] The formulations include those suitable for the aforementioned routes of administration. The formulations can conveniently be provided in unit dosage form and can be prepared by any suitable method. Techniques and formulations are generally found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0083] Formulations suitable for oral administration can be provided as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0084] Tablets can be made, optionally, by compression or molding, with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, a free-flowing form of the active ingredient, such as a powder or granules, which has been optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets can be optionally coated or scored and can be formulated so as to provide for the slow or controlled release of the active ingredient from the tablet.

[0085] The pharmaceutical preparations of this specification include one or more pharmaceutically acceptable carriers or excipients and optionally combinations with other therapeutic agents. The pharmaceutical preparation containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, troches, drops, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs may be prepared. The compositions intended for oral use may be prepared according to any method for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents, and preservatives to provide a palatable preparation. Tablets containing the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may or may not be coated, or may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, sustained release materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes.

[0086] Preparations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, for example, arachis oil, liquid paraffin or olive oil.

[0087] The aqueous suspension contains an active material mixed with an excipient suitable for the production of an aqueous suspension. Such excipients include suspending agents (e.g., sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum, and acacia gum), and dispersing or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxy cetanol), and condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

[0088] The oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oral suspensions can contain a thickening agent such as beeswax, solid paraffin, or cetyl alcohol. Sweetening and flavoring agents as described above may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0089] Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in a mixture of a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients such as sweetening, flavoring, and coloring agents may also be present.

[0090] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum acacia and tragacanth gum, naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids such as sorbitan monooleate and hexitol anhydride, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents such as glycerol, sorbitol or sucrose. Such formulations may also contain lubricants, preservatives, flavoring agents, or coloring agents.

[0091] The pharmaceutical composition may be in the form of a sterile injectable or intravenous preparation such as a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known techniques using the appropriate dispersing or wetting agents and suspending agents described above. The sterile injectable or intravenous preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3 - butanediol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, a sterilized fixed oil can conventionally be used as a solvent or suspending medium. For this purpose, any non-irritating non-volatile oil containing synthetic mono- or diglycerides can be used. Furthermore, fatty acids such as oleic acid can also be used in the preparation of injectables in the same manner.

[0092] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans may contain from about 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material, which can vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain from about 3 to 500 μg of active ingredient per milliliter of solution so as to permit administration of an appropriate volume at a rate of about 30 mL / hour.

[0093] Formulations suitable for topical administration to the eye include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5 to 20%, advantageously 0.5 to 10%, particularly about 1.5% w / w.

[0094] Formulations suitable for topical administration to the mouth include flavored bases, usually troches containing the active ingredient in sucrose and acacia or tragacanth; troches containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0095] Formulations for rectal administration can be provided, for example, as suppositories having a suitable base containing cocoa butter or a salicylate.

[0096] Formulations suitable for administration by inhalation to the lungs or nasally are administered, for example, by rapid inhalation through the nasal cavity or by inhalation through the mouth so as to reach the alveoli, and have a particle size in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35, etc. Suitable formulations include aqueous or oily solutions of the active ingredient.

[0097] Formulations suitable for vaginal administration can be provided as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, a carrier known to be suitable in the art.

[0098] Formulations suitable for parenteral administration can include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending and thickening agents.

[0099] The formulations can be provided, for example, in unit dose or multi-dose containers of sealed ampoules and vials and can be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier for injection, for example, water, immediately prior to use. Immediate injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the previously described types. Preferred unit dose formulations contain the active ingredient in a daily dose or unit daily sub-dose as listed above herein, or an appropriate fraction thereof.

[0100] In addition to the components specifically mentioned above, it should be understood that the formulations may include other agents conventional in the art, taking into account the type of formulation under consideration. For example, formulations suitable for oral administration may include flavoring agents.

[0101] In some embodiments, the veterinary composition includes at least one active ingredient as defined above, together with a veterinary carrier therefor.

[0102] The veterinary carrier can be a solid, liquid or gaseous substance that is useful for the purpose of administering the composition and is otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or by any other desired route.

[0103] The compounds of the present specification are used to provide a controlled release pharmaceutical formulation (a "controlled release formulation") containing one or more compounds as active ingredients, and the release of the active ingredient is controlled and regulated so as to allow for less frequent administration or to improve the pharmacokinetics or toxicity profile of a given active ingredient.

[0104] The effective dose of the active ingredient depends on at least the nature of the condition being treated, its toxicity, whether the compound is used prophylactically (at a low dose) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and is determined by a clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg / kg body weight per day; typically, from about 0.01 to about 10 mg / kg body weight per day; more typically, from about 0.01 to about 5 mg / kg body weight per day; and most typically, from about 0.05 to about 0.5 mg / kg body weight per day. For example, a candidate daily dose for an adult with a body weight of about 70 kg is in the range of 1 mg to 1000 mg, preferably 5 mg to 500 mg, and can be in the form of a single dose or multiple doses.

[0105] V. Route of Administration One or more of the compounds of formula (I), (Ia), (Ib) or (Ic) are administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). It is understood that the preferred route can vary, for example, depending on the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be administered orally.

[0106] The compounds of the present disclosure can be administered by any route suitable for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), among others. It will be understood that the preferred route can vary, for example, depending on the condition of the recipient. An advantage of the specific compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0107] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen over a desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. In one variation, the compound is administered daily or on an intermittent schedule over the lifetime of the individual.

[0108] The dosage or frequency of administration of the compounds of the present disclosure can be adjusted over the course of treatment based on the judgment of the physician administering the treatment.

[0109] The compound can be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0110] The compound can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example, from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or for example, from about 0.3 mg per day to about 30 mg, or for example, from about 30 mg per day to about 300 mg.

[0111] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compounds of the present disclosure (e.g., 1 mg to 1000 mg of the compound). Therapeutically effective amounts can include from about 1 mg / dose to about 1000 mg / dose, such as from about 50 mg / dose to about 500 mg / dose, or for example from about 100 mg / dose to about 400 mg / dose, or for example from about 150 mg / dose to about 350 mg / dose, or for example from about 200 mg / dose to about 300 mg / dose. Other therapeutically effective amounts of the compounds of the present disclosure can be about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg / dose. Other therapeutically effective amounts of the compounds of the present disclosure can be about 100 mg / dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg / dose. Single doses can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once a day, once every 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once a week, three times every two weeks, or once every four weeks. In some embodiments, a single dose can be administered once a week. A single dose can also be administered once a month.

[0112] Other therapeutically effective amounts of the compounds of the present disclosure can be about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg / dose.

[0113] The dosing frequency of the compounds of the present disclosure is determined by the needs of the individual patient and can be, for example, once a day or more than once a day. Administration of the compound continues as long as necessary to treat the viral infection. For example, the compound can be administered to a human infected with the virus for a period of 20 days to 180 days, or for example for a period of 20 days to 90 days, or for example for a period of 30 days to 60 days.

[0114] Administration can be intermittent, such that after a period of several days during which the patient receives a daily dose of the compounds of the present disclosure, there follows a period of several days during which the patient does not receive a daily dose of the compound. For example, the patient can receive the dose of the compound every other day, or three times a week. As another example, the patient can receive a daily dose of the compound for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive the dose of the compound, and then followed by a period (e.g., 1 to 14 days) during which the patient again receives a daily dose of the compound. The alternating periods of administration of the compound and subsequent non - administration of the compound can be repeated as clinically necessary to treat the patient.

[0115] In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 - 3, or 1 - 4) additional therapeutic agents and pharmaceutically acceptable excipients.

[0116] VI. Method or Use In some embodiments, a method or use for inhibiting LRRK2 in cells that need to have LRRK2 inhibited comprises administering to the cells an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, a method or use for inhibiting LRRK2 in cells comprises contacting the cells with an effective amount of a compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or its salt.

[0117] In some embodiments, a method for inhibiting LRRK2 in cells comprises contacting the cells with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0118] Inhibition of LRRK2 enzyme activity can be measured by any assay method known in the art, including in vitro assays such as those described in the assays described in WO 2011 / 141756, WO 2012 / 028629, WO 2012 / 058193, WO 2017 / 046675, WO 2018 / 163030, WO 2018 / 163066, WO 2021 / 080929, or US Patent Application Publication No. 20210002260. Other exemplary in vitro assays can be found in the examples herein. In some embodiments, the in vitro assay includes an enzyme assay or a cell assay.

[0119] In some embodiments, inhibition of LRRK2 enzyme activity is measured in an in vivo model. Exemplary in vivo models for LRRK2-related diseases are described in Xiong, Y. et al. Adv Neurobiol. 2017;14:163-191.

[0120] In some embodiments, a method of inhibiting LRRK2 includes administering an effective amount of a compound of the present disclosure, thereby reducing LRRK2 activity in the assays described herein as compared to a control not administered the compound of the present disclosure. In some embodiments, LRRK2 activity is reduced by about 5% to about 100%, such as about 10% to about 97%, about 20% to about 95%, about 20% to about 90%, about 20% to about 80%, or about 20% to about 70%. In some embodiments, LRRK2 activity is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

[0121] In some embodiments, a method or use for inhibiting LRRK2 in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, a method or use for inhibiting LRRK2 in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a salt thereof.

[0122] In some embodiments, a method or use for treating an LRRK2-related disease or condition such as neuropathy (e.g., Parkinson's disease) and certain immunological disorders (such as inflammatory bowel diseases such as ulcerative colitis or Crohn's disease) comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0123] In some embodiments, a method for treating an LRRK2-related disease or condition in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the present disclosure provides a method or use for treating an LRRK2-related disease or condition. In some embodiments, the LRRK2-related disease or condition is Parkinson's disease; brain injury; stroke; cerebrovascular disease (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, cerebral hypoxic-ischemia); cognitive impairment (including amnesia, senile dementia, HIV-related dementia, Alzheimer's disease, Huntington's disease, Lewy body dementia, vascular dementia, drug-related dementia, tardive dyskinesia, myoclonus, dystonia, delirium, Pick's disease, Creutzfeldt-Jakob disease, HIV disease, Gilles de la Tourette syndrome, epilepsy, myoclonic or muscle weakness-related disorders including cramps, and mild cognitive impairment); mental retardation (including spasticity, Down syndrome, and fragile X syndrome); sleep disorders (including hypersomnia, circadian rhythm sleep disorders, insomnia, parasomnias, and sleep apnea), and mental disorders such as anxiety (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, agoraphobia, and obsessive-compulsive disorder); factitious disorder (including acute hallucinatory mania); impulse control disorders (including compulsive gambling and intermittent explosive disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective states, major depression, chronic depression, seasonal depression, psychotic depression, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PDD), and postpartum depression); psychomotor disorders; psychotic disorders (including schizophrenia, schizoaffective disorder, schizophreniform, and delusional disorder); substance use disorders (including opioid use disorder, alcohol use disorder, amphetamine use disorder, cocaine intoxication, nicotine use disorder, and withdrawal syndromes); eating disorders (including anorexia nervosa, bulimia nervosa, binge eating disorder, polyphagia, obesity, compulsive overeating disorder, and pica); sexual dysfunction disorders; urinary incontinence; nerve injury disorders (including eye injury, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and deafness, and cerebral edema) and pediatric mental disorders (including attention deficit disorder, attention deficit / hyperactivity disorder, conduct disorder, and autism).

[0125] In some embodiments, the LRRK2-related disease or condition is Parkinson's disease, Lewy body dementia, frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, Alzheimer's disease, tauopathy disease, or alpha-synucleinopathy. In some embodiments, the LRRK2-related disease or condition is Parkinson's disease. In some embodiments, the LRRK2-related disease or condition is frontotemporal dementia. In some embodiments, the LRRK2-related disease or condition is corticobasal degeneration. In some embodiments, the LRRK2-related disease or condition is progressive supranuclear palsy. In some embodiments, the LRRK2-related disease or condition is Alzheimer's disease. In some embodiments, the LRRK2-related disease or condition is tauopathy disease. In some embodiments, the LRRK2-related disease or condition is alpha-synucleinopathy.

[0126] In some embodiments, the LRRK2-related disease or condition is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn's disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the inflammatory bowel disease is Crohn's disease.

[0127] Increased LRRK2 levels and / or activity have been associated with abnormal levels of autophagy in specific cell types in patients with Parkinson's disease. For example, the LRRK2 G2019S and LRRK2 R1441C mutations were associated with increased kinase activity and a decrease in the autophagy pathway via blocked clearance of autophagosomes. See Madureira, M. et al. Frontiers in Neuroscience 2020, 14, Article 498, 1-19. Inhibition of LRRK2 G2019S kinase activity in cell models enhanced autolysosome formation. See Obergasteiger, et al. Cell Death Discovery 2020, 6(45), 1-13.

[0128] Some diseases are associated with abnormal levels of autophagy, specifically, levels of autophagy that are decreased compared to healthy subjects. See Ichimiya, et al. Intl. J. Mol. Sci. 2020, 21, 8974, pages 1 - 21. Any of the autophagy - related diseases or conditions can benefit from LRRK2 inhibition by administration of the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0129] Accordingly, in some embodiments, the LRRK2 - related disease or condition is an autophagy - related disease or condition. Some embodiments are that the autophagy - related disease or condition relates to a decrease in the level of one or more of mitophagy, allophagy, ER - phagy, lysophagy, nucleophagy, pexophagy, lipophagy, xenophagy, aggrephagy, ribophagy, NPC - phagy, and RN / RN autophagy compared to the level in a control subject. In some embodiments, the autophagy - related disease or condition is a liver disease (e.g., non - alcoholic fatty liver disease (NAFLD), α1 - antitrypsin deficiency (AATD), or hereditary hypofibrinogenemia with hepatic storage (HHHS)), a kidney disease (e.g., type 1 diabetes, type 2 diabetes, acute kidney injury, and chronic kidney disease caused by diabetes, hypertension, or chronic nephritis), a heart disease (e.g., heart failure), inflammatory bowel disease (e.g., Crohn's disease), or a neurodegenerative disease (e.g., Parkinson's disease). In some embodiments, the autophagy - related disease or condition is α1 - antitrypsin deficiency (AATD).

[0130] In some embodiments, the use of the present invention for the manufacture of a medicament for treating an LRRK2 - related disease or condition comprises a compound or pharmaceutical composition described herein.

[0131] In some embodiments, the compound or composition for the use of the present invention for treating an LRRK2 - related disease or condition comprises a compound or pharmaceutical composition described herein.

[0132] In some embodiments, the kit is suitable for use in practicing the above methods or uses. In some embodiments, the kit of the invention comprises one or more compounds of the invention. In some embodiments, the kit comprises a first dosage form comprising one or more of the compounds of the invention in an amount sufficient to practice the method or use of the invention, and a container for administration.

[0133] VII. EXAMPLES Numerous general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley-Interscience, 2013).

[0134] The compounds described herein can be purified by any of the means known in the art, including chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase, including normal and reverse phases and ion exchange resins, can be used. For example, the disclosed compounds can be purified by silica gel chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0135] The compounds were characterized using standard measurement methods. The identity of the compounds was determined by hydrogen nuclear magnetic resonance spectroscopy ( 1 1H-NMR) and mass spectrometry (MS). 11H-NMR was measured at 400 MHz unless otherwise specified. In some cases, depending on the compound and the measurement conditions, exchangeable hydrogen may not be clearly observable. The terms br. or broad used herein refer to a broad signal. HPLC preparative chromatography was carried out in gradient mode using a commercially available ODS column and water / methanol (containing formic acid) as the eluent unless otherwise specified.

[0136] Certain abbreviations and acronyms are used when describing the details of the experiments. Most of these will be understood by those skilled in the art, but the following table includes a list of many of these abbreviations and acronyms.

Table 2

[0137] The examples provided herein illustrate the synthesis of the compounds disclosed herein and the intermediates used to prepare the compounds. It should be understood that the individual steps described herein can be combined. It should also be understood that separate batches of the compound can be combined and then proceed to the next synthetic step.

[0138] In the following description of the examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice specific embodiments of the disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. Accordingly, the following description is not intended to limit the scope of the disclosure.

[0139] The representative syntheses of the compounds of the disclosure are described in the following schemes and the following specific examples.

[0140] Intermediate 1

Chemical formula

[0141] (R)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)cyclopropan-1-ol: To a solution of methyl (R)-3-((tert-butyldimethylsilyl)oxy)butanoate (39 g, 151 mmol, 1.0 eq) in THF (350 mL, 0.4 M) was added tetraisopropoxytitanium (44 mL, 151 mmol, 1.0 eq) and EtMgBr (3 M in THF, 151 mL, 453 mmol, 3.0 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was quenched with saturated NH 4 4Cl (200 mL) and 20% citric acid (200 mL) at 0 °C. MTBE (200 mL) was added. The mixture was stirred at 0 °C for 20 min and filtered. The filtrate was extracted with MTBE (3 × 200 mL), dried over Na 2 SO 4 4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a brown oil, which was used in the next step without further purification. 1 1H NMR (400 MHz, CDCl3 ) δ ppm: 4.31 - 4.18 (m, 1H), 1.85 - 1.76 (m, 1H), 1.65 - 1.58 (m, 1H), 1.26 (d, J = 6.4 Hz, 3H), 0.93 - 0.89 (m, 9H), 0.82 - 0.76 (m, 1H), 0.72 - 0.65 (m, 1H), 0.49 - 0.43 (m, 1H), 0.40 - 0.34 (m, 1H), 0.13 (s, 3H), 0.12 (s, 3H).

[0142] (R)-5-((tert-butyldimethylsilyl)oxy)hex-1-en-3-one: To a solution of (R)-1-(2-((tert-butyldimethylsilyl)oxy)propyl)cyclopropan-1-ol (35 g, 152 mmol, 1.0 equiv) in DCM (400 mL, 0.4 M) was added NBS (27 g, 152 mmol, 1.0 equiv). The mixture was stirred at 0 °C for 1 h. TEA (42.3 mL, 304 mmol, 2.0 equiv) was added and the mixture was stirred at 0 °C for 2 h. The mixture was diluted with 20% citric acid (200 mL) and the layers were separated. The organic layer was washed with saturated NaHCO 3 (3 × 200 mL) and dried over Na 2 SO 4 and filtered. Hydroquinone (200 mg) was added to the organic layer. The organic layer was concentrated under reduced pressure. The residue was filtered through a silica gel pad (300 g) and the filter cake was washed with DCM (800 mL). The filtrate and washings were combined and concentrated at atmospheric pressure to give the title compound as a brown oil, which was used in the next step without further purification. 1 1H NMR (400 MHz, CDCl 3 ) δ ppm: 6.46 - 6.30 (m, 1H), 6.29 - 6.17 (m, 1H), 5.96 - 5.79 (m, 1H), 4.39 - 4.28 (m, 1H), 2.85 (dd, J = 7.2, 14.8 Hz, 1H), 2.54 (dd, J = 5.2, 14.8 Hz, 1H), 1.19 (d, J = 6.0 Hz, 3H), 0.86 - 0.82 (m, 9H), 0.05 (m, 3H), 0.01 (s, 3H).

[0143] (R)-2-Methyl-2,3-dihydro-4H-pyran-4-one: A mixture of (R)-5-((tert-butyldimethylsilyl)oxy)hex-1-en-3-one (10 g, 39 mmol, 1.0 equiv), PdCl 2 (MeCN) 2 (102 mg, 394 μmol, 0.01 equiv), benzoquinone (8.9 mL, 39 mmol, 1.0 equiv) and H 2 O (3.4 mL, 189 mmol, 4.8 equiv) in acetone (50 mL, 0.8 M) was stirred at 40 °C for 6 h under N 2 atmosphere. The solvent was removed under reduced pressure and the residue was dissolved in DCM (30 mL). The solution was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was distilled under vacuum (50 °C, oil pump, 10 mmHg) to give the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.33 (d, J = 6.0 Hz, 1H), 5.39 (dd, J = 1.2, 6.0 Hz, 1H), 4.61 - 4.48 (m, 1H), 2.62 - 2.34 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H). [α] 25 D = +167.009 (c = 0.109, CHCl3).

[0144] (R)-2-Methyltetrahydro-4H-pyran-4-one: A mixture of (R)-2-Methyl-2,3-dihydro-4H-pyran-4-one (1.0 g, 8.03 mmol, 1.0 equiv) and Pd / C (500 mg, 10 wt%) in THF (20 mL, 0.4 M) was stirred at 20 °C for 1 h under H 2 (15 psi). The mixture was filtered and concentrated under reduced pressure to give the title compound as a colorless oil, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 4.31 - 4.23 (m, 1H), 3.79 - 3.63 (m, 2H), 2.64 - 2.51 (m, 1H), 2.44 - 2.21 (m, 3H), 1.32 (d, J = 6.4 Hz, 3H).

[0145] Intermediate 1: A mixture of (R)-2-methyltetrahydro-4H-pyran-4-one (200 mg, 1.75 mmol, 1.0 equiv) and (2,4-dimethoxyphenyl)methanamine (396 μL, 2.63 mmol, 1.5 equiv) in MeOH (5 mL, 0.4 M) was stirred at 20 °C for 1 h. The mixture was cooled to -78 °C and LiBH 4 (38.2 mg, 1.75 mmol, 1.0 equiv) was added. The mixture was stirred at 20 °C for 12 h. Then, the mixture was quenched with saturated Na 2 CO 3 (20 mL) and diluted with water (20 mL). The mixture was extracted with DCM (3 × 20 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash silica gel chromatography (DCM / MeOH = 1 / 0 - 9 / 1) to give the title compound as a brown oil. [M+H] + = 266.2. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.12 (d, J = 8.0 Hz, 1H), 6.51 - 6.34 (m, 2H), 4.06 - 3.92 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.75 (s, 2H), 3.44 - 3.34 (m, 2H), 2.73 - 2.61 (m, 1H), 1.92 - 1.85 (m, 1H), 1.84 - 1.77 (m, 1H), 1.46 - 1.30 (m, 1H), 1.18 (d, J = 6.0 Hz, 3H), 1.15 - 1.03 (m, 1H).

[0146] Intermediate 2

Chemical Structure

[0147] Intermediate 2: POCl 3 (2.18 mL, 23.4 mmol, 2.8 equiv) was added to a solution of 4-hydroxy-3-nitroquinoline-6-carbonitrile (1.8 g, 8.37 mmol, 1.0 equiv) in DMF (60 mL, 0.1 M) under N 2 (g). After stirring at 20 °C for 12 h, the mixture was quenched by adding water (30 mL) and the solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over Na 2 SO 4 and filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 0 to 85 / 15) to give the title compound as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 9.39 (s, 1H), 8.84 (d, J = 1.2 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.10 (dd, J = 1.6, 8.4 Hz, 1H).

[0148] Intermediate 3

Chemical Structure

[0149] 4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)-3-nitroquinoline-6-carbonitrile: TFA (43.2 μL, 583 μmol, 3.0 eq) was added to a solution of 4-((3,4-dimethylbenzyl)((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)-3-nitroquinoline-6-carbonitrile (94.7 mg, 195 μmol, 1.0 eq) in DCM (2 mL, 0.1 M) under N2 (g) was added. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated to a volume of 5 mL and treated with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with DCM (3 × 20 mL), and the combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated in vacuo to afford the title compound as a yellow solid, which was used in the next step without further purification. LCMS [M+H] + = 313.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.08 (s, 2H), 8.29 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 3.91 (dd, J = 4.0, 11.2 Hz, 1H), 3.80 - 3.75 (m, 1H), 3.44 - 3.37 (m, 2H), 2.04 - 1.97 (m, 2H), 1.95 - 1.88 (m, 1H), 1.73 - 1.64 (m, 1H), 1.12 (d, J = 6.0 Hz, 3H).

[0150] Intermediate 3: H 2 O (0.5 mL) and EtOH (2 mL) were added to a mixture of 4 - (((2R,4R)-2 - methyltetrahydro - 2H - pyran - 4 - yl)amino)-3 - nitroquinoline - 6 - carbonitrile (70 mg, 224 μmol, 1.0 equiv), NH 4 Cl (120 mg, 2.24 mmol, 10 equiv) and Fe (125 mg, 2.24 mmol, 10 equiv). The reaction mixture was heated to 80 °C for 1 h. Then the mixture was diluted with ethanol (20 mL) and filtered. The filtrate was concentrated in vacuo, and the resulting solid was partitioned between saturated aqueous sodium bicarbonate (20 mL) and DCM (30 mL). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to afford the title compound as a brown solid, which was used directly in the next step without further purification. LCMS [M+H] + = 283.2. 1 H NMR (400 MHz, MeOD - d 4)δ ppm: 8.55 (d, J = 1.6 Hz, 1H), 8.51 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 1.6, 8.8 Hz, 1H), 3.99 - 3.94 (m, 1H), 3.65 - 3.58 (m, 1H), 3.48 - 3.40 (m, 2H), 1.93 - 1.79 (m, 2H), 1.67 - 1.58 (m, 1H), 1.30 - 1.28 (m, 1H), 1.17 (d, J = 6.4 Hz, 3H).

[0151] Intermediate 4 [Chemical formula] Intermediate 4 was prepared in the same manner as Intermediate 3 using 4,6 - dichloro - 3 - nitroquinoline as the starting material.

[0152] 6 - chloro - N - (3,4 - dimethylbenzyl) - N - ((2R,4R) - 2 - methyltetrahydro - 2H - pyran - 4 - yl) - 3 - nitroquinoline - 4 - amine: LCMS [M + H] + = 472.2. 1 H NMR (400 MHz, DMSO - d 6 )δ ppm: 9.06 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.88 (dd, J = 2.4, 8.9 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.30 - 6.23 (m, 2H), 4.27 (br s, 2H), 3.93 - 3.83 (m, 1H), 3.80 - 3.70 (m, 1H), 3.62 (s, 3H), 3.46 (s, 3H), 3.41 - 3.34 (m, 2H), 1.94 (d, J = 13.6 Hz, 1H), 1.89 - 1.81 (m, 1H), 1.79 - 1.64 (m, 1H), 1.50 - 1.38 (m, 1H), 1.08 (d, J = 6.0 Hz, 3H).

[0153] 6 - chloro - N - ((2R,4R) - 2 - methyltetrahydro - 2H - pyran - 4 - yl) - 3 - nitroquinoline - 4 - amine: LCMS [M + H] + = 322.1. 1 H NMR (400 MHz, CDCl 3)δ ppm: 9.38 (s, 1H), 9.13 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 2.4, 8.8 Hz, 1H), 4.38 - 4.22 (m, 1H), 4.17 - 4.09 (m, 1H), 3.63 - 3.51 (m, 2H), 2.25 - 2.11 (m, 2H), 1.86 - 1.73 (m, 1H), 1.55 - 1.45 (m, 1H), 1.29 (d, J = 6.4 Hz, 3H).

[0154] Intermediate 4: LCMS [M + H] + = 292.1. 1 H NMR (400 MHz, CDCl 3 )δ ppm: 8.48 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 2.0, 8.8 Hz, 1H), 4.02 (dd, J = 3.6, 11.6 Hz, 1H), 3.89 (br s, 2H), 3.55 - 3.35 (m, 4H), 1.97 - 1.78 (m, 2H), 1.62 - 1.50 (m, 1H), 1.21 (d, J = 6.0 Hz, 3H).

[0155] Intermediate 5

Chemical Structure

[0156] Intermediate 5: AcOH (1.0 mL, 17.5 mmol, 20 equiv) was added to a solution of 2-chloro-N-(6-cyano-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)quinolin-3-yl)acetamide (337 mg, 845 μmol, 1.0 equiv) in dioxane (6 mL, 0.1 M) under N 2 atmosphere. The mixture was stirred at room temperature for 12 h at 100 °C. The reaction was poured into water (20 mL), then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo and the resulting crude material was purified by silica gel chromatography (100% EtOAc) to give Intermediate 5 as a yellow solid. LCMS [M+H]+ = 341.1. 1 H NMR (400 MHz, DMSO-d 6)δ ppm: 9.39 (s, 1H), 9.01 (br s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 1.6, 8.4 Hz, 1H), 5.33 (br s, 2H), 4.30 - 4.13 (m, 1H), 3.89 - 3.66 (m, 2H), 3.40 - 3.37 (m, 1H), 2.55 - 2.51 (m, 1H), 2.29 - 2.01 (m, 3H), 1.26 (d, J = 6.4 Hz, 3H).

[0157] Intermediate 6 [Chemical formula] Ethyl 5-(2-hydroxyethyl)isoxazole-3-carboxylate: To a solution of homopropargyl alcohol (5.40 mL, 71.34 mmol, 1 equiv) and ethyl (chlorohydroxyimino)acetate (32.43 g, 214 mmol, 3 equiv) in EtOAc (500 mL, 0.1 M) was added NaHCO 3 (17.98 g, 214 mmol, 3 equiv). The reaction mixture was stirred at 100 °C for 2 h. The mixture was filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (15% EtOAc in petroleum ether) to give the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 6.52 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.94 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 2.64 (br s, 1H), 1.37 (t, J = 7.2 Hz, 3H).

[0158] Ethyl 5-(2-((methylsulfonyl)oxy)ethyl)isoxazole-3-carboxylate: A mixture of ethyl 5-(2-hydroxyethyl)isoxazole-3-carboxylate (4 g, 20.5 mmol, 1 equiv) and MsCl (2.05 mL, 26.5 mmol, 1.29 equiv) in DCM (80 mL, 0.25 M) was cooled to 0 °C. Et 3N (8.57 mL, 61.5 mmol, 3 eq) was added dropwise, and the mixture was warmed to room temperature over 2.5 h. The reaction mixture was then slowly poured into ice water (100 mL), and the mixture was extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo to afford the title compound as a yellow oil, which was used directly in the next step without further purification. LCMS [M+H]+ = 264.0. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 6.61 - 6.57 (m, 1H), 4.56 - 4.49 (m, 2H), 4.47 - 4.38 (m, 2H), 3.33 - 3.25 (m, 2H), 3.02 - 2.98 (m, 3H), 1.44 - 1.38 (m, 3H).

[0159] Ethyl 5-(2-(methylthio)ethyl)isoxazole-3-carboxylate: A mixture of sodium methanethiolate (2.64 mL, 41.5 mmol, 2 eq) in DMF (60 mL) was sealed with a rubber septum in a round-bottom flask and placed under N 2 atmosphere. Ethyl 5-(2-((methylsulfonyl)oxy)ethyl)isoxazole-3-carboxylate (5.46 g, 20.7 mmol, 1 eq) in DMF (100 mL) was added to the reaction mixture, and then the mixture was stirred at 80 °C for 6 h. The reaction mixture was poured into water (200 mL), and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo to afford the title compound as a yellow oil, which was used directly in the next step without further purification. LCMS [M+H]+ = 216.1. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 6.50 (s, 1H), 4.42 (q, J = 7.2 Hz, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H), 2.12 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).

[0160] Ethyl 5-(2-(methylsulfonyl)ethyl)isoxazole-3-carboxylate: To a solution of ethyl 5-(2-(methylthio)ethyl)isoxazole-3-carboxylate (1.6 g, 6.47 mmol, 1 equiv) in DCE (50 mL, 0.1 M) was added m-CPBA (4.18 g, 19.4 mmol, 3 equiv) portionwise at 0 °C. The reaction mixture was stirred at 85 °C for 3 h. The reaction mixture was poured into a 1:1 mixture of saturated NaHCO 3 (100 mL) and saturated Na 2 SO 3 (100 mL). The solution was extracted with DCM (3 × 100 mL), and the combined organic layers were washed with brine (3 × 200 mL). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo to give the title compound as a yellow solid, which was used in the next step without further purification. LCMS [M+H]+ = 248.0. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 6.59 (s, 1H), 4.44 (q, J = 7.2 Hz, 2H), 3.45 - 3.40 (m, 4H), 2.95 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

[0161] (5-(2-(methylsulfonyl)ethyl)isoxazol-3-yl)methanol: To a solution of ethyl 5-(2-(methylsulfonyl)ethyl)isoxazole-3-carboxylate (900 mg, 3.64 mmol, 1 equiv) in MeOH (10 mL, 0.4 M) was added NaBH 4 (1.38 g, 36.4 mmol, 10 equiv) slowly at 0 °C. The reaction mixture was stirred at 20 °C for 12 h under N 2 atmosphere. The mixture was quenched with H 2 O (5 mL) and saturated NH 4 Cl (5 mL), and the reaction mixture was concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (3% MeOH in DCM) to give the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ ppm 6.37 (s, 1H), 5.47 (t, J = 6.0 Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.57 - 3.50 (m, 2H), 3.23 - 3.16 (m, 2H), 3.03 (s, 3H).

[0162] (5-(2-(Methylsulfonyl)ethyl)isoxazol-3-yl)methyl methanesulfonate: To a solution of (5-(2-(methylsulfonyl)ethyl)isoxazol-3-yl)methanol (930 mg, 4.08 mmol, 1 equiv) in DCM (20 mL, 0.2 M) were slowly added TEA (1.70 mL, 12.2 mmol, 3 equiv) and MsCl (574 μL, 7.42 mmol, 1.82 equiv) at 0 °C. The reaction mixture was stirred at 20 °C for 1 h under N 2 atmosphere. The reaction mixture was slowly poured into ice water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo to give the title compound as a white solid, which was used directly in the next step without further purification. LCMS [M + H]+ = 284.0. 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 6.57 (s, 1H), 5.33 (s, 2H), 3.59 - 3.54 (m, 2H), 3.28 (s, 3H), 3.28 - 3.23 (m, 2H), 3.03 (s, 3H).

[0163] 2-(5-(2-(Methylsulfonyl)ethyl)isoxazol-3-yl)acetonitrile: To a solution of (5-(2-(methylsulfonyl)ethyl)isoxazol-3-yl)methyl methanesulfonate (1.07 g, 3.78 mmol, 1 equiv) in DMF (15 mL, 0.25 M) was added NaCN (277 mg, 5.65 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h under N 2 atmosphere. The reaction mixture was slowly poured into ice water (50 mL) and the mixture was extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL). The organic layer was dried over Na2 SO 4 It was dried over, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (5% MeOH in DCM) to afford the title compound as a yellow oil. Note: 2 M aqueous NaOH solution was added to the separated aqueous phase until pH = 14, and the mixture was quenched with saturated aqueous NaClO solution (100 mL). LCMS [M+H]+ = 215.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 6.48 (s, 1H), 4.19 (s, 2H), 3.58 - 3.52 (m, 2H), 3.27 - 3.21 (m, 2H), 3.03 (s, 3H).

[0164] Intermediate 6: H 2 To a solution of 2-(5-(2-(methylsulfonyl)ethyl)isoxazol-3-yl)acetonitrile (150 mg, 595 μmol, 1 equiv) in O (0.5 mL), a solution of concentrated HCl (2 mL, 20.1 mmol, 33 equiv) was added. The reaction mixture was stirred at 90 °C for 7 h under N 2 atmosphere. The reaction mixture was directly lyophilized to afford Example 6 as a white solid. The crude product was used directly for the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.67 (s, 1H), 6.38 (s, 1H), 3.66 (s, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 6.4 Hz, 2H), 3.02 (s, 3H).

[0165] Intermediate 7

Chemical Structure

[0166] Intermediate 7: To a solution of methyl 2-(5-(methylsulfonyl)pyridin-2-yl)acetate (180 mg, 785 μmol, 1 eq) in THF (3 mL) and H 2 O (3 mL) was added LiOH·H 2 O (65.90 mg, 1.57 mmol, 2 eq) at 0 °C. Then the mixture was stirred at 20 °C for 2 h. The reaction mixture was slowly poured into water (5 mL) and extracted with EtOAc (1 × 5 mL). The aqueous phase was purified directly by RP-chromatography (0% MeCN in water) to give Intermediate 7 as a white solid. 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.88 - 8.82 (m, 1H), 8.16 - 8.09 (m, 1H), 7.59 - 7.51 (m, 1H), 3.55 - 3.49 (m, 2H), 3.27 (s, 3H).

[0167] Intermediate 8

Chemical Structure

[0168] tert-Butyl (Z)-3-amino-3-(((1-(methylsulfonyl)cyclopropane-1-carbonyl)oxy)imino)propanoate: PyBOP (1.58 g, 3.05 mmol, 1 equiv) and DIPEA (2.12 mL, 12.2 mmol, 4 equiv) were added to a solution of 1-(methylsulfonyl)cyclopropanecarboxylic acid (500 mg, 3.05 mmol, 1 equiv) and tert-butyl (Z)-3-amino-3-(hydroxyimino)propanoate (589 mg, 3.05 mmol, 1 equiv) in DCM (15 mL, 0.2 M) at 25 °C. The mixture was then stirred at 25 °C for 12 h. The mixture was quenched with water (40 mL) and extracted with DCM (2 × 40 mL). The combined organic layers were washed with brine (2 × 40 mL). The organic layer was dried over Na 2 SO 4It was dried, filtered, and concentrated in vacuo. The obtained crude material was purified by silica gel chromatography (10 - 50% EtOAc in petroleum ether) to give the title compound as a brown oil. LCMS [M+H]+ = 321.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 6.91 - 6.17 (m, 2H), 3.25 (s, 3H), 3.08 (s, 2H), 1.80 - 1.73 (m, 2H), 1.66 - 1.60 (m, 2H), 1.42 (s, 9H).

[0169] tert-Butyl 2-(5-(1-(methylsulfonyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)acetate: A solution of tert-butyl (Z)-3-amino-3-(((1-(methylsulfonyl)cyclopropane-1-carbonyl)oxy)imino)propanoate (650 mg, 1.83 mmol, 1 equiv) in pyridine (7 mL, 87 mmol, 48 equiv) was stirred at 90 °C for 12 h under a N2 atmosphere. The mixture was concentrated in vacuo, and the obtained crude material was purified by preparative HPLC (NH 4 HCO 3 conditions) to give the title compound as a brown oil. LCMS [M - 56+H]+ = 247.0. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 3.76 (s, 2H), 3.32 (s, 3H), 2.11 - 2.05 (m, 2H), 1.86 - 1.81 (m, 2H), 1.48 (s, 9H).

[0170] Intermediate 8: To a solution of tert-butyl 2-(5-(1-(methylsulfonyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)acetate (90 mg, 267 μmol, 1 equiv) in DCM (2 mL) was added TFA (2 mL, 27 mmol, 100 equiv). The mixture was stirred at 25 °C for 6 h. The solution was concentrated in vacuo to give Intermediate 8 as a brown oil, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl 3)δ ppm: 3.92 (s, 2H), 3.32 (s, 3H), 2.13 - 2.05 (m, 2H), 1.89 - 1.82 (m, 2H).

[0171] Intermediate 9

Chem.

[0172] Intermediate 9: CuSO 4 (1 M in water, 178.78 μL, 0.3 equiv) and sodium L - ascorbate (1 M in water, 178 μL, 0.3 equiv) were added to a solution of 3 - Azido - 1 - (methylsulfonyl)azetidine (105 mg, 595 μmol, 1 equiv), citric acid (125 mg, 595 μmol, 1 equiv) and 3 - butynoic acid (50.1 mg, 595 μmol, 1 equiv) in t - BuOH (2 mL), DMSO (2 mL) and H 2 O (2 mL). N 2It was added under an atmosphere. The reaction mixture was stirred at 20 °C for 12 h. Subsequently, the solution was extracted with DCM (3 × 10 mL) and EtOAc (1 × 10 mL). The aqueous layer was lyophilized under reduced pressure to obtain a pink solid, which was dissolved in DCM (100 mL). The solution was filtered and the filtrate was concentrated in vacuo to obtain the title compound, which was used in the next step without further purification. 1 H NMR (500 MHz, CDCl 3 ) δ ppm: 8.18 (br s, 1H), 5.62 - 5.47 (m, 1H), 4.45 - 4.35 (m, 2H), 4.33 - 4.24 (m, 2H), 3.71 (s, 2H), 3.14 (s, 3H).

[0173] Example 1. Procedure A: Synthesis of Compound 1

Chemical Structure

[0174] 2-{[5-(3-Hydroxyazetidin-1-yl)-1,2,4-oxadiazol-3-yl]methyl}-1-[(2R,4R)-2-methyloxan-4-yl]-1H-imidazo[4,5-c]quinoline-8-carbonitrile (Compound 1): Cs 2 CO 3 (53.7 mg, 164 μmol, 3 equiv) was added to a solution of 1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2-((5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)methyl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (30 mg, 54.9 μmol, 1 equiv) and azetion-3-ol hydrochloride (18.1 mg, 164 μmol, 3 equiv) in DMF (1 mL, 0.05 M) under N 2 atmosphere. The reaction mixture was stirred at 20 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The obtained residue was purified by preparative HPLC (NH 4 OH conditions) to give Compound 1 as a white solid. LCMS [M + H]+ = 446.2. 1 H NMR (400 MHz, DMSO-d 6)δ ppm 9.35 (s, 1H), 9.02 (br s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 5.90 (d, J = 6.8 Hz, 1H), 5.32 (br s, 1H), 4.63 - 4.58 (m, 1H), 4.56 (br s, 2H), 4.36 - 4.30 (m, 2H), 4.26 - 4.14 (m, 1H), 3.90 (dd, J = 4.4, 8.8 Hz, 2H), 3.83 - 3.58 (m, 2H), 2.42 - 2.38 (m, 1H), 2.17 (br s, 2H), 2.09 - 1.99 (m, 1H), 1.24 (d, J = 6.0 Hz, 3H).

[0175] Example 2. Procedure B: Synthesis of Compound 2 [Chemical formula] Methyl 1 - ((8 - cyano - 1 - ((2R,4R) - 2 - methyltetrahydro - 2H - pyran - 4 - yl) - 1H - imidazo[4,5 - c]quinolin - 2 - yl)methyl) - 2 - oxo - 1,2 - dihydropyridine - 3 - carboxylate: A mixture of intermediate 5 (10 mg, 29.3 μmol, 1 equivalent), methyl 2 - hydroxynicotinate (8.99 mg, 58.7 μmol, 2 equivalents) and Cs 2 CO 3 (28.7 mg, 88.0 μmol, 3 equivalents) in DMF (2 mL, 0.01 M) was stirred at 35 °C for 12 h. The mixture was filtered and the filtrate was purified by preparative HPLC (NH 4 HCO 3 conditions) to give the title compound as a white solid. LCMS [M + H]+ = 458.2. 1 H NMR (400 MHz, DMSO - d 6)δ ppm: 9.28 (s, 1H), 9.01 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.22 (dd, J = 2.0, 6.8 Hz, 1H), 8.15 (dd, J = 2.0, 7.2 Hz, 1H), 8.05 (dd, J = 1.6, 8.4 Hz, 1H), 6.49 (t, J = 6.8 Hz, 1H), 5.69 (s, 2H), 5.60 - 5.41 (m, 1H), 4.23 - 4.10 (m, 1H), 3.94 - 3.75 (m, 2H), 3.71 (s, 3H), 2.47 - 2.36 (m, 1H), 2.30 - 2.05 (m, 3H), 1.27 (d, J = 6.4 Hz, 3H).

[0176] 1 - ({8 - Cyano - 1 - [(2R,4R) - 2 - methyloxan - 4 - yl] - 1H - imidazo[4,5 - c]quinolin - 2 - yl}methyl) - 2 - oxo - 1,2 - dihydropyridine - 3 - carboxylic acid (Compound 2): A mixture of methyl 1 - ((8 - cyano - 1 - ((2R,4R) - 2 - methyltetrahydro - 2H - pyran - 4 - yl) - 1H - imidazo[4,5 - c]quinolin - 2 - yl)methyl) - 2 - oxo - 1,2 - dihydropyridine - 3 - carboxylate (67 mg, 146 μmol, 1 equiv) and LiOH·H 2 O (30.7 mg, 732 μmol, 5 equiv) in THF (5 mL, 0.03 M) was stirred at 25 °C for 12 h. The mixture was adjusted to pH = 3 with 1 N HCl and concentrated in vacuo. The resulting residue was purified by preparative HPLC (NH 4 HCO 3 conditions) to give Example 2 as a white solid. LCMS [M + H]+ = 444.2. 1 1H NMR (400 MHz, DMSO - d 6)δ ppm: 14.03 (s, 1H), 9.28 (s, 1H), 9.02 (s, 1H), 8.53 - 8.47 (m, 1H), 8.45 - 8.40 (m, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.07 (dd, J = 1.6, 8.8 Hz, 1H), 6.87 (t, J = 6.8 Hz, 1H), 5.91 (s, 2H), 5.53 (brs, 1H), 4.17 (brs, 1H), 3.97 - 3.76 (m, 2H), 2.46 - 2.39 (m, 1H), 2.31 - 2.05 (m, 3H), 1.27 (d, J = 6.0 Hz, 3H).

[0177] Example 3. Procedure C: Synthesis of Compound 3 [Chemical formula] The compound of Example 3 was prepared by the same method as in Example 1 using Intermediate 4 as the starting material.

[0178] 3 - ((8 - chloro - 1 - ((2R,4R) - 2 - methyltetrahydro - 2H - pyran - 4 - yl) - 1H - imidazo[4,5 - c]quinolin - 2 - yl)methyl) - 5 - (trichloromethyl) - 1,2,4 - oxadiazole: LCMS [M + H]+ = 502.0.

[0179] 1 - [3 - ({8 - chloro - 1 - [(2R,4R) - 2 - methyloxan - 4 - yl] - 1H - imidazo[4,5 - c]quinolin - 2 - yl}methyl) - 1,2,4 - oxadiazol - 5 - yl]azetidin - 3 - ol (Compound 3): LCMS [M + H]+ = 455.2. 1 H NMR (400 MHz, DMSO - d 6)δ ppm 9.20 (s, 1H), 8.68 (br s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.76 (dd, J = 2.0, 8.8 Hz, 1H), 5.90 (d, J = 6.4 Hz, 1H), 5.24 (br s, 1H), 4.64 - 4.57 (m, 1H), 4.53 (s, 2H), 4.32 (t, J = 7.8 Hz, 2H), 4.22 - 4.13 (m, 1H), 3.90 (dd, J = 4.4, 8.8 Hz, 2H), 3.76 - 3.58 (m, 2H), 2.47 - 2.38 (m, 1H), 2.27 - 2.11 (m, 2H), 2.06 - 1.97 (m, 1H), 1.23 (d, J = 6.0 Hz, 3H).

[0180] Example 4. Procedure D: Synthesis of Compound 4 [Chemical formula] 2 - ((3 - Bromo - 1H - pyrazol - 1 - yl)methyl) - 1 - ((2R,4R) - 2 - methyltetrahydro - 2H - pyran - 4 - yl) - 1H - imidazo[4,5 - c]quinoline - 8 - carbonitrile: To a solution of 3 - bromo - 1H - pyrazole (63.1 mg, 429 μmol, 1.5 eq) in THF (5 mL) was added NaH (60% in mineral oil, 22.9 mg, 572 μmol, 2 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. Then, a solution of intermediate 5 (100 mg, 286 μmol, 1 eq) in THF (3 mL) was added dropwise. Subsequently, the reaction mixture was stirred at 0 - 5 °C for an additional 2 hours. Then, the mixture was slowly poured into ice - water (10 mL), and the mixture was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The resulting crude mixture of isomers was purified by silica gel chromatography (80 - 100% EtOAc in petroleum ether) to give the title compound as a yellow solid. LCMS [M + H]+ = 451.0 / 453.0. 1 1H NMR (500 MHz, DMSO - d 6)δ ppm 9.42 - 9.34 (m, 1H), 8.97 (br s, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.00 (br s, 1H), 6.50 (d, J = 2.5 Hz, 1H), 5.99 (s, 2H), 5.50 - 5.28 (m, 1H), 4.24 - 4.10 (m, 1H), 3.81 - 3.59 (m, 2H), 2.48 - 2.39 (m, 1H), 2.22 - 2.05 (m, 1H), 2.02 - 1.69 (m, 2H), 1.23 (d, J = 6.0 Hz, 3H).

[0181] N-(1-{[8-Cyano-1-(2-methyloxan-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}-1H-pyrazol-3-yl)methanesulfonamide (Compound 4): To a solution of 2-((3-bromo-1H-pyrazol-1-yl)methyl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (40 mg, 82.7 μmol, 1 equiv) and methanesulfonamide (78.7 mg, 826 μmol, 10 equiv) in dioxane (2 mL, 0.04 M), t-BuBrettPhos Pd G3 (7.1 mg, 8.27 μmol, 0.1 equiv) and tBuONa (23.8 mg, 248 μmol, 3 equiv) were added successively under N 2 atmosphere. The reaction mixture was heated to 120 °C and stirred for 16 h under N 2 atmosphere. The reaction mixture was concentrated in vacuo. The resulting residue was diluted with DCM (10 mL) and ice water (10 mL). The mixture was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The obtained crude material was purified by preparative HPLC (NH 4 HCO 3 conditions) to give Example 4 as a white solid. LCMS [M+H]+ = 466.1. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 9.79 (broad singlet, 1H), 9.38 (singlet, 1H), 8.98 (broad singlet, 1H), 8.34 (doublet, J = 8.8 Hz, 1H), 8.07 (doublet of doublets, J = 1.2, 8.8 Hz, 1H), 7.89 (broad singlet, 1H), 6.09 (doublet, J = 2.4 Hz, 1H), 5.88 (singlet, 2H), 5.46 - 5.24 (multiplet, 1H), 4.25 - 4.04 (multiplet, 1H), 3.79 - 3.56 (multiplet, 2H), 2.96 (singlet, 3H), 2.46 - 2.35 (multiplet, 1H), 2.19 - 2.03 (multiplet, 1H), 2.02 - 1.68 (multiplet, 2H), 1.22 (doublet, J = 6.0 Hz, 3H).

[0182] Example 5. Procedure E: Synthesis of Compound 5

Chemical Structure

[0183] Example 6. Procedure F: Synthesis of Compound 6

Chemical Structure

[0184] N-(5-{[8-Cyano-1-(2-methyloxan-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}pyridin-2-yl)methanesulfonamide (Compound 6): To a solution of 2-((6-chloropyridin-3-yl)methyl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (50 mg, 87.34 μmol, 1 equiv) and methanesulfonamide (83.1 mg, 873 μmol, 10 equiv) in dioxane (2 mL, 0.04 M), tBuBrettPhos Pd G3 (7.46 mg, 8.73 μmol, 0.1 equiv) and t-BuONa (25.2 mg, 262 μmol, 3 equiv) were added successively under N 2 atmosphere. Then, the reaction mixture was heated to 120 °C and stirred for 16 h under N 2 atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (3 × 10 mL). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The resulting residue was purified by preparative HPLC (NH 4 OH conditions) to afford Example 6 as a white solid. LCMS [M+H]+ = 477.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.56 (brs, 1H), 9.31 (s, 1H), 8.97 (s, 1H), 8.35 - 8.21 (m, 2H), 8.03 (dd, J = 1.2, 8.4 Hz, 1H), 7.69 (dd, J = 2.0, 8.4 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 5.43 - 5.15 (m, 1H), 4.53 (s, 2H), 4.19 - 4.10 (m, 1H), 3.25 (brs, 3H), 2.22 - 2.02 (m, 2H), 1.89 (brs, 2H), 1.21 (d, J = 6.1 Hz, 3H).

[0185] Example 7. Procedure G: Synthesis of Compound 7

Chemical Structure

[0186] Ethyl 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetate: To a solution of ethyl 3-((6-cyano-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)quinolin-3-yl)amino)-3-oxopropanoate (500 mg, 941 μmol, 1 equiv) in DMF (5 mL, 0.2 M) was added AcOH (0.5 mL, 8.74 mmol, 0.5 mL, 9.3 equiv). The mixture was stirred under microwave (2 bar) at 130 °C for 9 h. The reaction mixture was concentrated in vacuo and the resulting crude material was purified by silica gel chromatography (50 - 100% EtOAc in petroleum ether) to afford the title compound as a brown solid. LCMS [M + H]+ = 365.1. 11H NMR (400 MHz, CDCl 3 ) δ ppm: 9.43 (s, 1H), 9.10 (d, J = 18.8 Hz, 1H), 8.66 (br s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 4.93 (br s, 1H), 4.37 (br s, 1H), 4.30 (s, 2H), 3.83 (s, 3H), 3.76 (br s, 2H), 2.41 (br s, 1H), 2.17 (br s, 1H), 2.02 (s, 2H), 1.40 (d, J = 6.0 Hz, 3H).

[0187] 2-(8-Cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetohydrazide: A solution of ethyl 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetate (50 mg, 112 μmol, 1 equiv) and hydrazine hydrate (11.2 μL, 225 μmol, 2.0 equiv) in EtOH (2 mL, 0.05 M) was stirred at 0 °C for 2 h. The reaction mixture was filtered and purified by preparative HPLC (NH 4 HCO 3 conditions) and lyophilized to give the title compound as a white solid. LCMS [M + H]+ = 365.1. 1 1H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.48 (br s, 1H), 9.33 (s, 1H), 9.04 (br s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.05 (dd, J = 1.6, 8.4 Hz, 1H), 5.29 (br s, 1H), 4.35 (d, J = 4.0 Hz, 2H), 4.20 (br s, 1H), 4.12 (br s, 2H), 3.74 (br s, 2H), 2.28 - 2.04 (m, 4H), 1.25 (d, J = 6.0 Hz, 3H).

[0188] 1-[(2R,4R)-2-Methyloxan-4-yl]-2-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]-1H-imidazo[4,5-c]quinoline-8-carbonitrile z(Compound 7): To a solution of 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetohydrazide (17 mg, 45.1 μmol, 1 equiv) in DMSO (0.5 mL, 0.1 M), CDI (14.6 mg, 90.2 μmol, 2.0 equiv) was added. The mixture was stirred at 70 °C for 1 h under microwave (2 bar). The reaction mixture was filtered, purified by preparative HPLC (formic acid conditions), and lyophilized to give Example 7 as a white solid. LCMS [M+H]+ = 391.2. 1 H NMR(400MHz,DMSO-d 6 )δ ppm: 12.37(s,1H), 9.40(s,1H), 9.02(br s,1H), 8.34(d,J = 8.4Hz,1H), 8.08(dd,J = 1.2,8.8Hz,1H), 5.21(br s,1H), 4.71(s,2H), 4.18(br s,1H), 3.92 - 3.60(m,2H), 2.48 - 2.40(m,1H), 2.23 - 1.92(m,3H), 1.24(d,J = 6.0Hz,3H).

[0189] Example 8. Procedure H: Synthesis of Compound 8

Chemical formula

[0190] 2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetaldehyde: A suspension of 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethan-1-ol (4 g, 16.5 mmol, 1 equiv) and Dess-Martin periodinane (7.30 mL, 23.6 mmol, 1.43 equiv) in DCM (50 mL) was stirred at 25 °C for 4 h. The reaction mixture was diluted with DCM (250 mL) and washed with saturated NaHCO 3 aqueous solution (250 mL), water (250 mL) and brine (100 mL). The organic layer was dried over Na 2 SO 4 and filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (20% EtOAc in petroleum ether) to afford the title compound as a yellow oil. LCMS [M + H]+ = 241.1. 1 H NMR (400 MHz, CDCl 3)9.74 (t, J = 1.6 Hz, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 5.42 - 5.41 (m, 2H), 3.63 - 3.60 (m, 1H), 3.61 (d, J = 1.5 Hz, 1H), 3.56 (d, J = 8.0 Hz, 2H), 0.93 - 0.89 (m, 2H), -0.02 (s, 9H).

[0191] 2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetic acid: To a solution of 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetaldehyde (1 g, 4.16 mmol, 1 equiv) and 2-methylbut-2-ene (2.64 mL, 25.0 mmol, 6 equiv) in t-BuOH (20 mL), THF (10 mL) and water (5 mL), NaH 2 PO 4 (1.5 g, 12.5 mmol, 3 equiv) and NaClO 2 (933 μL, 12.5 mmol, 3 equiv) were added at 25 °C. The reaction mixture was stirred at 25 °C for 1 h and then concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo to give the title compound as a colorless oil, which was used in the next step without further purification. LCMS [M + H]+ = 257.1.

[0192] 1-((2R,4R)-2-Methyltetrahydro-2H-pyran-4-yl)-2-((1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile: A solution of 2-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)acetic acid (600 mg, 2.34 mmol, 1.32 eq), intermediate 3 (500 mg, 1.77 mmol, 1 eq), DIPEA (1.8 g, 13.93 mmol, 2.43 mL, 7.86 eq) and T3P (50% in EtOAc, 1.40 mL, 4.71 mmol, 2.7 eq) in EtOAc (10 mL) was stirred at 80 °C for 6 h under microwave irradiation. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (100% EtOAc) to give the title compound as a yellow oil. LCMS [M+H]+ = 503.2.

[0193] 2-((1H-Pyrazol-4-yl)methyl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile: TFA (3 mL) was added to a solution of 1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methyl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (280 mg, 557 μmol, 1 eq) in DCM (10 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 3 h. Then the reaction mixture was concentrated in vacuo to give the title compound as a yellow oil, which was used in the next step without further purification. LCMS [M+H]+ = 373.1.

[0194] 1-[(2R,4R)-2-Methyloxan-4-yl]-2-{[1-(oxetan-3-yl)-1H-pyrazol-4-yl]methyl}-1H-imidazo[4,5-c]quinoline-8-carbonitrile (Compound 8): In a glove box, 2-((1H-pyrazol-4-yl)methyl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (80 mg, 214 μmol, 1 equiv) and Cs 2 CO 3 (160 mg, 491 μmol, 2.3 equiv) in DMF (1 mL) was added 3-iodooxetane (160 mg, 869 μmol, 4.1 equiv) at 25 °C. The reaction mixture was stirred at 70 °C for 4 h in the glove box. Then the reaction mixture was cooled to 25 °C, diluted with MeOH (2 mL) and filtered. The filtrate was purified by preparative HPLC (NH 4 HCO 3 conditions) to give Example 8 as a yellow solid. LCMS [M+H]+ = 429.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.35 (s, 1H), 8.99 - 8.95 (m, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.06 - 8.02 (m, 1H), 7.83 (s, 1H), 7.57 (s, 1H), 5.54 (quin, J = 7.2 Hz, 1H), 5.47 - 5.09 (m, 1H), 4.92 - 4.86 (m, 2H), 4.85 - 4.81 (m, 2H), 4.42 (s, 2H), 4.13 (br s, 1H), 3.73 (br s, 2H), 2.16 - 1.63 (m, 4H), 1.20 (d, J = 6.0 Hz, 3H).

[0195] Example 9. Synthesis of Further Compounds of Formula (I) Further compounds of the present invention were synthesized according to the above procedure as described in Table 3 below.

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

[0196] The property evaluation of the exemplary compounds of the present disclosure is shown in Table 4.

Table 4-1

Table 4-2

Table 5

[0197] A 10 mM compound solution was prepared in DMSO. An 11-point three-fold dilution was performed, and the highest concentration was 10 μM. The 10 mM compound DMSO solution was added to a Labcyte LDV plate, and the compound concentration in the source plate was 10 mM. The first compound concentration in the Inter-plate (Labcyte 384-well PP plate) was 4.938×10 -1 mM, which was prepared by transferring 1.5 μL of the 10 mM compound from the source plate to 28.9 μL of DMSO. The second compound concentration in the Inter-plate was 1.829×10 -2 mM, which was prepared by transferring 60 nL of the 10 mM compound from the source plate to 32.7 μL of DMSO. The third compound concentration in the Inter-plate was 6.774×10 -4It was mM, which was prepared by transferring 2.5 nL of 10 mM compound from the source plate to 36.9 μL of DMSO. 100 nL of the reference compound was dispensed into column 1 of the low control wells, and 100 nL of DMSO was dispensed into column 24 of the high control wells. The compound was dispensed into columns 2 - 23 of the assay plate, and DMSO was filled to make the total volume 100 nL.

[0198] 2X LRRK2 enzyme solution (final concentration 3 nM) was prepared in assay buffer (Tris - HCl pH 8.0: 50 mM, MgCl 2 : 5 mM, EDTA: 1 mM, Brij - 35: 0.01%, 2 mM DTT). 2X substrate solution was prepared: LRRK2tide substrate (final concentration 400 nM) and ATP (final concentration 25 μM) in assay buffer. 5 μL of the 2X LRRK2 enzyme solution was dispensed into each well of the assay plate by Multidrop. The assay plate was rotated at 1,000 rpm for 1 minute and incubated at 23 °C for 15 minutes. 5 μL of the 2X ATP / LRRKtide solution was dispensed into each well in the assay plate by Multidrop. The assay plate was rotated at 1,000 rpm for 1 minute and incubated at 23 °C for 120 minutes.

[0199] 2X detection solution was prepared: Tb - pERM (pLRRKtide) antibody (final concentration 0.25 nM) and EDTA (final concentration 10 mM) in TR - FRET dilution buffer. 10 μL of the 2X detection solution was dispensed into each well of the assay plate to stop the kinase reaction by Multidrop. The assay plate was rotated at 1,000 rpm for 1 minute and incubated at 23 °C for 30 minutes. Then, the assay plate was read on an Envision configured for LanthaScreen® TR - FRET.

[0200] pS935 LRRK2 Cell Assay The following protocol describes an in vitro method for measuring phosphorylation at Ser935 on wild-type LRRK2 overexpressed in recombinant HEK-293T cells. This method is based on the HTRF technology that combines fluorescence resonance energy transfer (FRET) with time-resolved measurement (TR). Phospho-LRRK2(Ser935) is detected in a sandwich assay format using two different specific antibodies, one labeled with Eu 3+ -cryptate (donor) and the second labeled with d2 (acceptor). When the fluorophores are in close proximity, excitation of the donor by a light source (flash lamp) stimulates FRET to the acceptor, which then fluoresces at a specific wavelength (665 nm). Fluorescence emission from the donor at 615 nm is also measured to enable ratiometric reduction of the data. The specific signal is proportional to phospho-LRRK2(Ser935).

Table 6

[0201] Protocol: Day 0 Plasmid transient transfection: DMEM medium, FBS, DPBS, Trans-IT, and OPTI-MEM reagents were warmed to room temperature. HEK293T cells were cultured in DMEM + 10% FBS complete medium in a T150 flask to approximately 80% confluence density before transfection. Next, the cells were washed with 10 mL of PBS and detached with 3 mL of 0.25% trypsin. 30×10E6 HEK293T cells were seeded in a 15 cm dish in DMEM + 10% FBS complete medium.

[0202] DNA, TransIT-LT1, OPTI-MEM complex was prepared: 2000 μL of OPTI-MEM was added to a 15 mL conical tube, then 20 μg of plasmid was added to the OPTI-MEM and mixed, followed by adding 60 μL of TransIT-LT1 to the plasmid OPTI-MEM mixture and mixing. The resulting mixture was incubated for 15 minutes.

[0203] The above plasmid, DNA, and OPTI-MEM mixture were dropped onto a 15-cm dish and the droplets were ensured to be evenly distributed. The culture dish was gently rocked back and forth and from left to right to evenly distribute the complex. The transfection dish was incubated at 37 °C in 5% CO 2 for 24 hours.

[0204] Day 1: The transfected HEK293T cells were collected in a 15-cm dish. The medium was aspirated from the tissue culture dish and the dish was washed by dispensing 10 mL of 1X DPBS into the 15-cm dish. The 1X DPBS was aspirated and 3 mL of trypsin was dispensed into the 15-cm dish. The dish was incubated with trypsin at room temperature for 3 minutes until the cells detached. 10 mL of DMEM + 10% FBS medium was added to the 15-cm dish and triturated to ensure a homogeneous cell suspension.

[0205] The homogeneous cell suspension was transferred to a 50-mL tube and centrifuged at 1,000 rmp / min for 5 minutes. The supernatant was aspirated and the pellet was resuspended in 20 mL of complete medium. 1 mL of the cell suspension was transferred for cell counting. The cell suspension was diluted to 2×10E5 cells / mL. 50 μL of the cell suspension was added to a 384-well plate. The plate was rapidly rotated at 800 rpm for 1 minute and then incubated overnight at 37 °C in 5% CO 2 2.

[0206] Day 2: Compound dispensing: The compound was diluted (10 mM DMSO stock solution) and added in duplicate to the assay plate by a Tecan liquid handler (highest concentration: 10 μM, 3-fold serial dilution, 9 doses). The DMSO concentration in each well was normalized to 0.2%. The plate was rapidly rotated at 1,000 rpm for 1 minute. The plate was incubated at 37 °C in 5% CO 2 for 2 hours.

[0207] 1X lysis buffer supplemented with the blocking reagent was prepared (e.g., 1 mL of 4X lysis buffer + 3 mL of water + 40 μL of 100X stock blocking reagent). Antibody diluent was prepared by diluting 40-fold d2 and cryptate antibodies in detection buffer (e.g., 1520 μL of detection buffer + 40 μL of d2-antibody stock solution + 40 μL of cryptate-antibody stock solution).

[0208] After incubating for 2 hours, the cell plates were removed from the incubator. The medium was removed by a plate washer, then 16 μL of the supplemented lysis buffer was added at 1X to each well and incubated for 30 minutes at room temperature with shaking (800 rpm / min). 4 μL of the antibody diluent was added to each well, covered with a top seal, and incubated overnight in a 23 °C incubator.

[0209] Day 3: The HTRF signal was read on a Wallac 2104 EnVision® multilabel reader (665 nm and 615 nm). The data was analyzed by XL fit software.

[0210] The biochemical data of the exemplary compounds of the present disclosure are shown in Table 6.

Table 7

[0211] The above invention has been described in some detail by way of illustration and example for the purpose of a clear understanding. However, those skilled in the art will understand that certain changes and modifications can be made within the scope of the appended claims. In addition, each reference provided in this specification is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. If there is a conflict between this application and the references provided in this specification, this application shall prevail.

Claims

1. A compound of formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6-membered heterocycloalkyl having 1 to 2 heteroatoms each independently being N, O or S, or a 5- or 6-membered heteroaryl having 1 to 2 heteroatoms each independently being N, O or S Each R １ is independently C １～６ alkyl or =O, and ring B is a 5- or 6-membered heteroaryl having 1 to 4 heteroatoms each independently being N, O or S Each R ２ is C １～６ alkyl, -OH, =O, C(O)R ２ａ , C(O)OR ２ｂ , OC(O)R ２ａ , S(O) ２ R ２ａ , S(O) ２ OR ２ｂ , OS(O) ２ R ２ａ , N(R ２ｂ ), S(O) ２ R ２ａ , S(O) ２ N(R ２ｂ )(R ２ｃ ), C ３～６ cycloalkyl, C １～６ alkyl-C ３～６ cycloalkyl, or 3- to 6-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S, each alkyl or cycloalkyl being substituted with 1 to 3 R ２ｄ groups, and each heterocycloalkyl being substituted with 0 to 3 R ２ｅ groups, Each R ２ｂ and R ２ｃ is hydrogen or C １～６ alkyl, Each R ２ｄ is independently C(O)R ２ｄ１ or S(O) ２ R ２ｄ１ and Each R ２ｅ is independently C １～６ alkyl, -OH, =O, C(O)R ２ｅ１ or S(O) ２ R ２ｅ１ wherein Each R ２ａ , R ２ｄ１ and R ２ｅ１ is independently C １～６ alkyl, Each R ３ and R ４ is hydrogen, C １～６ alkyl, C １～６ alkoxy, halogen, C １～６ haloalkyl, C １～６ haloalkoxy, or -CN, subscript n is 0, 1 or 2 subscripts m and p are each independently an integer from 1 to 4, a compound or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein subscript n is 1 or 2.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein subscript m is 1.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein subscript p is 1.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6-membered heterocycloalkyl having 1 heteroatom being N, O or S, or a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms each independently being N, O or S.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is tetrahydropyranyl.

7. Each R １ is independently C １～６ alkyl, a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. Each R １ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is Me.

9. R ３ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or halogen.

10. R ３ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

11. Each R ４ is independently halogen or -CN, a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. Each R ４ is independently Cl or -CN, a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. Formula Ia: [Chemical Formula 2] The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, having the structure of

14. Formula Ib: [Chemical Formula 3] The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, having the structure of

15. Formula Ic: 【Chemical Formula 4】 The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, having the structure of

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms each independently being N, O or S.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein ring B is pyrazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, or pyridyl.

18. The group 【Chemical Formula 5】 is ​ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

19. Each R ２ is C １～３ alkyl, =O, C(O)OR ２ｂ , OC(O)R ２ａ , S(O) ２ R ２ａ , N(R ２ｂ S(O) ２ R ２ａ , S(O) ２ N(R ２ｂ (R ２ｃ ) is C ３～６ cycloalkyl, or 3- to 6-membered heterocycloalkyl having 1 to 3 heteroatoms each independently being N, O or S, each alkyl or cycloalkyl being substituted with 1 to 2 R ２ｄ groups, and each heterocycloalkyl being optionally substituted with 1 to 2 R ２ｅ groups, Each R ２ｂ and R ２ｃ is hydrogen or C １～３ alkyl, Each R ２ｄ is independently C(O)R ２ｄ１ or S(O) ２ R ２ｄ１ and Each R ２ｅ is independently C １～３ alkyl, -OH, =O, C(O)R ２ｅ１ or S(O) ２ R ２ｅ１ and Each R ２ａ , R ２ｄ１ and R ２ｅ１ is, independently, C １～３ alkyl, the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

20. Each R ２ is independently =O, -COOH, -C(O)OMe, -SO ２ Me, -NHSO ２ Me, -CH ２ CH ２ SO ２ Me 【Chemical Formula 7】 The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

21. The group [Chemical 8] is 【Chemical Formula 9】 The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of the compound in Table 1.

23. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

24. A method of inhibiting LRRK2 in a cell, the method comprising contacting the cell with an effective amount of the compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

25. A method of treating an LRRK2-related disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

26. The method according to claim 25, wherein the LRRK2-related disease or condition is Parkinson's disease, Lewy body dementia, frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, Alzheimer's disease, tauopathy disease, or α-synucleinopathy.

27. The method according to claim 25, wherein the LRRK2-related disease or condition is inflammatory bowel disease.

28. The method according to claim 25, wherein the LRRK2-related disease or condition is an autophagy-related disease or condition.

29. The method according to claim 28, wherein the autophagy-related disease or condition is α1-antitrypsin deficiency (AATD).

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