LRRK2 inhibitor

Abstract

The present invention relates to imidazo[4,5-c]quinoline compounds of formula (I) and pharmaceutically acceptable salts thereof. The present invention also relates to pharmaceutical compositions 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 / 341,068, filed May 12, 2022, the entire disclosure of which is incorporated herein by reference for all purposes.

Background Art

[0002] LRRK2 is a 286 kDa protein in the ROCO protein family with a complex multi - domain structure. Established protein motifs for LRRK2 include an armadillo - like (ARM) domain, ankyrin - like (ANK) domain, leucine - rich repeat (LRR) domain, Ras (renin - angiotensin system) complex (ROC) domain, the C - terminus of the ROC (COR) domain, a kinase domain, and a 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 is structurally homologous to mitogen - activated protein kinase kinase kinase (MAPKKK) and has been shown to phosphorylate many cellular proteins in vitro, but its endogenous substrates have not yet been identified. LRRK2 has been found in various regions of the brain and in some peripheral tissues including the heart, lungs, spleen, and kidneys.

[0003] Due to its multi-domain architecture, each related to putative protein-protein interactions, guanosine triphosphatase (GTPase) activity, and kinase activity, LRRK2 can play complex roles in numerous cellular processes. For example, LRRK2 has been associated with NFAT inhibition in the immune system, and is linked to vesicular transport, presynaptic homeostasis, mammalian target of rapamycin (mTOR) signaling, receptor tyrosine kinase MET-mediated signaling in papillary and thyroid cancers, cytoskeletal dynamics, the mitogen-activated protein kinase (MAPK) pathway, the tumor necrosis factor-α (TNF-α) pathway, the Wnt pathway, and autophagy. Genome-wide association (GWA) genetic studies have suggested that LRRK2 is involved in the etiology of various human diseases such as PD and inflammatory bowel disease (e.g., 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 pro-inflammatory cytokines (high levels of TNF-α, IL-10, IL-12, and low 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 more than 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 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 characteristic pathological processes. The most common pathological processes that cause dementia are Alzheimer's disease (AD), cerebral amyloid angiopathy (CM), and prion-mediated diseases (see, for example, 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, 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. The LRRK2 mutation has 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, which is likely the result of 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 disclosed in WO2011 / 141756, WO2012 / 028629, WO2012 / 058193, WO2017 / 046675, WO2018 / 163030, WO2018 / 163066, WO2021 / 080929, and U.S. Patent Application Publication No. 2021 / 0002260, are described. It is desirable to provide a compound that is a potent and selective inhibitor of LRRK2 and has a favorable pharmacokinetic profile and the ability to cross the blood-brain barrier. The present invention aims to address these and other problems. SUMMARY OF THE INVENTION

[0008] In some aspects, the present disclosure provides a compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein Ring A is C 3~8 cycloalkyl, or a 3- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms each independently being N, O, or S, or a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms each independently being N, O, or S; Each R 1 is independently C 1~6 alkyl, -CN, or =O; R 2 is -N(R 2a )(R 2b ), -C(O)R 2b , -C(O)OR 2b , -OC(O)R 2b , -C(O)N(R 2a )(R 2b ), -N(R 2a C(O)R 2b , -OC(O)N(R 2a )(R 2b ), -N(R 2a)C(O)OR 2b 、 -S(O)R 2b 、 -S(O)2R 2b 、 -S(O)2N(R 2a )(R 2b )、 -N(R 2a )S(O)2R 2b 、 -S(O)(NH)N(R 2a )(R 2b )、 or -N(R 2a )S(O)(NH)R 2b ; R 2a is hydrogen or C 1~6 alkyl; R 2b is hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, C 1~6 alkyl-C 3~8 cycloalkyl, heterocycloalkyl, C 1~6 alkyl-heterocycloalkyl, C 6~10 aryl, C 1~6 alkyl-C 6~10 aryl, heteroaryl or C 1~6 alkyl-heteroaryl, each heterocycloalkyl has 3 to 10 ring members and has 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S, each cycloalkyl, heterocycloalkyl, and heteroaryl is substituted with 0 to 3 R 2b1 groups; each alkyl is substituted with 0 to 6 R 2b3 groups; or alternatively, R 2a and R 2bcombine with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms, each independently N, O, or S, heterocycloalkyl is substituted with 0 to 3 R 2c groups; each R 2b1 and R 2c is independently C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, =O, -C(O)R 2d , -C(O)OR 2d , -OC(O)R 2d , -C(O)N(R 2d )(R 2e ), -N(R 2d )C(O)R 2e , -OC(O)N(R 2d )(R 2e ), -N(R 2d )C(O)OR 2e , -P(O)(OR 2d )(OR 2e ), -S(O)R 2d , -S(O)2R 2d , -S(O)2OR 2d , -S(O)2N(R 2d )(R 2e ), -N(R 2d )S(O)2R 2e , -S(O)(NH)N(R 2d )(R 2e ), -N(R 2d )S(O)(NH)R 2e , C 3~8 cycloalkyl, heterocycloalkyl, C 6~10 aryl, or heteroaryl, and each alkoxy is substituted with 0 to 3 heteroaryls, Each heterocycloalkyl has 3 to 10 ring members and has 1 to 3 heteroatoms each independently being N, O or S. Each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S. Each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with 0 to 3 R 2f groups; Each R 2b3 is independently C 1~6 alkoxy, halogen, C 1~6 haloalkoxy, -N(R 2b2 )2, OH, or -CN; Each R 2b2 is independently hydrogen or C 1~6 alkyl; Each R 2d and R 2e are independently hydrogen or C 1~6 alkyl; Each R 2f is C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, or =O; Each R 2y is independently hydrogen or C 1~6 alkyl; R 2x and R 2z are each independently hydrogen, C 1~6 alkyl, halogen, or C 1~6 haloalkyl; or alternatively, R 2x and R 2z are combined with the atom to which they are attached to form C 3~8 cycloalkyl; alternatively, R 2a and R 2x , or R 2a and one R 2ycombine with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having from 0 to 2 additional heteroatoms, each independently N, O or S, substituted with C 1~6 Each R 3 and R 4 is independently hydrogen, C 1~6 alkyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, -N(R 3a )(R 3b ), -C(O)N(R 3a )(R 3b ), C 3~8 cycloalkyl or C 1~6 alkyl-C 3~8 cycloalkyl; Each R 3a and R 3b is independently hydrogen, C 1~6 alkyl, C 3~8 cycloalkyl, or C 1~6 alkyl-C 3~8 cycloalkyl; The subscript n is 0, 1 or 2, and the subscripts m and p are each independently 0, 1, 2, 3 or 4.

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

[0010] In some embodiments, the 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 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.

Mode for Carrying Out the Invention

[0012] I. General The compounds of the present disclosure include compounds of formula (I), (Ia), (Ib), (Ic), (Ic-1), (Id), and (Id-1), including the compounds of the examples. These compounds are useful for inhibiting LRRK2 and are also useful 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 alpha-synucleinopathy, but are not limited thereto.

[0013] II. Definitions Unless otherwise noted, 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 not only one member but also embodiments having two or more members. For example, the singular forms "a", "an", and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells, and a reference to "the agent" includes a reference to one or more agents known to those of ordinary skill in the art.

[0015] When referring to a value, "about" includes the indicated value + / - 10% of the indicated 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" means + / - 10% of the indicated value with respect to the indicated 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" is a straight-chain or branched-chain saturated monovalent hydrocarbon. An alkyl group has 1 to 18 carbon atoms (i.e., C 1~18 alkyl), or 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 1~4It can have an alkyl group. Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2, and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, but are not limited thereto. Other alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl. The alkyl group can be substituted or unsubstituted.

[0017] "Hydroxyalkyl" refers to one or more hydroxyl (-OH) groups linked to an alkyl group, where the alkyl group is linked to the remainder of the compound and is divalent. The hydroxyalkyl can have any suitable number of carbons, e.g., 1 to 6 (C 1~6 hydroxyalkyl), 1 to 5 (C 1~5 hydroxyalkyl), 1 to 4 (C 1~4 hydroxyalkyl), or 1 to 3 (C 1~3 hydroxyalkyl). Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl (HOCH2-), hydroxyethyl (HOCH2CH2-), etc.

[0018] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment, i.e., alkyl-O-. Regarding the alkyl group, the alkoxy group can have any suitable number of carbon atoms such as C 1~6 . Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexyloxy, etc. The alkoxy group can be further substituted with various substituents described herein. The alkoxy group can be substituted or unsubstituted.

[0019] "Alkoxyalkyl" refers to an alkoxy group linked to an alkyl group, where the alkyl group is linked to the remainder of the compound and is divalent. The alkoxyalkyl can have 2 to 6 (C 2~6 alkoxyalkyl), 2 to 5 (C 2~5 alkoxyalkyl), 2 to 4 (C 2~4 alkoxyalkyl), or 2 to 3 (C 2~3It can have any suitable number of carbons, such as (alkoxyalkyl). The number of carbons refers to the total number of carbons in the alkoxy group and the alkyl group. For example, C6 alkoxyalkyl refers to ethoxy (C2 alkoxy) linked to butyl (C4 alkyl), and also refers to n-propoxy (C3 alkoxy) linked to isopropyl (C3 alkyl). Alkoxy and alkyl are as defined above where the alkyl is divalent, and examples include methoxymethyl (CH3OCH2-), methoxyethyl (CH3OCH2CH2-), etc., but are not limited thereto.

[0020] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

[0021] 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).

[0022] As used herein, "haloalkyl" refers to alkyl as defined herein, wherein 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. 1~4 Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl. The haloalkyl group can be substituted or unsubstituted.

[0023] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. For the alkyl group, the hydroxyalkyl group is C 1~6It can have any suitable number of carbon atoms such as etc. The alkoxy group can be substituted with 1, 2, 3 or more halogens. When all hydrogens are replaced with a 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, etc. The haloalkoxy group can be substituted or unsubstituted.

[0024] "Cycloalkyl" means a single saturated or partially unsaturated all-carbon ring having 3 to 20 cyclic carbon atoms (i.e., C 3~20 Cycloalkyl), for example, having 3 to 12 cyclic atoms, for example, 3 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or 3 to 4 cyclic atoms. The term "cycloalkyl" also includes a number of fused, saturated and partially unsaturated all-carbon ring systems (for example, a ring system containing 2, 3 or 4 carbocyclic rings). Thus, cycloalkyl includes bicyclic carbon rings (for example, bicyclic carbon rings having 6 to 12 cyclic carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbon rings (for example, tricyclic and tetracyclic carbon rings having up to 20 cyclic carbon atoms). The rings of a multiple condensed ring system can be connected to each other via condensation, spiro and bridging bonds when permitted by valence requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl group and 1-cyclohex-3-enyl. The cycloalkyl group can be substituted or unsubstituted.

[0025] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component at the point of attachment. The alkyl component is at least divalent, i.e., an alkylene, and except for linking the cycloalkyl component and the point of attachment, the alkyl component is as defined above. The alkyl component can have any number of carbons, e.g., 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 、C 3~6 、C 4~5 、C 4~6 and C 5~6 can be included. 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 can be substituted or unsubstituted.

[0026] As used herein, "heterocyclyl" or "heterocyclic" or "heterocycloalkyl" refers to a single saturated or partially unsaturated non-aromatic ring or multiple ring system having at least one heteroatom in the ring (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur), and the multiple ring system includes at least a non-aromatic ring containing at least one heteroatom. The multiple ring 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. Thus, the 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 polycondensed ring (e.g., bicyclic heterocyclyl) system can be connected to each other via condensation, spiro and crosslinking bonds when permitted by valence requirements. Examples of 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. Heterocycloalkyl can be substituted or unsubstituted.

[0027] The heterocycloalkyl ring also includes 9- to 15-membered fused-ring heterocycloalkyl having 2, 3 or more rings, at least one of which is an aryl ring and at least one of which 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, which are shown by the following structures, i.e., [Chemistry] is as follows. The fused bicyclic heterocycloalkyl also has the following structure: [Chemistry] can also be represented by, where X 1 , X 2 , X 3 and X 4 are each independently absent, -CH2-, -NH-, -O or -S-, and at least one of X 1 , X 2 , X 3 and X 4 is -NH-, -O or -S-, and the dashed circle represents a saturated or partially unsaturated non-aromatic ring. The fused bicyclic heterocycloalkyl can be substituted or unsubstituted.

[0028] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, and the alkyl component connects the heterocycloalkyl component to the point of attachment. Except that the alkyl component is at least divalent, i.e., alkylene, and connects to the heterocycloalkyl component and the point of attachment, the alkyl component is as defined above. The alkyl component can have any number of carbons, e.g., 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 5~6It can include. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group can be substituted or unsubstituted. The alkyl-heterocycloalkyl group can be substituted or unsubstituted.

[0029] 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 ring 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 multi-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), where at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbon rings). Such multi-fused ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbon ring portion of the multi-fused ring system. The rings of the multi-fused ring system can be connected to each other via fused, spiro, and bridged bonds when permitted by valence requirements. When referring to a particular atomic range of aryl (e.g., 6- to 10-membered aryl), it should also be understood that the atomic range is for the total 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. The aryl group can be substituted or unsubstituted.

[0030] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, wherein the alkyl component connects the aryl component to the point of attachment. Except that the alkyl component is at least divalent, i.e., alkylene, and is connected to the aryl component and the point of attachment, the alkyl component is as defined above. The alkyl component can have any number of carbons, e.g., C 1~6 , C 1~2 , C1~3 , 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 can include. In some cases, the alkyl component may not be present. 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 can be substituted or unsubstituted.

[0031] "Heteroaryl", as used herein, refers to a single aromatic ring having at least one atom other than carbon in the ring, the atom being selected from the group consisting of oxygen, nitrogen and sulfur, and "heteroaryl" also includes a multi-condensed ring system having at least one such aromatic ring, which multi-condensed ring system is further described below. Thus, "heteroaryl" includes a single aromatic ring of 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 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 multi-condensed ring systems (e.g., ring systems containing 2, 3 or 4 rings), and the heteroaryl groups defined above can condense with one or more rings selected from heteroaryl (e.g., to form 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl) and aryl (e.g., to form indazolyl) to form a multi-condensed ring system. Thus, heteroaryl (single aromatic ring or multi-condensed ring system) has 1 to 20 carbon atoms and 1 to 6 heteroatoms in the heteroaryl ring. Such multi-condensed ring systems can be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocyclic or heterocyclic moiety of the condensed ring. The rings of the multi-condensed ring system can be connected to each other via condensation, spiro and bridging bonds when permitted by valence requirements. It should be understood that the individual rings of the multi-condensed ring system can be connected to each other in any order. The point of attachment of the heteroaryl or heteroaryl multi-condensed ring system can be any suitable atom of the heteroaryl or heteroaryl multi-condensed ring system including carbon atoms and heteroatoms (e.g., nitrogen). When referring to a particular atom range of heteroaryl (e.g., 5- to 10-membered heteroaryl), the atom range is with respect to the total 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 can be substituted or unsubstituted.

[0032] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, wherein the alkyl component connects the heteroaryl component to the point of attachment. The alkyl component is at least divalent, i.e., an alkylene, and except for connecting to the heteroaryl component and the point of attachment, the alkyl component is as defined above. The alkyl component can have any number of carbons, for example, 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 and can include. In some cases, the alkyl component can be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group can be substituted or unsubstituted.

[0033] "The compounds of the present disclosure" include the compounds disclosed herein. For example, the compounds of the present disclosure include compounds of formula (I), (Ia), (Ib), (Ic), (Ic-1), (Id), and (Id-1) including the compounds of the examples.

[0034] Pharmaceutically acceptable salts, tautomers, 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.

[0035] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from suitable bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 + (wherein X is C1-C4 alkyl), etc. Also included are base addition salts, such as sodium salts or potassium salts.

[0036] When the compounds are represented in their chiral forms, it is understood that the embodiments include, but are not limited to, specifically diastereomerically or enantiomerically enriched forms. If chirality is not specified but present, it is understood that the embodiments are directed to either a specifically diastereomerically or enantiomerically enriched form of such compound(s), or a racemic or scaemic mixture. As used herein, a "scaemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0037] "Racemate" refers to a mixture of enantiomers. The mixture can contain equal or unequal amounts of each enantiomer.

[0038] "Stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Enantiomers and diastereomers are examples of stereoisomers. A compound may exist in stereoisomeric forms if it has one or more asymmetric centers or double bonds with asymmetric substitution, and can thus be produced as individual stereoisomers or as a mixture. Unless otherwise stated, this description is intended to include individual stereoisomers as well as 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).

[0039] "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 the tautomeric forms of heteroaryl groups containing ring atoms bonded to both ring-NH- and ring=N-, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0040] 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, and the chemical groups can be shown with or without one or more dashes without losing their ordinary 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. When not required chemically or structurally, the direction is not shown or implied by the order in which the chemical groups are described or the position where the chemical group is attached to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be connected in either direction. Similarly, an "arylalkyl" group can be attached to the rest of the molecule through either the aryl or alkyl part of the group. "C u~v " or (C u ~C vPrefixes such as indicate that the following group has u to v carbon atoms. For example, both "C 1~6 alkyl" and "C1-C6 alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0041] As used herein, "composition" is intended to include products containing specific components in specific amounts, as well as any products directly or indirectly resulting from combinations of specific amounts of specific components. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipient.

[0042] "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.

[0043] As used herein, "pharmaceutical composition" refers to a product containing specific formulated ingredients in specific amounts, as well as any product directly or indirectly resulting from combinations of specific amounts of specific formulated ingredients. Pharmaceutical compositions are generally safe for biological use.

[0044] "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.

[0045] As used herein, "inhibiting" or "inhibition of" LRRK2 refers to reducing the activity and / or function of the LRRK2 enzyme. LRRK2 enzyme activity can be measured by any assay method known in the art, including 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. 2021 / 0002260, or assays found in the Examples, or other assays described herein.

[0046] As used herein, "treatment", "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", "treating", or "treatment of" includes, for example, a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or attenuating the degree of the disease or condition), b) slowing 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 or condition, e.g., regressing clinical symptoms, improving the disease state, delaying the progression of the disease, improving the quality of life, and / or extending survival.

[0047] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount effective to induce a desired biological or medical response and, when administered to a subject for treating a disease, includes an amount of a compound sufficient to achieve such treatment of the disease. The therapeutically 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 is understood in the art, the effective amount may be in one or more doses, i.e., single or multiple administrations may be required to achieve the desired therapeutic endpoint. "Effective amount" may be considered in the context of administering one or more therapeutic agents, and when a desired or beneficial result can be achieved or is achieved by administering one or more other agents in combination, a single agent can be considered to be administered in an effective amount. The preferred dosage of any co-administered compound can be reduced as needed based on the combined action of the compounds (e.g., additive or synergistic effect).

[0048] "Administration" 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, into a subject. Administration can be carried out according to a schedule specifying the frequency of administration, the dosage administered, and other factors.

[0049] As used herein, "co-administration" refers to administering a unit dosage of a compound disclosed herein before or after administration of a unit dosage of one or more additional therapeutic agents, e.g., within seconds, minutes, or hours of 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 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 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 administration of a unit dose of one or more additional therapeutic agents hours (e.g., 1 to 12 hours) later. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure hours (e.g., 1 to 12 hours) later. Co-administration of a compound disclosed herein and one or more additional therapeutic agents generally refers to 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.

[0050] The term "subject" refers to an animal such as a mammal including, but not limited to, primates (e.g., human), bovine, ovine, caprine, equine, canine, feline, rabbit, rat, mouse, etc. In some embodiments, the subject is a human.

[0051] "Disease" or "condition" refers to the state of being or health condition of a patient or subject that can be treated with a compound, pharmaceutical composition, or method provided herein.

[0052] III. Compounds The compounds of the present disclosure include compounds of formula (I), (Ia), (Ib), (Ic), (Ic-1), (Id), and (Id-1), including the compounds of the examples.

[0053] In some embodiments, the present disclosure provides a compound of formula (I):

Chemical formula

[0054] In some embodiments, the present disclosure provides a compound of formula (I):

Chemical formula

[0055] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which the subscript p is 0, 1, 2, 3, or 4. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which the subscript p is 1 or 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which the subscript p is 1. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which the subscript p is 2.

[0056] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is of formula Ia:

Chemical formula

[0057] 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 N or O heteroatom, or a 5- to 6-membered heteroaryl having one N heteroatom. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or pyridyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is cyclopentyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is cyclohexyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is pyrrolidinyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is piperidinyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is tetrahydropyranyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which ring A is pyridyl.

[0058] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is each R 1is, independently, C 1~3 is a compound that is alkyl, -CN, or =O. In some embodiments, the compound or a pharmaceutically acceptable salt thereof has each R 1 is, independently, Me, -CN, or =O. In some embodiments, the compound or a pharmaceutically acceptable salt thereof has each R 1 is a compound where each R is Me. In some embodiments, the compound or a pharmaceutically acceptable salt thereof has each R 1 is a compound where each R is -CN.

[0059] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound where the subscript m is 0, 1, 2, 3, or 4. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound where the subscript m is 0, 1, or 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound where the subscript m is 1, 2, or 3. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound where the subscript m is 0. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound where the subscript m is 1 or 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound where the subscript m is 1. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound where the subscript m is 2.

[0060] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the group

Chemical formula

[0061] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound where ring A is tetrahydropyranyl, R 1 is methyl, and the subscript m is 1.

[0062] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a group [Chem.] is a compound.

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

[0064] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that R 2x and R 2z are each independently hydrogen, C 1~6 alkyl, halogen, or C 1~6 haloalkyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that R 2x and R 2z are each independently hydrogen, C 1~6 alkyl, or halogen. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that R 2x is hydrogen or C 1~6 alkyl, and R 2z is hydrogen or halogen. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that R 2x is hydrogen, and R 2z is hydrogen or halogen. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that R 2x and R 2z are each hydrogen.

[0065] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that R 2 is -N(R 2a )(R 2b ), -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b -OC(O)N(R 2a)(R 2b )、 -N(R 2a )C(O)OR 2b 、 -S(O)2R 2b 、 -S(O)2N(R 2a )(R 2b )、 or -N(R 2a )S(O)2R 2b ; R 2a is hydrogen or C 1~6 alkyl; R 2b is hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, C 1~6 alkyl - C 3~8 cycloalkyl, heterocycloalkyl, C 1~6 alkyl - heterocycloalkyl, heteroaryl or C 1~6 alkyl - heteroaryl, each heterocycloalkyl having 3 to 10 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and having 1 to 4 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 3 R 2b1 groups; or, R 2a and R 2b combine with the atoms to which they are attached to form a 3 - to 6 - membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently being N, O or S; each R 2b1 is independently C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, or C 3~8 cycloalkyl; R 2c is -C(O)OH; each R 2y is hydrogen; R 2x and R2z is each hydrogen or halogen; or R 2a and R 2x 、or R 2a and one R 2y combine with the atom to which they are attached to form a 4- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently N, O or S substituted with 0 to 3 C 1~6 alkyl; Preferably, a compound wherein the subscript n is 0, 1 or 2.

[0066] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 is -N(R 2a )(R 2b ), -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b , -OC(O)N(R 2a )(R 2b ), -N(R 2a )C(O)OR 2b , -S(O)2R 2b , -S(O)2N(R 2a )(R 2b ), or -N(R 2a )S(O)2R 2b ; R 2a is hydrogen or C 1~6 alkyl; R 2b is hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, C 1~6 alkyl-C 3~8 cycloalkyl, heterocycloalkyl, C 1~6 alkyl-heterocycloalkyl, heteroaryl or C 1~6alkyl - heteroaryl, each heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and 1 to 4 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 3 R 2b1 groups; or alternatively, R 2a and R 2b combine with the atoms to which they are attached to form a 3 - to 6 - membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently being N, O or S, the heterocycloalkyl being substituted with 0 to 3 R 2c groups; each R 2b1 is independently C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, or C 3~8 cycloalkyl; R 2c is - C(O)OH; each R 2y is hydrogen; R 2x and R 2z are each hydrogen; or alternatively, R 2a and R 2x , or R 2a and one R 2y combine with the atoms to which they are attached to form a 4 - to 6 - membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently being N, O or S and substituted with 0 to 3 C 1~6 alkyl; a compound wherein the subscript n is 0, 1 or 2.

[0067] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 is - N(R 2a )(R 2b ), - C(O)N(R 2a )(R 2b ), - N(R2a )C(O)R 2b 、 -OC(O)N(R 2a )(R 2b )、 -N(R 2a )C(O)OR 2b 、 -S(O)2R 2b 、 -S(O)2N(R 2a )(R 2b )、 or -N(R 2a )S(O)2R 2b ; R 2a is hydrogen or C 1~6 alkyl; R 2b is hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, C 1~6 alkyl - C 3~8 cycloalkyl, heterocycloalkyl, C 1~6 alkyl - heterocycloalkyl, heteroaryl or C 1~6 alkyl - heteroaryl, each heterocycloalkyl having 3 to 10 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and having 1 to 4 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 3 R 2b1 groups; each R 2b1 is independently C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, or C 3~8 cycloalkyl; each R 2y is hydrogen; R 2x and R 2z are each hydrogen; a compound wherein the subscript n is 0, 1 or 2.

[0068] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 is -N(R 2a )(R 2b ), -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b ), -N(R 2a )C(O)OR 2b ), -S(O)2R 2b ), -S(O)2N(R 2a )(R 2b ), or -N(R 2a )S(O)2R 2b ; R 2a is hydrogen or C 1~3 alkyl; R 2b is hydrogen, C 1~3 alkyl, C 1~3 hydroxyalkyl, C 2~4 alkoxyalkyl, C 1~3 haloalkyl, C 3~6 cycloalkyl, C 1~3 alkyl-C 3~8 cycloalkyl, heterocycloalkyl, C 1~3 alkyl-heterocycloalkyl, heteroaryl or C 1~6 alkyl-heteroaryl, each heterocycloalkyl having 4 to 6 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 6 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 2 R 2b1 groups; each R 2b1 is independently C 1~3 alkyl, C 1~3 hydroxyalkyl, or C 2~4 alkoxyalkyl; each R 2y is hydrogen; R 2x and R 2z are hydrogen; A compound wherein the subscript n is 0 or 1.

[0069] In some embodiments, the compound or a pharmaceutically acceptable salt thereof R 2 is -N(R 2a )(R 2b ), -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b , -OC(O)N(R 2a )(R 2b ), -N(R 2a )C(O)OR 2b , -S(O)2N(R 2a )(R 2b ), or -N(R 2a )S(O)2R 2b ; R 2b is hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, C 1~6 alkyl-C 3~8 cycloalkyl, heterocycloalkyl, heteroaryl or C 1~6 alkyl-heteroaryl, each heterocycloalkyl having 3 to 10 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and having 1 to 4 heteroatoms each independently being N, O or S, and each heterocycloalkyl and heteroaryl being substituted with 0 to 3 R 2b1 groups; each R 2b1 is independently C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, or C 3~8 cycloalkyl; R 2a and R 2x , or R 2a and one R 2yare combined with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having from 0 to 2 additional heteroatoms each independently selected from N, O or S and substituted with C 1~6 alkyl; each R 2x and R 2y is hydrogen when not combined with R 2a ; R 2z is hydrogen; and the subscript n is 0, 1 or 2.

[0070] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 is -N(R 2a )(R 2b ), -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b , -OC(O)N(R 2a )(R 2b ), -N(R 2a )C(O)OR 2b , -S(O)2N(R 2a )(R 2b ), or -N(R 2a )S(O)2R 2b ; R 2b is hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, C 1~6 alkyl-C 3~8 cycloalkyl, heterocycloalkyl, heteroaryl or C 1~6 alkyl-heteroaryl, each heterocycloalkyl having from 3 to 10 ring members and from 1 to 3 heteroatoms each independently selected from N, O or S, each heteroaryl having from 5 to 10 ring members and from 1 to 4 heteroatoms each independently selected from N, O or S, and each heterocycloalkyl and heteroaryl being unsubstituted or substituted with from 0 to 3 R2b1 is substituted with a radical; Each R 2b1 is independently C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, or C 3~8 cycloalkyl; R 2a and R 2x combine with the atom to which they are attached to form a 4- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms, each independently N, O or S, substituted with 0 to 3 C 1~6 alkyl; Each R 2y is hydrogen; R 2z is hydrogen; The subscript n is 0, 1 or 2, and the compound is a compound.

[0071] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 is -N(R 2a )(R 2b ), -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b , -OC(O)N(R 2a )(R 2b ), -N(R 2a )C(O)OR 2b , -S(O)2N(R 2a )(R 2b ), or -N(R 2a )S(O)2R 2b ; R 2b is hydrogen, C 1~3 alkyl, C 1~3 hydroxyalkyl, C 2~4 alkoxyalkyl, C 1~3 haloalkyl, C 3~6 cycloalkyl, C 1~3 alkyl-C 3~6 cycloalkyl, heterocycloalkyl, heteroaryl or C 1~3It is alkyl - heteroaryl, each heterocycloalkyl has 4 to 6 ring members and has 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl has 5 to 6 ring members and has 1 to 3 heteroatoms each independently being N, O or S, and each heterocycloalkyl and heteroaryl is substituted with 0 to 2 R 2b1 groups; Each R 2b1 is independently C 1~3 alkyl, C 1~3 hydroxyalkyl, C 2~4 alkoxyalkyl, or C 3~6 cycloalkyl; R 2a and R 2x combine with the atoms to which they are attached to form a 4 - to 6 - membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently being N, O or S, each R 2y is hydrogen; R 2z is hydrogen; A compound wherein the subscript n is 0, 1 or 2.

[0072] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 is - N(R 2a )(R 2b ), - C(O)N(R 2a )(R 2b ), - N(R 2a )C(O)R 2b , - OC(O)N(R 2a )(R 2b ), - N(R 2a )C(O)OR 2b , - S(O)2N(R 2a )(R 2b ), or - N(R 2a )S(O)2R 2b ; R 2b is hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, C1~6 Alkyl-C 3~8 Cycloalkyl, heterocycloalkyl, heteroaryl or C 1~6 is alkyl-heteroaryl, each heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and 1 to 4 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 3 R 2b1 groups; Each R 2b1 is independently C 1~6 alkyl, C 1~6 hydroxyalkyl, or C 3~8 cycloalkyl; R 2a and one R 2y when combined with the atom to which they are attached, form a 4- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently being N, O or S substituted with 0 to 3 C 1~6 alkyl; R 2y when not combined with R 2a is hydrogen; R 2x and R 2z are hydrogen; a compound wherein the subscript n is 1 or 2.

[0073] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 is -N(R 2a )(R 2b ), -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b ), -OC(O)N(R 2a )(R 2b ), -N(R 2a )C(O)OR 2b ), -S(O)2N(R 2a )(R 2b ), or -N(R 2a)S(O)2R 2b wherein; R 2b is hydrogen, C 1~3 alkyl, C 1~3 haloalkyl, C 3~6 cycloalkyl, C 1~3 alkyl-C 3~6 cycloalkyl, heterocycloalkyl, heteroaryl or C 1~3 alkyl-heteroaryl, each heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 2 R 2b1 groups; each R 2b1 is independently C 1~3 alkyl, C 1~3 hydroxyalkyl, or C 3~6 cycloalkyl; R 2a and R 2y combine with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently being N, O or S, R 2x and R 2z are each hydrogen; a compound wherein the subscript n is 1.

[0074] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 is -N(R 2a )(R 2b ), -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b , -OC(O)N(R 2a )(R 2b ), -N(R 2a )C(O)OR 2b , -S(O)2N(R 2a )(R 2b)、 or -N(R 2a )S(O)2R 2b ; R 2a and R 2b combine with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently being N, O or S, and the heterocycloalkyl is substituted with 0 to 3 R 2c groups; R 2c is -C(O)OH; each R 2y is hydrogen; R 2x and R 2z are each hydrogen; a compound wherein the subscript n is 0, 1 or 2.

[0075] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 is -N(R 2a )(R 2b ), -C(O)N(R 2a )(R 2b ), -N(R 2a )C(O)R 2b , or -N(R 2a )S(O)2R 2b ; R 2a and R 2b combine with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently being N, O or S, and the heterocycloalkyl is substituted with 0 to 3 R 2c groups; R 2c is -C(O)OH; R 2x and R 2z are each hydrogen; a compound wherein the subscript n is 0.

[0076] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is, R 3 is hydrogen, C1~6 alkyl, C 1~6 alkoxy, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, or -CN. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that R 3 is hydrogen, C 1~3 alkyl, halogen, C 1~3 haloalkyl, or -CN. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which each R 3 is hydrogen.

[0077] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which each R 4 is independently C 1~6 alkyl, C 1~6 alkoxy, halogen, C 1~6 haloalkoxy, -CN, -(C=O)N(R 3a )(R 3b ), or C 3~8 cycloalkyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which each R 4 is C 1~3 alkyl, C 1~3 alkoxy, halogen, C 1~3 haloalkoxy, -CN, -(C=O)N(R 3a )(R 3b ), or C 3~6 cycloalkyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which each R 4 is -CH3, -OCH3, Cl, -OCF3, -CN, -(C=O)N(CH3)2, or cyclopropyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound in which each R 4 is -CN.

[0078] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, is a compound where the subscript n is 0 or 1. In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, is a compound where the subscript n is 0. In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, is a compound where the subscript n is 1.

[0079] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, has the structure of formula Ib: [ka] It is a compound having the formula:

[0080] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, has the structure of formula Ic: [ka] It is a compound having the formula:

[0081] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, has the structure of formula Ic-1: [ka] It is a compound having the formula:

[0082] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is base [ka] [ka] [ka] [ka] [ka] [Chemistry] [Chemistry] is a compound.

[0083] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is group [Chemistry] [Chemistry] [Chemistry] [Chemistry] is a compound.

[0084] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is group [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] is a compound.

[0085] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is group [Chemistry]

Chem.

[0086] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is group

Chem.

Chem.

[0087] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is group

Chem.

[0088] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is group

Chem.

[0089] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is group

Chem.

[0090] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Id:

Chem.

[0091] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Id-1: [Chemical formula] It is a compound having the following.

[0092] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has R 2b being hydrogen, C 1~6 alkyl, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, C 1~6 haloalkyl, C 3~8 cycloalkyl, C 1~6 alkyl-C 3~8 cycloalkyl, heterocycloalkyl, C 1~6 alkyl-heterocycloalkyl, C 6~10 aryl, heteroaryl or C 1~6 alkyl-heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms each independently being N, O or S, and each heterocycloalkyl and heteroaryl is substituted with 0 to 3 R 2b1 groups. In some embodiments, the compound or a pharmaceutically acceptable salt thereof has R 2b being C 3~8 cycloalkyl, C 1~6 alkyl-C 3~8 cycloalkyl, heterocycloalkyl, C 1~6 alkyl-heterocycloalkyl, heteroaryl or C 1~6 alkyl-heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms each independently being N, O or S, and each heterocycloalkyl and heteroaryl is substituted with 0 to 3 R 2b1A compound substituted with a group. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2b wherein C 3~8 is cycloalkyl or heteroaryl, each heteroaryl having 5 to 6 ring members and having 1 to 3 heteroatoms each independently being N, O or S, and being substituted with 0 to 3 R 2b1 groups. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2b wherein is cyclopropyl, cyclobutyl, cyclopentenyl, cyclopentyl, spiro[2.2]pentyl, cyclohexyl, pyrazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and pyrazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl are substituted with 0 to 3 R 2b1 groups.

[0093] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is such that each R 2b1 is independently C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, halogen, C 1~6 haloalkyl, C 1~6 haloalkoxy, -CN, =O, C 3~8 cycloalkyl, heterocycloalkyl, C 6~10 aryl, or heteroaryl, wherein the alkoxy is substituted with 0 to 3 heteroaryls, each heterocycloalkyl having 3 to 10 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and having 1 to 4 heteroatoms each independently being N, O or S, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl being substituted with 0 to 3 C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 2~6An alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, or =O. In some embodiments, the compound or a pharmaceutically acceptable salt thereof has each R 2b1 independently being C 1~6 alkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 2~6 alkoxyalkyl, halogen, or C 3~8 cycloalkyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof has each R 2b1 independently being C 1~6 alkyl or C 1~6 alkoxy. In some embodiments, the compound or a pharmaceutically acceptable salt thereof has each R 2b1 independently being C 1~3 alkyl or C 1~3 alkoxy. In some embodiments, the compound or a pharmaceutically acceptable salt thereof has each R 2b1 independently being -CH3, -CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2OH, -CH2CH2OH, -CH2C(CH3)2OH, -CH2OCH3, -CH2CH2OCH3, cyclopropyl, cyclobutyl, oxetan-2-yl, F, Cl, CH2F, CHF2, C(CH3)2F, CF3, -OCHF2,

Chemical formula

[0094] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has each R 2b1 independently being -CH3 or -OCH3.

[0095] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has R 2bis H, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2OH, -CH2CH2CH2OH, -CH2C(CH3)2CH2OH, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2C(CH3)2CH2OCH3, -CH2CF3, -CH2CH2CF3, -CH2CF2CH2OH, -CH2C(CH3)2CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Chem.

Chem.

Chem.

[0096] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2b is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Chem.

[0097] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of the compounds in Table 1A.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

[0098] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of the compounds in Table 1B.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

[0099] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of the compounds in Table 1A or Table 1B.

[0100] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of any one of Compound 2, Compound 54, Compound 183, Compound 184, and Compound 193. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of Compound 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of Compound 54. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of Compound 183. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of Compound 184. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound having the structure of Compound 193.

[0101] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure:

Chem.

[0102] In some embodiments, the compound has the structure:

Chem.

[0103] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure:

Chem.

[0104] In some embodiments, the compound has the structure:

Chem.

[0105] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure: [Chemistry] It is a compound having

[0106] In some embodiments, the compound has the structure: [Chemistry] It is a compound having

[0107] In some embodiments, the compound or its pharmaceutically acceptable salt has the structure: [Chemistry] It is a compound having

[0108] In some embodiments, the compound has the structure: [Chemistry] It is a compound having

[0109] In some embodiments, the compound or its pharmaceutically acceptable salt has the structure: [Chemistry] It is a compound having

[0110] In some embodiments, the compound has the structure: [Chemistry] It is a compound having

[0111] In some embodiments, the compound or its pharmaceutically acceptable salt has the structure: [Chemistry] It is a compound having

[0112] In some embodiments, the compound has the structure: [Chemical formula] is a compound having

[0113] In some embodiments, the compound has the structure: [Chemical formula] is a compound having

[0114] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure: [Chemical formula] is a compound having

[0115] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure: [Chemical formula] is a compound having

[0116] In some embodiments, the compound has the structure: [Chemical formula] is a compound having

[0117] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure: [Chemical formula] is a compound having

[0118] In some embodiments, the compound has the structure: [Chemical formula] is a compound having

[0119] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure:

Chemical formula

[0120] In some embodiments, the compound has the structure:

Chemical formula

[0121] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure:

Chemical formula

[0122] In some embodiments, the compound has the structure:

Chemical formula

[0123] 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 a compound that have the desired pharmacological activity. These salts can be derived from inorganic or organic acids or bases. Examples of pharmaceutically acceptable salts of the compounds of formula (I) of the present invention 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, further salts with alkaline earth metals such as magnesium or calcium, further salts with organic amines such as lower alkylamines or lower alcoholamines, further 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, propionate, 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, 21 stApproved by Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0124] In some embodiments, a compound of the disclosure herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, is a compound in which one to n hydrogen atoms bonded to a carbon atom can be replaced by 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 may increase resistance to metabolism and, thus, may be useful for extending the half-life of a compound or a pharmaceutically acceptable salt, isomer, or mixture 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 well known in the art, e.g., by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0125] 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 125 I are also included. 11 C, 18 F, 15 O and 13Substitution with a positron-emitting isotope such as N can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotope-labeled compounds of formula (I) can generally be prepared by processes similar to those described in the examples below using suitable isotope-labeling reagents by the prior art known to those skilled in the art or in place of previously used unlabeled reagents.

[0126] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may contain one or more asymmetric centers and, thus, from the perspective of absolute stereochemistry, for amino acids, enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- or (D)- or (L)- can occur. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using a chiral synthon or chiral reagent or 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 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, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included.

[0127] 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.

[0128] Activity against LRRK2 can also be measured by any cell assay known in the art to be useful for evaluating LRRK2, as described in Hermanson, SB et al. PLOS ONE 7(8):e43580 and as described herein, for example, by the phospho-LRRK2 (Ser935) cell kit (Cisbio Bioassays, France). 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.

[0129] In some embodiments, the compounds of the present disclosure have selectivity for LRRK2 that is greater than one or more of the other kinases, for example, greater than one or more of LRRK1, LIMK1, LIMK2, RIPK1, RIPK2, RIPK3, ANKRD3, SgK288, IRAK1, IRAK2, IRAK3, IRAK4, JAK1, JAK2, JAK3, TESK1, and / or TESK2. The selectivity can be measured by relative values in the corresponding biochemical assay, for example, by the activity of inhibiting LRRK2 that is greater than one or more of LRRK1, LIMK1, LIMK2, RIPK1, RIPK2, RIPK3, ANKRD3, SgK288, IRAK1, IRAK2, IRAK3, IRAK4, JAK1, JAK2, JAK3, TESK1, and / or TESK2.

[0130] In some embodiments, the compounds of the present disclosure have selectivity for LRRK2 that is greater than one or more of the other kinases including LRRK1, LIMK1, LIMK2, RIPK1, RIPK2, RIPK3, ANKRD3, SgK288, IRAK1, IRAK2, IRAK3, IRAK4, JAK1, JAK2, JAK3, TESK1, and / or TESK2, for example, greater than 2, 3, 4, 5, 6, 7, 8, or 9 or more, and is at least about 1.2, about 1.5, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 200, about 300, about 400, about 500, about 1000, about 2000, about 3000, about 4000, about 5000 times, or about 10,000 times or more greater than LRRK2.

[0131] 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), (Ic), (Ic-1), (Id), or (Id-1), or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0132] In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. Any suitable additional therapeutic agent or combination therapy can be used with a compound of formula (I), (Ia), (Ib), (Ic), (Ic-1), (Id), or (Id-1), or a pharmaceutically acceptable salt thereof, e.g., with the agents and therapies described herein.

[0133] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (Ia), (Ib), (Ic), (Ic-1), (Id), or (Id-1), and an additional therapeutic agent, wherein the additional therapeutic agent is an anti-Parkinson's disease drug.

[0134] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (Ia), (Ib), (Ic), (Ic-1), (Id), or (Id-1), and an additional therapeutic agent, wherein the additional therapeutic agent is an anti-inflammatory bowel disease drug.

[0135] 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 when delivery by means other than oral administration is intended. All formulations contain excipients, e.g., excipients described in "Handbook of Pharmaceutical Excipients" (1986), as needed. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. The pH of the formulation ranges from about 3 to about 11, e.g., from about 7 to 10.

[0136] Although it is possible to administer the active compounding ingredients alone, it may be preferable to provide them as pharmaceutical formulations. Formulations for both veterinary and human use include at least one active compounding ingredient as defined above, together with one or more acceptable carriers and, optionally, other therapeutic compounding ingredients, particularly those additional therapeutic compounding ingredients discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to its recipient.

[0137] 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 compounding 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 compounding ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0138] Formulations suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compounding 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 compounding ingredient can also be administered as a bolus, a lick or a paste.

[0139] Tablets are prepared by compression or molding, optionally 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 have 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 formulated to provide for the slow or controlled release of the active ingredient therefrom, as desired.

[0140] The pharmaceutical formulations of the present specification include combinations with one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. When used for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents including sweetening, flavoring, coloring, and preserving agents 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 can 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 acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or can be coated by known methods including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time delay materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes.

[0141] Compositions 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.

[0142] An aqueous suspension contains the active material admixed with excipients suitable for the manufacture of an aqueous suspension. Such excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum), and dispersing or wetting agents, for example, naturally occurring phosphatides (for example, lecithin), condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, for example, sucrose or saccharin.

[0143] An oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oral suspensions may contain a thickening agent, for example, beeswax, solid paraffin or cetyl alcohol. To provide a palatable oral preparation, sweetening agents and flavoring agents as described above may be added. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0144] Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide an active ingredient which is admixed with 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 agents, flavoring agents and coloring agents, may also be present.

[0145] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase may be, for example, a vegetable oil such as olive oil or arachis oil, or a mineral oil such as, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents include naturally occurring gums such as gum acacia and tragacanth gum, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and anhydrous hexitols such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents and flavoring agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, sorbitol or sucrose. Such formulations may also contain demulcents, preservatives, flavoring agents or coloring agents.

[0146] The pharmaceutical composition may be in the form of a sterile injectable or intravenous preparation, for example, a sterile injectable aqueous or oily suspension. This suspension may be formulated according to known techniques using the suitable dispersing or wetting agents and suspending agents mentioned 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 may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic mono - or diglycerides may be used. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0147] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form varies depending on the host treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans may contain about 1-1000 mg of active ingredient compounded with an appropriate and convenient amount of carrier material, which may 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 may contain about 3-500 μg of active ingredient per milliliter of solution in order to allow for infusion of a suitable volume at a rate of about 30 mL / hour.

[0148] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5% w / w.

[0149] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth, pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia, and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0150] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0151] Formulations suitable for pulmonary or nasal administration have a particle size in the range of 0.1 to 500 microns, e.g., 0.5, 1, 30, 35 microns, and are administered by rapid inhalation through the nasal passages, or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient.

[0152] Formulations suitable for vaginal administration can be provided as pessaries, tampons, creams, gels, pastes, foams or spray formulations that contain, in addition to the active ingredient, a carrier known to be appropriate in the art.

[0153] Formulations suitable for parenteral administration may include aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may include suspending and thickening agents.

[0154] The formulations are presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier, for example, only the addition of water, immediately prior to use for injection. Immediate injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the above-described types. A preferred unit dosage formulation is one that contains a daily dose or daily unit sub-dose of the active ingredient as listed above herein, or an appropriate fraction thereof.

[0155] In addition to the ingredients 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 in question, for example, formulations suitable for oral administration may include flavoring agents.

[0156] In some embodiments, the veterinary composition includes at least one active ingredient as defined above, together with a veterinary carrier therefor.

[0157] A veterinary carrier is a material useful for the purpose of administering the composition and is a solid, liquid or gaseous material that 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.

[0158] The compounds of the present specification are used to provide a sustained-release pharmaceutical preparation (the "sustained-release preparation") containing one or more compounds as active ingredients, and the release of the active ingredients is controlled and regulated to enable less frequent dosing or to improve the pharmacokinetics or toxicity profile of a given active ingredient.

[0159] The effective dose of the active ingredient depends at least on the nature of the condition being treated, its toxicity, whether the compound is used prophylactically (at a low dose), or whether it is used 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 about 0.0001 to about 100 mg / kg body weight per day, typically about 0.01 to about 10 mg / kg body weight per day, more typically about 0.01 to about 5 mg / kg body weight per day, and most typically about 0.05 to about 0.5 mg / kg body weight per day. For example, the candidate daily dose for an adult of about 70 kg body weight 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.

[0160] V. Route of Administration One or more of the compounds of formula (I), (Ia), (Ib), (Ic), (Ic-1), (Id), or (Id-1) are administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including oral and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It is understood that the preferred route may 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.

[0161] The compounds of the present disclosure can be administered by any route appropriate 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). It is understood that the preferred route can vary, for example, depending on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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 be from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as 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 to about 30 mg per day, or for example, from about 30 mg to about 300 mg per day.

[0166] The compounds of the present disclosure may 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). The therapeutically effective amount may 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 may be about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure may be about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. Single doses can be administered hourly, daily, or weekly. For example, single doses can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. Single doses can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. Single doses can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, single doses can be administered once a week. Single doses can also be administered once a month.

[0167] Other therapeutically effective amounts of the compounds of the present disclosure may be about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose.

[0168] 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. The 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.

[0169] Administration can be intermittent, and a patient can receive daily administration of the compounds of the present disclosure for several days or more, followed by a period of several days or more during which the patient does not receive daily administration of the compound. For example, a patient can receive compound administration every other day or three times a week. To give another example, a patient can receive daily administration of the compound over a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive compound administration, and then followed by a period (e.g., 1 to 14 days) during which the patient again receives daily administration of the compound. The alternating periods of compound administration and subsequent non - administration of the compound can be repeated if clinically necessary to treat the patient.

[0170] 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 a pharmaceutically acceptable excipient. VI. Method or Use

[0171] In some embodiments, the present disclosure provides a method or use for inhibiting LRRK2 in a cell in need of a method or use for inhibiting LRRK2, the method or use comprising administering to the cell 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, the method or use for inhibiting LRRK2 in a cell comprises contacting the cell with an effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Ic - 1), (Id) or (Id - 1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or its salt.

[0172] In some embodiments, the present disclosure provides a method for 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.

[0173] Inhibition of LRRK2 enzyme activity can be measured by any assay method known in the art, such as the in vitro assays described in International Publication No. WO 2011 / 141756, International Publication No. WO 2012 / 028629, International Publication No. WO 2012 / 058193, International Publication No. WO 2017 / 046675, International Publication No. WO 2018 / 163030, International Publication No. WO 2018 / 163066, International Publication No. WO 2021 / 080929, or U.S. Patent Application Publication No. US 2021 / 0002260. 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.

[0174] In some embodiments, inhibition of LRRK2 enzyme activity is measured in an in vivo model. Exemplary in vivo methods for LRRK2-related diseases are described in Xiong, Y. et al. Adv Neurobiol. 2017;14:163-191.

[0175] In some embodiments, a method of inhibiting LRRK2 includes administering an effective amount of a compound of the present disclosure, whereby LRRK2 activity is reduced in the assays described herein as compared to a control that does not receive 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%.

[0176] In some embodiments, the present disclosure provides a method or use for inhibiting LRRK2 in a cell that requires a method or use for inhibiting LRRK2, the method or use including administering to a 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.

[0177] In some embodiments, the present disclosure is a method or use for inhibiting LRRK2 in a subject in need thereof, the method or use comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Ic-1), (Id), or (Id-1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or its salt.

[0178] In some embodiments, the present disclosure is a method or use for treating LRRK2-related diseases or conditions such as neuropathy (e.g., Parkinson's disease) and certain immunological disorders (e.g., inflammatory bowel diseases such as ulcerative colitis or Crohn's disease), the method or use comprising 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.

[0179] In some embodiments, the present disclosure is a method for 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.

[0180] In some embodiments, the present disclosure provides a method or use for treating an LRRK2-related disease or condition, the method or use comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, LRRK2-related diseases or conditions include Parkinson's disease; brain injury; stroke; cerebrovascular diseases (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, cerebral hypoxia ischemia); cognitive impairment (including amnesia, senile dementia, HIV-associated 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, muscle spasm, and disorders related to muscle spasticity or muscle weakness (including tremors), 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 depressive disorder, 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 disorder, and delusional disorder); drug dependence (including narcotic dependence, alcoholism, amphetamine dependence, cocaine addiction, nicotine dependence, and drug withdrawal syndrome); eating disorders (including anorexia nervosa, bulimia nervosa, binge eating disorder, hyperphagia, obesity, compulsive eating disorder and pica); sexual dysfunction; urinary incontinence; nerve injury disorders (including eye injury, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and cerebral edema) and pediatric mental disorders (including attention deficit disorder, attention deficit / hyperactivity disorder, conduct disorder, and autism).

[0181] 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, 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. In some embodiments, the LRRK2-related disease or condition is alpha-synucleinopathy.

[0182] In some embodiments, the LRRK2-related disease or condition is an 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.

[0183] An increase in LRRK2 level and / or activity has been associated with abnormal levels of autophagy in certain cell types in patients with Parkinson's disease. For example, the mutations LRRK2 G2019S and LRRK2 R1441C were associated with increased kinase activity and decreased autophagic flux due to blocked clearance of autophagosomes. See Madureira, M. et al. Frontiers in Neuroscience 2020, 14, Article 498, pages 1-19. Inhibition of LRRK2 G2019S kinase activity in cell models enhanced autolysosome formation. See Obergasteiger, et al. Cell Death Discovery 2020, 6(45), pages 1-13.

[0184] Some diseases are associated with abnormal levels of autophagy, specifically, a decrease in autophagy levels compared to healthy subjects. See Ichimiya, et al. Intl. J. Mol. Sci. 2020, 21, 8974, pages 1 - 21. Any autophagy-related disease or condition can benefit from LRRK2 inhibition by administration of the compounds of the present disclosure or pharmaceutically acceptable salts thereof.

[0185] Accordingly, in some embodiments, an LRRK2-related disease or condition is an autophagy-related disease or condition. In some embodiments, an autophagy-related disease or condition is associated with 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, an autophagy-related disease or condition is a liver disease (e.g., non-alcoholic fatty liver disease (NAFLD), alpha1-antitrypsin deficiency (AATD), or hereditary hypofibrinogenemia with liver 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), an inflammatory bowel disease (e.g., Crohn's disease), or a neurodegenerative disease (e.g., Parkinson's disease). In some embodiments, an autophagy-related disease or condition is alpha1-antitrypsin deficiency (AATD).

[0186] In some embodiments, the present disclosure provides the use of the present invention for the manufacture of a medicament for treating an LRRK2-related disease or condition, comprising a compound or pharmaceutical composition described herein.

[0187] In some embodiments, the present disclosure provides a compound or composition for use of the invention for treating an LRRK2-related disease or condition, the compound or composition comprising a compound or pharmaceutical composition described herein.

[0188] In some embodiments, the present disclosure provides a kit suitable for use in practicing the above-described method or use. 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 perform the method or use of the invention, and a container for administration.

[0189] VII. EXAMPLES Numerous general references are available that provide generally known chemical synthesis schemes and conditions useful for synthesizing the disclosed compounds (see, for example, Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th edition, Wiley-Interscience, 2013).

[0190] 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 can be used, including normal and reverse phases as well as ion exchange resins. 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.

[0191] The compound was characterized using standard measurement methods. The identification of the compound was performed by hydrogen nuclear magnetic resonance spectrum ( 1 1H-NMR) and mass spectrum (MS). 1 1H-NMR was measured at 400 MHz unless otherwise specified. In some cases, depending on the compound and measurement conditions, exchangeable hydrogen could not be clearly observed. The notations "br." or "broad" used in this specification refer to broad signals. HPLC preparative chromatography was performed in gradient mode using water / methanol (containing formic acid) as the eluent on a commercially available ODS column, unless otherwise specified.

[0192] Specific 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 lists many of these abbreviations and acronyms.

Table 3

[0193] The examples provided in this specification 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.

[0194] In the following description of the examples, specific embodiments are described. These embodiments are described in sufficient detail so that those skilled in the art can carry out specific embodiments of the present disclosure. Without departing from the scope of the present disclosure, other embodiments may be utilized and other logical changes may be made. Therefore, the following description is not intended to limit the scope of the present disclosure.

[0195] The representative synthesis of the compounds of the present disclosure is described in the following schemes and the following specific examples.

[0196] Intermediate 1

Chem.

[0197] (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 equiv) in THF (350 mL, 0.4 M) was added titanium tetraisopropoxide (44 mL, 151 mmol, 1.0 equiv) and EtMgBr (3 M in THF, 151 mL, 453 mmol, 3.0 equiv) at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was quenched at 0 °C with saturated NH4Cl (200 mL) and 20% citric acid (200 mL). MTBE (200 mL) was added. The mixture was stirred at 0 °C for 30 min. The filtrate was extracted with MTBE (3 × 200 mL), dried over Na2SO4, 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 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).

[0198] (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 NaHCO3 (3 × 200 mL), dried over Na2SO4, filtered, and 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, CDCl3) δ 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).

[0199] (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 eq), PdCl2(MeCN)2 (102 mg, 394 μmol, 0.01 eq), benzoquinone (8.9 mL, 39 mmol, 1.0 eq), and H2O (3.4 mL, 189.14 mmol, 4.8 eq) in acetone (50 mL, 0.8 M) was stirred at 40 °C for 6 h under a N2 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 in vacuo (50 °C, oil pump, 10 mmHg) to give the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 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] D 25 = +167.009 (c = 0.109, CHCl3).

[0200] (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 eq) and Pd / C (500 mg, 10 wt%) in THF (20 mL, 0.4 M) was stirred at 20 °C for 1 h under H2 (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, CDCl3) δ 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).

[0201] 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 LiBH4 (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 Na2CO3 (20 mL) and diluted with water (20 mL). The mixture was extracted with DCM (3 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by flash silica gel chromatography (DCM / MeOH = 1 / 0 to 9 / 1) to give the title compound as a brown oil. LCMS (ESI) [M+H]+ = 266.2. 1 H NMR (400 MHz, CDCl3) δ 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).

[0202] Intermediate 2

Chemical Structure

[0203] Intermediate 2: POCl3 (2.18 mL, 23.4 mmol, 2.8 equiv) was added under N2(g) 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). 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 Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 0 - 85 / 15) to give the title compound as a white solid. 1 H NMR (400 MHz, CDCl3) δ 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).

[0204] Intermediate 3 [Chem.] 4-((3,4-Dimethylbenzyl)((2R,4R)-2-Methyltetrahydro-2H-pyran-4-yl)amino)-3-nitroquinoline-6-carbonitrile: DIPEA (64.3 μL, 369 μmol, 1.15 eq) was added to a solution of 4-chloro-3-nitroquinoline-6-carbonitrile (79.0 mg, 321 μmol, 1.0 eq) and (2R,4R)-N-(3,4-dimethylbenzyl)-2-methyltetrahydro-2H-pyran-4-amine (94.7 mg, 321 μmol, 1.0 eq) in MeCN (5 mL, 0.06 M) under N2(g). The mixture was stirred at 20 °C for 2 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc (30 mL). The solution was washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 0 to 4 / 1) to give the title compound as an orange oil. LCMS [M+H]+ = 463.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.55 (s, 1H), 8.16 (d, J = 0.8 Hz, 2H), 6.88 (d, J = 8.0 Hz, 1H), 6.31 - 6.24 (m, 2H), 4.39 - 4.27 (m, 2H), 3.92 - 3.77 (m, 2H), 3.63 (s, 3H), 3.42 (s, 3H), 3.41 - 3.35 (m, 2H), 1.97 - 1.85 (m, 2H), 1.83 - 1.71 (m, 1H), 1.48 (q, J = 11.6 Hz, 1H), 1.09 (d, J = 6.2 Hz, 3H).

[0205] 4-(((2R,4R)-2-Methyltetrahydro-2H-pyran-4-yl)amino)-3-nitroquinoline-6-carbonitrile: TFA (43.2 μL, 583 μmol, 3.0 equiv) 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 equiv) in DCM (2 mL, 0.1 M) under N2(g). 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 Na2SO4, 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-d6) δ 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).

[0206] Intermediate 3: Water (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), NH4Cl (120 mg, 2.24 mmol, 10 equiv), and Fe (125 mg, 2.24 mmol, 10 equiv). The reaction mixture was heated at 80 °C for 1 hour. 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 Na2SO4, filtered, and concentrated under reduced pressure to give 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-d4) δ 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).

[0207] Intermediate 4

Chem.

[0208] 6-Chloro-N-(3,4-dimethylbenzyl)-N-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-3-nitroquinolin-4-amine: LCMS [M+H]+ = 472.2. 11H NMR (400 MHz, DMSO-d6) δ 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).

[0209] 6-Chloro-N-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-3-nitroquinolin-4-amine: LCMS [M+H]+ = 322.1. 1 1H NMR (400 MHz, CDCl3) δ 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).

[0210] Intermediate 4: LCMS [M+H]+ = 292.1. 1 1H NMR (400 MHz, CDCl3) δ 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).

[0211] Intermediate 5 [Chemistry] 2-Chloro-N-(6-cyano-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)quinolin-3-yl)acetamide: Triethylamine (739 μL, 5.31 mmol, 3.0 equiv) was added to a solution of compound intermediate 3 (500 mg, 1.77 mmol, 1.0 equiv) in DCM (10 mL). A solution of chloroacetyl chloride (141 μL, 1.77 mmol, 1.0 equiv) in DCM (5 mL) was added dropwise to the reaction mixture at -10 °C. The reaction mixture was stirred at -10 °C for 1 hour under a N2 atmosphere. The mixture was gradually warmed to 10 °C and stirred for an additional 1 hour under a N2 atmosphere. The mixture was poured into water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (90% EtOAc in petroleum ether) to give the title compound as a yellow solid. LCMS [M+H]+ = 359.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.03 (s, 1H), 8.34 (s, 1H), 7.94 - 7.91 (m, 2H), 6.50 (d, J = 8.8 Hz, 1H), 4.35 (s, 2H), 4.12 - 4.04 (m, 1H), 3.92 - 3.85 (m, 1H), 3.42 - 3.39 (m, 2H), 1.90 - 1.85 (m, 1H), 1.82 - 1.76 (m, 1H), 1.61 - 1.51 (m, 1H), 1.20 - 1.14 (m, 1H), 1.10 (d, J = 6.4 Hz, 3H).

[0212] Intermediate 5: AcOH (1.0 mL, 17.5 mmol, 20 eq) 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 eq) in dioxane (6 mL, 0.1 M) under an N2 atmosphere. The mixture was stirred at room temperature for 12 h. The mixture was poured into water (20 mL) and then extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, 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-d6) δ 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).

[0213] Intermediate 6

Chemical formula

[0214] 6-Bromo-N-(3,4-dimethylbenzyl)-N-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-3-nitroquinolin-4-amine: LCMS [M+H]+ = 518.2. 11H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 7.94 - 7.81 (m, 2H), 6.84 (d, J = 8.8 Hz, 1H), 6.37 - 6.07 (m, 2H), 4.36 (s, 2H), 4.10 - 4.03 (m, 1H), 3.71 (s, 3H), 3.58 (s, 3H), 3.52 - 3.41 (m, 2H), 2.10 - 2.01 (m, 2H), 1.99 - 1.94 (m, 2H), 1.23 (d, J = 5.2 Hz, 3H).

[0215] 6 - Bromo - N - ((2R,4R) - 2 - methyltetrahydro - 2H - pyran - 4 - yl) - 3 - nitroquinolin - 4 - amine: LCMS [M + H]+ = 366.0. 1 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 9.21 - 9.05 (m, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.92 - 7.80 (m, 2H), 4.31 - 4.20 (m, 1H), 4.15 - 4.08 (m, 1H), 3.58 - 3.50 (m, 2H), 2.23 - 2.07 (m, 2H), 1.83 - 1.71 (m, 1H), 1.53 - 1.43 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H).

[0216] Intermediate 6: LCMS [M + H]+ = 335.9. 1 1H NMR (400 MHz, DMSO - d6) δ 8.42 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 2.0, 8.8 Hz, 1H), 5.24 (s, 2H), 4.67 (d, J = 10.8 Hz, 1H), 3.87 - 3.78 (m, 1H), 3.30 - 3.18 (m, 2H), 2.53 - 2.51 (m, 1H), 1.79 - 1.72 (m, 1H), 1.71 - 1.62 (m, 1H), 1.59 - 1.46 (m, 1H), 1.30 - 1.18 (m, 1H), 1.06 (d, J = 6.0 Hz, 3H).

[0217] Intermediate 7 [Chemical Structure] Intermediate 7 was prepared in the same manner as Intermediate 3 using Intermediate 7A as the starting material.

[0218] 3-Nitro-6-(trifluoromethyl)quinolin-4-ol: A solution of 6-(trifluoromethyl)quinolin-4-ol (2 g, 9.38 mmol, 1 equiv) in fuming HNO3 (20 g, 317.40 mmol, 33.83 equiv) was stirred at 60 °C for 12 h. The reaction mixture was poured into ice water (100 mL), and a solid formed. The mixture was filtered, and the filter cake was dried under reduced pressure to give the title compound as a crude yellow solid, which was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 13.30 (br s, 1H), 9.33 (s, 1H), 8.48 (s, 1H), 8.13 (dd, J = 2.0, 8.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H).

[0219] Intermediate 7A: A solution of 3-nitro-6-(trifluoromethyl)quinolin-4-ol (300 mg, 1.16 mmol, 1 equiv) in POCl3 (10 mL) was stirred at 110 °C for 2 h. The reaction mixture was poured into ice water (20 mL), and saturated NaHCO3 was added to adjust the pH to 6 - 7. The aqueous layer was then extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (3 × 15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give Intermediate 7A as a crude yellow oil, which was used in the next step without further purification. LCMS [M+H]+ = 277.0. 1 H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.76 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.14 (dd, J = 1.6, 8.8 Hz, 1H).

[0220] N-(3,4-Dimethylbenzyl)-N-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-3-nitro-6-(trifluoromethyl)quinolin-4-amine: LCMS [M+H]+ = 506.2. 11H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.60 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 1.6, 8.8 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.22 (dd, J = 2.4, 8.4 Hz, 1H), 6.16 (d, J = 2.4 Hz, 1H), 4.39 (d, J = 2.4 Hz, 2H), 4.09 - 4.03 (m, 1H), 3.82 - 3.75 (m, 1H), 3.69 (s, 3H), 3.50 (s, 3H), 3.46 - 3.37 (m, 2H), 2.05 - 1.95 (m, 3H), 1.77 - 1.66 (m, 1H), 1.23 (d, J = 6.0 Hz, 3H).

[0221] N - ((2R,4R)-2 - methyltetrahydro - 2H - pyran - 4 - yl)-3 - nitro - 6 - (trifluoromethyl)quinolin - 4 - amine: 1 1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 9.40 (d, J = 8.4 Hz, 1H), 8.48 (s, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.03 - 7.92 (m, 1H), 4.36 - 4.23 (m, 1H), 4.14 - 4.12 (m, 1H), 3.59 - 3.47 (m, 2H), 2.29 - 2.12 (m, 2H), 1.85 - 1.80 (m, 1H), 1.56 - 1.50 (m, 1H), 1.29 (d, J = 6.0 Hz, 3H).

[0222] Intermediate 7: LCMS [M + H]+ = 326.2. 1 1H NMR (400 MHz, DMSO - d6) δ 8.53 (s, 1H), 8.45 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 1.6, 8.8 Hz, 1H), 5.33 (s, 2H), 4.98 (d, J = 10.3 Hz, 1H), 3.92 - 3.79 (m, 1H), 3.29 - 3.15 (m, 2H), 1.82 - 1.64 (m, 2H), 1.55 - 1.50 (m, 1H), 1.27 - 1.21 (m, 2H), 1.06 (d, J = 6.0 Hz, 3H).

[0223] Intermediate 8 [Chemical Structure] 6-Bromo-3-nitro-N-(tetrahydro-2H-pyran-4-yl)quinolin-4-amine: A solution of 6-bromo-4-chloro-3-nitroquinoline (1 g, 3.13 mmol, 1 equiv), 4-aminotetrahydropyran (316.64 mg, 3.13 mmol, 1 equiv), and DIPEA (817.89 μL, 4.70 mmol, 1.5 equiv) in MeCN (25 mL) was degassed and purged with N2 (3×). The solution was stirred at 80 °C for 3 h under an N2 atmosphere. The reaction mixture was concentrated in vacuo to remove MeCN. The resulting crude material was purified by silica gel chromatography (petroleum ether / EtOAc = 100 / 0 to 75 / 25) to give the title compound as a yellow solid. LCMS [M+H]+ = 353.7. 1 H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.94 - 7.82 (m, 2H), 4.37 - 4.26 (m, 1H), 4.10 - 4.02 (m, 2H), 3.63 - 3.52 (m, 2H), 2.21 - 2.11 (m, 2H), 1.93 - 1.77 (m, 2H).

[0224] 3-Nitro-4-((tetrahydro-2H-pyran-4-yl)amino)quinoline-6-carbonitrile: A mixture of 6-bromo-3-nitro-N-(tetrahydro-2H-pyran-4-yl)quinolin-4-amine (600 mg, 1.53 mmol, 1 equiv), Zn(CN)2 (291.98 μL, 4.60 mmol, 3 equiv), Pd2(dba)3 (88.17 mg, 153.33 μmol, 0.1 equiv), and dppf (170.01 mg, 306.66 μmol, 0.2 equiv) in DMF (15 mL) was degassed and purged with N2 (3×). The reaction mixture was stirred at 140 °C for 6 h under N2. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The obtained crude material was purified by silica gel chromatography (PE / EtOAc = 100 / 0~40 / 60) to give the title compound as a brown solid. LCMS [M+H]+ = 298.8. 1 H NMR (400 MHz, DMSO-d6) δ 9.11 - 9.03 (m, 2H), 8.43 (d, J = 8.1 Hz, 1H), 8.20 - 8.09 (m, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.59 - 7.44 (m, 1H), 3.98 - 3.70 (m, 4H), 1.97 - 1.91 (m, 2H), 1.79 - 1.73 (m, 2H).

[0225] Intermediate 8: To a solution of 3-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)quinoline-6-carbonitrile (200.00 mg, 536.38 μmol, 1 equiv) in water (0.5 mL) and EtOH (2 mL) were added Fe (299.57 mg, 5.36 mmol, 10 equiv) and NH4Cl (286.91 mg, 5.36 mmol, 10 equiv). The mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (DCM / MeOH = 99 / 1 to 95 / 5) to give Intermediate 8 as a yellow solid. LCMS [M+H]+ = 268.9. 1 H NMR(400MHz,CDCl3)δ 8.60(s,1H),8.19(d,J=1.6Hz,1H),8.04(d,J=8.4Hz,1H),7.6-7.57(m,1H),4.06-3.98(m,2H),3.93(s,2H),3.61-3.49(m,2H),3.46-3.36(m,2H),1.89(d,J=12.4Hz,2H),1.65-1.60(m,1H).

[0226] Intermediate 9

Chemical Structure

[0227] 6-Bromo-4-chloro-2-methyl-3-nitroquinoline: A solution of 6-bromo-2-methyl-3-nitroquinolin-4-ol (1.50 g, 5.30 mmol, 1 equiv) in POCl3 (30 mL) was stirred at 110 °C for 2.5 h. The mixture was cooled to room temperature and added dropwise to stirred ice water (60 mL), then extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale pink solid, which was used in the next step without further purification. LCMS [M+H]+ = 302.7. 1 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 1.6 Hz, 1H), 8.03 - 7.91 (m, 2H), 2.75 (s, 3H).

[0228] 6-Bromo-N-(3,4-dimethylbenzyl)-2-methyl-N-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-3-nitroquinolin-4-amine: To a solution of 6-bromo-4-chloro-2-methyl-3-nitroquinoline (1.00 g, 2.98 mmol, 1 equiv) in MeCN (20 mL) were added DIPEA (2.08 mL, 11.94 mmol, 4.0 equiv) and Intermediate 1 (1.50 g, 5.37 mmol, 1.8 equiv). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (0 - 30% EtOAc in PE) to give the title compound as a red oil. LCMS [M+H]+ = 531.9. 11H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 2.4 Hz, 1H), 7.82 - 7.78 (m, 1H), 7.74 - 7.69 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 6.19 (dd, J = 2.4, 8.4 Hz, 1H), 4.29 (s, 2H), 3.98 - 3.85 (m, 1H), 3.71 (s, 3H), 3.60 (s, 3H), 3.54 - 3.37 (m, 3H), 2.63 (s, 3H), 1.94 - 1.78 (m, 2H), 1.61 (s, 2H), 1.17 (d, J = 6.0 Hz, 3H).

[0229] 2-Methyl-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)-3-nitroquinoline-6-carbonitrile: To a solution of 6-bromo-N-(3,4-dimethylbenzyl)-2-methyl-N-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-3-nitroquinoline-4-amine (500 mg, 942.67 μmol, 1.0 equiv) in DMF (20 mL) were added Zn(CN)2 (460 mg, 3.92 mmol, 4.16 equiv), Pd2(dba)3 (172.64 mg, 188.53 μmol, 0.2 equiv), and dppf (209.04 mg, 377.07 μmol, 0.4 equiv). The mixture was stirred at 120 °C for 15 h under N2. The mixture was diluted with DCM (20 mL) and washed with brine (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (0 - 30% EtOAc in PE) to afford the title compound as a white solid. LCMS [M+H]+ = 477.2. 11H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 1.6 Hz, 1H), 8.14 - 8.03 (m, 1H), 8.02 (d, J = 3.6 Hz, 1H), 7.78 (dd, J = 1.6, 8.4 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.33 - 6.08 (m, 2H), 4.31 (s, 2H), 3.98 - 3.90 (m, 1H), 3.71 (s, 3H), 3.59 (s, 3H), 3.54 - 3.46 (m, H), 3.45 - 3.36 (m, 2H), 2.69 (s, 3H), 1.90 - 1.83 (m, 2H), 1.76 - 1.51 (m, 2H), 1.17 (d, J = 6.0 Hz, 3H).

[0230] 2-Methyl-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)-3-nitroquinoline-6-carbonitrile: To a solution of 2-methyl-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)-3-nitroquinoline-6-carbonitrile (400 mg, 671.5 μmol, 1 equiv) in DCM (4 mL) was added TFA (0.15 mL, 2.01 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 (25 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, 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]+ = 327.1.

[0231] Intermediate 9: To a solution of 2-methyl-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)-3-nitroquinoline-6-carbonitrile (350 mg, 1.07 mmol, 1 equiv) in H2O (3 mL) and EtOH (10 mL) were added Fe (898.38 mg, 16.09 mmol, 15 equiv) and NH4Cl (860.52 mg, 16.09 mmol, 15 equiv). The mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting material was diluted with DCM (30 mL) and washed with saturated NaHCO3 (1×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (basic conditions) to give the title compound as a yellow solid. LCMS [M+H]+ = 297.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.58 - 7.55 (m, 1H), 5.10 (s, 2H), 4.79 (d, J = 10.8 Hz, 1H), 3.85 - 3.81 (m, 1H), 3.27 - 3.21 (m, 2H), 2.52 (s, 3H), 2.44 - 2.50 (m, 1H), 1.77 - 1.70 (m, 2H), 1.57 - 1.55 (m, 1H), 1.29 - 1.23 (m, 1H), 1.06 (d, J = 6.4 Hz, 3H).

[0232] Example 1. Procedure A: Synthesis of Compound 179

Chemical Structure

[0233] Methyl 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetate: T3P (178 μL, 50% in EtOAc, 300 μmol, 2.4 equiv) was added to a solution of 3-((6-cyano-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)quinolin-3-yl)amino)-3-oxopropanoate (50 mg, 125 μmol, 1.0 equiv) and DIEA (65.3 μL, 375 μmol, 3.0 equiv) in toluene (3 mL, 0.4 M) at 20 °C under a N2 atmosphere. The reaction mixture was irradiated in a microwave reactor for 4 h (110 °C, 2 bar). The mixture was slowly poured into ice water (50 mL) and extracted with DCM (2 × 50 mL). The separated organic layers were combined, washed with brine (2 × 50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The resulting crude material was purified by silica gel chromatography (5 - 8% MeOH in DCM) to give the title compound as a yellow solid. LCMS [M+H]+ = 365.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 9.03 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 5.37 - 5.00 (m, 1H), 4.45 (s, 2H), 4.27 - 4.08 (m, 1H), 3.85 - 3.72 (m, 2H), 3.71 (s, 3H), 2.44 - 2.37 (m, 1H), 2.24 - 1.92 (m, 3H), 1.24 (d, J = 5.6 Hz, 3H).

[0234] Lithium 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetate (Intermediate 10): To a solution of methyl 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetate (450 mg, 1.17 mmol, 1 equiv) in THF (1.5 mL, 0.8 M) was added a solution of LiOH·H2O (73.8 mg, 1.76 mmol, 1.5 equiv) in H2O (0.5 mL) at 0 °C under a N2 atmosphere. The reaction mixture was then stirred at 20 °C for 2 h. The mixture was slowly diluted with water (50 mL) and MeCN (20 mL) and freeze-dried directly to give Intermediate 10 as a brown solid, which was used directly in the next step without further purification. LCMS [M+H]+ = 351.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 9.05 (br s, 1H), 8.30 (br d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 5.28 - 5.03 (m, 1H), 4.31 - 4.00 (m, 1H), 3.79 (br s, 2H), 3.72 - 3.55 (m, 2H), 2.46 - 2.39 (m, 1H), 2.30 - 2.05 (m, 3H), 1.23 (d, J = 5.2 Hz, 3H).

[0235] 2-(8-Cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N-((5-methylisoxazol-4-yl)methyl)acetamide (Compound 179): To a solution of lithium 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetate (Intermediate 10, 30 mg, 69.6 μmol, 1.0 equiv) in DMF (2.5 mL, 0.03 M) were added 5-methyl-4-isoxazolemethylamine hydrochloride (20.7 mg, 139 μmol, 2.0 equiv) and DIEA (36 μL, 208.89 μmol, 3.0 equiv), followed by T3P (50% in EtOAc, 49.7 μL, 167 μmol, 2.4 equiv) at 20 °C under N2 atmosphere. The reaction mixture was then stirred at 20 °C for 2 h. The mixture was slowly poured into ice water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (acidic conditions) and lyophilized to give the title compound as a white solid. LCMS [M+H]+ = 445.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.01 (br s, 1H), 8.73 (br s, 1H), 8.40 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.05 (dd, J = 1.2, 8.4 Hz, 1H), 5.24 - 5.00 (m, 1H), 4.26 - 4.04 (m, 5H), 3.81 - 3.46 (m, 2H), 2.48 - 2.42 (m, 1H), 2.39 (s, 3H), 2.19 - 1.94 (m, 3H), 1.28 - 1.14 (m, 3H).

[0236] Example 2. Procedure B: Synthesis of Compound 182

Chemical Structure

[0237] 2-(1-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-5-oxopyrrolidin-3-yl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile: A mixture of 4-bromo-1-(2-(t-butyldimethylsilyloxy)ethyl)pyrazole (30 mg, 0.1 mmol, 1.23 equiv), 1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2-(5-oxopyrrolidin-3-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (30 mg, 0.08 mmol, 1 equiv), CuI (6.09 mg, 0.03 mmol, 0.4 equiv), N,N’-dimethyl-1,2-diaminocyclohexane (6.25 mg, 0.044 mmol, 0.55 equiv), and K2CO3 (55.22 mg, 0.4 mmol, 5 equiv) in 1,4-dioxane (2 mL, 0.04 M) was stirred at 110 °C for 16 h under N2. The reaction mixture was concentrated to give a residue, which was purified by preparative TLC (EtOAc) to afford the title compound as a yellow oil. 1 H NMR (500 MHz, CD3OD) δ 9.33 (s, 2H), 8.39 (d, J = 8.5 Hz, 1H), 8.13 (s, 1H), 8.03 (dd, J = 1.5, 8.5 Hz, 1H), 7.83 (s, 1H), 4.97 - 5.46 (m, 3H), 4.57 - 4.63 (m, 1H), 4.25 - 4.44 (m, 5H), 3.86 - 4.04 (m, 4H), 3.19 - 3.28 (m, 1H), 3.08 - 3.19 (m, 1H), 2.12 - 2.85 (m, 3H), 1.42 (d, J = 6.0 Hz, 3H), 0.86 (d, J = 2.0 Hz, 9H), 0.05 - 0.04 (m, 6H).

[0238] 2-(1-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)-5-oxopyrrolidin-3-yl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile: To a solution of 2-(1-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-5-oxopyrrolidin-3-yl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (16 mg, 26.7 μmol, 1 equiv) in dioxane (2 mL, 0.1 M) was added HCl / dioxane (4 M, 0.2 mL). The mixture was stirred at 25 °C for 1 h. The solution was concentrated to give a residue, which was purified by preparative HPLC (acidic conditions) and lyophilized to give the title compound. LCMS [M+H]+ = 486.4. 1 H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.06 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.03 - 8.12 (m, 2H), 7.71 (d, J = 4.0 Hz, 1H), 5.32 (s, 1H), 4.89 (t, J = 5.5 Hz, 1H), 4.54 (s, 1H), 4.08 - 4.31 (m, 5H), 3.66 - 3.91 (m, 4H), 3.07 - 3.17 (m, 1H), 2.76 - 3.00 (m, 1H), 2.55 - 2.62 (m, 1H), 2.01 - 2.26 (m, 3H), 1.27 (d, J = 6.0 Hz, 3H).

[0239] Example 3. Procedure C: Synthesis of Compound 163

Chemical Structure

[0240] Methyl 3-((6-chloro-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)quinolin-3-yl)amino)-3-oxopropanoate: LCMS [M+H]+ = 392.0.

[0241] Methyl 2-(8-chloro-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetate: LCMS [M+H]+ = 374.1.

[0242] Lithium 2-(8-chloro-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetate: LCMS [M+H]+ = 360.0. 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.69 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 5.12 (br s, 1H), 4.17 (br s, 1H), 3.76 (s, 2H), 3.70 - 3.56 (m, 2H), 2.43 - 2.37 (m, 1H), 2.26 - 2.06 (m, 3H), 1.22 (d, J = 4.8 Hz, 3H).

[0243] N-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2-(8-chloro-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)acetamide: LCMS [M+H]+ = 517.2.

[0244] 2-{8-Chloro-1-[(2R,4R)-2-methyloxan-4-yl]-1H-imidazo[4,5-c]quinolin-2-yl}-N-(2-hydroxyethyl)acetamide (Compound 163): LCMS [M+H]+ = 403.2. 11H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.69 (br s, 1H), 8.43 (br s, 1H), 8.20 (d, J = 9.2 Hz, 1H), 7.74 (dd, J = 2.0, 8.8 Hz, 1H), 5.24 - 5.03 (m, 1H), 4.82 - 4.72 (m, 1H), 4.24 - 4.09 (m, 3H), 3.77 - 3.56 (m, 2H), 3.48 - 3.41 (m, 2H), 3.21 - 3.15 (m, 2H), 2.48 - 2.43 (m, 1H), 2.26 - 2.09 (m, 2H), 2.07 - 1.98 (m, 1H), 1.23 (d, J = 6.0 Hz, 3H).

[0245] Example 4. Procedure D: Synthesis of Compound 13

Chemical Structure

[0246] 1-((6-Methylpyridin-3-yl)methyl)-5-oxopyrrolidine-3-carboxylic acid: To a solution of methyl 1-((6-methylpyridin-3-yl)methyl)-5-oxopyrrolidine-3-carboxylate (450 mg, 1.63 mmol, 1.0 equiv) in THF (6 mL) and H2O (2 mL) was added LiOH·H2O (137 mg, 3.26 mmol, 2.0 equiv). The reaction mixture was stirred at 80 °C for 12 h. THF was concentrated under reduced pressure, and the aqueous phase was adjusted to pH = 1 with 1N HCl. The aqueous phase was then lyophilized to give the title compound as a colorless gum. 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 4.62 - 4.44 (m, 2H), 3.55 - 3.50 (m, 2H), 3.42 (d, J = 5.6 Hz, 2H), 3.30 - 3.21 (m, 1H), 2.70 (s, 3H).

[0247] 1-[(2R,4R)-2-Methyloxan-4-yl]-2-{1-[(6-methylpyridin-3-yl)methyl]-5-oxopyrrolidin-3-yl}-1H-imidazo[4,5-c]quinoline-8-carbonitrile (Compound 13): Intermediate 3 (30 mg, 95.6 μmol, 1.0 equiv), 1-((6-methylpyridin-3-yl)methyl)-5-oxopyrrolidine-3-carboxylic acid (27.38 mg, 105.2 μmol, 1.1 equiv), DIPEA (50.0 μL, 287 μmol, 3 equiv), T3P (50% in EtOAc, 137 μL, 230 μmol, 2.4 equiv) and toluene (2 mL, 0.05 M) were placed in a microwave tube. The sealed tube was heated at 110 °C for 8 h under microwave irradiation (1 bar). The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (acidic conditions) to give Example 4 (Compound 13) as a yellow solid. LCMS [M+H]+ = 481.2. 11H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 9.01 (br.s, 1H), 8.39 (br.s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.60 (t, J = 5.6 Hz, 1H), 7.22 (dd, J = 5.6, 7.6 Hz, 1H), 5.47 - 5.09 (m, 1H), 4.55 - 4.40 (m, 2H), 4.34 (d, J = 7.2 Hz, 1H), 4.16 (br.s, 1H), 3.90 - 3.64 (m, 4H), 3.07 - 2.93 (m, 1H), 2.87 - 2.72 (m, 1H), 2.42 (d, J = 2.8 Hz, 3H), 2.26 - 1.87 (m, 4H), 1.23 (d, J = 6.0 Hz, 3H).

[0248] Example 5. Procedure E: Synthesis of Compound 77 [Chemical Structure] Methyl 1-((8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidine-3-carboxylate: To a solution of methyl pyrrolidine-3-carboxylate hydrochloride (13.12 mg, 79.2 μmol, 1.0 equiv) and Intermediate 5 (30 mg, 79.2 μmol, 1.0 equiv) in DMF (1 mL, 0.1 M) was added DIPEA (41.4 μL, 237.67 μmol, 3.0 equiv). The reaction mixture was stirred at 20 °C for 12 h under a N2 atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as a yellow solid, which was used directly in the next step without further purification. LCMS [M+H]+ = 434.2. 11H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.98 (br s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.05 (dd, J = 1.6, 8.8 Hz, 1H), 5.49 - 5.20 (m, 1H), 4.24 - 4.02 (m, 3H), 3.81 - 3.63 (m, 2H), 3.58 (s, 3H), 3.10 - 3.00 (m, 1H), 2.87 - 2.80 (m, 1H), 2.72 - 2.63 (m, 2H), 2.48 - 2.42 (m, 2H), 2.22 - 2.13 (m, 1H), 2.12 - 2.05 (m, 1H), 2.04 - 1.95 (m, 3H), 1.24 (d, J = 6.0 Hz, 3H).

[0249] 1-({8-Cyano-1-[(2R,4R)-2-methyloxan-4-yl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)pyrrolidine-3-carboxylic acid (Compound 77): To a solution of methyl 1-((8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)pyrrolidine-3-carboxylate (45 mg, 103.81 μmol, 1.0 equiv) in THF (2 mL) and H2O (1 mL) was added LiOH·H2O (8.71 mg, 207.6 μmol, 2.0 equiv). The reaction mixture was stirred at 20 °C for 1.5 h under a N2 atmosphere. The reaction mixture was adjusted to pH = 3 - 4 by the addition of 2 M HCl. Then the mixture was concentrated in vacuo to remove most of the THF. The residual aqueous phase was purified by preparative HPLC (acidic conditions) and lyophilized to give Example 5 (Compound 77) as a pale yellow solid. LCMS [M + H]+ = 420.2. 11H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.98 (br s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.05 (dd, J = 1.6, 8.8 Hz, 1H), 5.46 - 5.33 (m, 1H), 4.23 - 4.14 (m, 1H), 4.10 (br s, 3H), 3.78 - 3.60 (m, 1H), 2.99 - 2.90 (m, 1H), 2.87 - 2.79 (m, 1H), 2.69 - 2.62 (m, 2H), 2.48 - 2.41 (m, 2H), 2.28 - 2.04 (m, 3H), 1.98 (q, J = 7.2 Hz, 3H), 1.24 (d, J = 6.0 Hz, 3H).

[0250] Example 6. Procedure F: Synthesis of Compound 23 [Chemical formula] tert-Butyl ((8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)carbamate: A mixture of intermediate 3 (50 mg, 159 μmol, 1.0 equiv), Boc-glycine (33.5 mg, 191 μmol, 1.2 equiv), DIPEA (83.3 μL, 478 μmol, 3.0 equiv), and T3P (50% in EtOAc, 227.5 μL, 383 μmol, 2.4 equiv) in toluene (2 mL, 0.1 M) was purged three times with N2(g). The mixture was stirred at 110 °C for 5 h under microwave irradiation (1 bar). The mixture was slowly poured into ice water (5 mL) and then extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (acidic conditions) and lyophilized to give the title compound as a white solid. LCMS [M+H]+ = 422.1. 11H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.97 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 1.6, 8.8 Hz, 1H), 7.64 (s, 1H), 5.44 - 5.17 (m, 1H), 4.69 (d, J = 4.8 Hz, 2H), 4.19 (d, J = 3.6 Hz, 1H), 3.88 - 3.61 (m, 2H), 2.48 - 2.36 (m, 1H), 2.21 - 1.90 (m, 3H), 1.41 (s, 9H), 1.24 (d, J = 6.0 Hz, 3H).

[0251] 2-(Aminomethyl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile: TFA (2.5 mL, 34 mmol, 21 equiv) was added to a solution of tert-butyl ((8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)carbamate (670 mg, 1.59 mmol, 1.0 equiv) in DCM solution (10 mL, 0.2 M) at 0 °C under a N2 atmosphere. The reaction mixture was then stirred at 20 °C for 12 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with DCM (20 mL) and cooled to 0 °C. Ammonium hydroxide (aqueous solution) was added dropwise to the reaction mixture until pH = 9 - 10. The reaction mixture was then concentrated in vacuo, and the resulting crude product was purified by preparative HPLC (acidic conditions) and lyophilized to give the title compound as a yellow solid. LCMS [M+H]+ = 322.1. 1 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.99 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 5.47 - 5.28 (m, 1H), 4.22 (s, 2H), 4.20 - 4.11 (m, 1H), 3.87 - 3.66 (m, 2H), 2.94 - 2.64 (m, 1H), 2.47 - 2.41 (m, 1H), 2.21 - 2.12 (m, 2H), 2.10 - 2.01 (m, 1H), 1.24 (d, J = 6.0 Hz, 3H).

[0252] N-({8-Cyano-1-[(2R,4R)-2-methyloxan-4-yl]-1H-imidazo[4,5-c]quinolin-2-yl}methyl)acetamide (Compound 23): To a stirred solution of 2-(aminomethyl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (20 mg, 60.3 μmol, 1.0 equiv) and TEA (20 μL, 144 μmol, 2.4 equiv) in DCM (1 mL, 0.06 M) at 0 °C was added acetyl chloride (7 μL, 98 μmol, 1.6 equiv). The mixture was stirred at 0 °C for 1 h. The mixture was then concentrated in vacuo and the resulting crude material was purified by preparative HPLC (acidic conditions) and lyophilized to afford the title compound as a white solid. LCMS [M+H]+ = 364.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.98 (s, 1H), 8.68 (br t, J = 5.2 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 5.61 - 5.05 (m, 1H), 4.85 - 4.76 (m, 2H), 4.28 - 4.08 (m, 1H), 3.85 - 3.61 (m, 2H), 2.45 - 2.37 (m, 1H), 2.23 - 2.07 (m, 2H), 2.03 - 1.95 (m, 1H), 1.92 (s, 3H), 1.24 (d, J = 6.0 Hz, 3H).

[0253] Example 7. Procedure G: Synthesis of Compound 160

Chemical Structure

[0254] N-Cyclopropyl-2-{8-methoxy-1-[(2R,4R)-2-methyloxan-4-yl]-1H-imidazo[4,5-c]quinolin-2-yl}acetamide (Compound 160): To a solution of 2-(8-bromo-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-N-cyclopropylacetamide (40 mg, 32.6 μmol, 1.0 equiv) in dioxane (10 mL, 0.003 M) were added NaOMe (16.5 mg, 171 μmol, 3.0 equiv), Cs2CO3 (83.8 mg, 257 μmol, 3.0 equiv) and tBuBrettPhos Pd G3 (7.32 mg, 8.57 μmol, 0.1 equiv). The mixture was then stirred at 90 °C for 15 h. Thereafter, the reaction mixture was filtered and the filtrate was concentrated to give the crude product. The obtained crude material was purified by preparative HPLC (acidic conditions) and lyophilized to give the title compound as a white solid. LCMS [M+H]+ = 395.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.49 (br s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.93 (s, 1H), 7.36 - 7.34 (m, 1H), 5.15 - 5.10 (m, 1H), 4.21 (d, J = 7.2 Hz, 1H), 4.08 (s, 2H), 3.98 (s, 3H), 3.73 - 3.54 (m, 2H), 2.73 - 2.61 (m, 2H), 2.40 - 2.23 (m, 1H), 2.20 - 2.09 (m, 1H), 2.02 (d, J = 8.0 Hz, 1H), 1.23 (d, J = 6.0 Hz, 3H), 0.67 - 0.63 (m, 2H), 0.45 - 0.40 (m, 2H).

[0255] Example 8. Procedure H: Synthesis of Compound 109

Chemical Structure

[0256] 6-Bromo-N-cyclopentyl-N-(3,4-dimethylbenzyl)-3-nitroquinolin-4-amine: To a solution of 6-bromo-4-chloro-3-nitroquinoline (2 g, 6.26 mmol, 1.0 equiv) and N-(3,4-dimethylbenzyl)cyclopentanamine (2.46 g, 9.39 mmol, 1.5 equiv) in CH3CN (20 mL, 0.3 M) was added DIPEA (3.27 mL, 18.8 mmol, 3.0 equiv). The reaction mixture was stirred at 75 °C for 12 h and then concentrated in vacuo. The resulting crude material was purified by flash silica gel chromatography (0 - 11% EtOAc in petroleum ether) to give the title compound as a red solid. 11H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.93 - 7.84 (m, 1H), 7.83 - 7.72 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.28 - 6.14 (m, 2H), 4.41 (s, 2H), 4.10 - 4.00 (m, 1H), 3.71 (s, 3H), 3.49 (s, 3H), 2.05 - 1.95 (m, 2H), 1.95 - 1.84 (m, 2H), 1.80 - 1.67 (m, 2H), 1.64 - 1.57 (m, 2H).

[0257] 4-Cyclopentyl(3,4-dimethylbenzyl)amino)-3-nitroquinoline-6-carbonitrile: To a solution of 6-bromo-N-cyclopentyl-N-(3,4-dimethylbenzyl)-3-nitroquinoline-4-amine (500 mg, 925.25 μmol, 1.0 equiv) in DMF (10 mL, 0.1 M) were added zinc dicyanide (108 μL, 1.70 mmol, 1.84 equiv), Pd2(dba)3 (169.5 mg, 185 μmol, 0.2 equiv) and dppf (205.17 mg, 370.1 μmol, 0.4 equiv) under N2 atmosphere. The mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by flash silica gel chromatography (0 - 20% EtOAc in petroleum ether) to afford the title compound as a yellow solid. LCMS [M+Na]+ = 455.1. 1 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.61 (d, J = 1.2 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 2.0, 8.8 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.25 (dd, J = 2.4, 8.4 Hz, 1H), 6.20 (d, J = 2.4 Hz, 1H), 4.45 (s, 2H), 4.08 - 4.00 (m, 1H), 3.72 (s, 3H), 3.48 (s, 3H), 2.05 - 1.97 (m, 2H), 1.94 - 1.84 (m, 2H), 1.81 - 1.69 (m, 2H), 1.66 - 1.59 (m, 2H).

[0258] 4-(Cyclopentylamino)-3-nitroquinoline-6-carbonitrile: To a solution of 4-(cyclopentyl(3,4-dimethylbenzyl)amino)-3-nitroquinoline-6-carbonitrile (290 mg, 603.5 μmol, 1.0 equiv) in DCM (3 mL, 0.2 M) was added TFA (0.5 mL, 6.75 mmol, 11.2 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by adding saturated NaHCO3 (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by flash silica gel chromatography (0 - 30% EtOAc in petroleum ether) to give the title compound as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 10.02 (br s, 1H), 9.45 (s, 1H), 8.72 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 1.6, 8.8 Hz, 1H), 4.70 - 4.59 (m, 1H), 2.39 - 2.23 (m, 2H), 1.98 - 1.82 (m, 6H).

[0259] 3-Amino-4-(cyclopentylamino)quinoline-6-carbonitrile: To a solution of 4-(cyclopentylamino)-3-nitroquinoline-6-carbonitrile (100 mg, 318.8 μmol, 1.0 equiv) in EtOH:H2O (4:1, 5 mL, 0.06 M) were added Fe (178 mg, 3.19 mmol, 10 equiv) and NH4Cl (170.5 mg, 3.19 mmol, 10 equiv). The mixture was stirred at 75 °C for 40 min. The reaction mixture was filtered and concentrated in vacuo. The residue was diluted with NaHCO3 (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by flash silica gel chromatography (0 - 80% EtOAc in petroleum ether) to give the title compound as a yellow solid. LCMS [M + H]+ = 253.2. 11H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 1.6 Hz, 1H), 8.51 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.58 (dd, J = 1.6, 8.4 Hz, 1H), 5.29 (s, 2H), 4.99 (d, J = 10.0 Hz, 1H), 4.07 - 3.94 (m, 1H), 1.87 - 1.67 (m, 4H), 1.49 (br s, 4H).

[0260] 2-{8-Cyano-1-cyclopentyl-1H-imidazo[4,5-c]quinolin-2-yl}-N-(cyclopropylmethyl)acetamide (Compound 109): To a solution of 3-amino-4-(cyclopentylamino)quinoline-6-carbonitrile (20 mg, 71.34 μmol, 1.0 equiv) and 3-(cyclopropylmethylamino)-3-oxopropanoic acid (11.21 mg, 71.34 μmol, 1.0 equiv) in EtOAc (3 mL) were added T3P (50% in EtOAc, 102 μL, 171.2 μmol, 2.4 equiv) and DIPEA (37.3 μL, 214 μmol, 3.0 equiv). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated in vacuo and the residue was dissolved in toluene (2 mL). The mixture was stirred at 110 °C for 6 h under microwave irradiation (2 bar). The reaction mixture was quenched by addition of saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (acidic conditions) and lyophilized to give the title compound as a pale yellow solid. LCMS [M+H]+ = 374.2. 11H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.67 (s, 1H), 8.44 (t, J = 5.2 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.21 (s, 0.2H), 8.04 (dd, J = 1.6, 8.8 Hz, 1H), 5.48 - 5.33 (m, 1H), 4.13 (s, 2H), 2.99 (t, J = 6.4 Hz, 2H), 2.37 - 2.28 (m, 2H), 2.25 - 2.07 (m, 4H), 1.94 (d, J = 6.0 Hz, 2H), 1.00 - 0.89 (m, 1H), 0.47 - 0.40 (m, 2H), 0.23 - 0.15 (m, 2H).

[0261] Example 9. Procedure I: Synthesis of Compound 37 [Chemical Structure] Methyl (S)-3-((cyclopropylmethyl)amino)-2-hydroxypropanoate: A mixture of methyl (2S)-glycidate (200 mg, 1.96 mmol, 1.0 equiv), cyclopropanemethylamine (140 mg, 1.97 mmol, 1.0 equiv), and DMAP (24 mg, 196 μmol, 0.1 equiv) in dioxane (8 mL, 0.2 M) was stirred at 80 °C for 2 h. The mixture was concentrated to give the title compound as a colorless oil, which was used in the next step without further purification. LCMS [M+H]+ = 174.2.

[0262] (S)-Methyl 3-(cyclopropylmethyl)-2-oxooxazolidine-5-carboxylate: To a solution of methyl (S)-3-((cyclopropylmethyl)amino)-2-hydroxypropanoate (300 mg, 1.73 mmol, 1.0 equiv) and DMAP (21.16 mg, 173 μmol, 0.1 equiv) in dioxane (8 mL, 0.2 M) was added CDI (421.27 mg, 2.60 mmol, 1.5 equiv). The mixture was stirred at 70 °C for 2 h. The reaction mixture was then diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with 1N HCl (2 × 20 mL) and aqueous NaHCO3 (3 × 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (acidic conditions) and lyophilized to give the title compound as a white solid. LCMS [M+H]+ = 200.1. 1 1H NMR (400 MHz, CD3OD) δ 5.08 (dd, J = 5.2, 9.6 Hz, 1H), 4.01 (t, J = 9.6 Hz, 1H), 3.82 (s, 3H), 3.77 (dd, J = 5.2, 9.6 Hz, 1H), 3.12 (dd, J = 2.4, 7.2 Hz, 2H), 0.99 - 0.95 (m, 1H), 0.59 - 0.54 (m, 2H), 0.27 - 0.23 (m, 2H).

[0263] (S)-3-(Cyclopropylmethyl)-2-oxooxazolidine-5-carboxylic acid: To a solution of methyl (S)-3-(cyclopropylmethyl)-2-oxooxazolidine-5-carboxylate (25 mg, 126 μmol, 1.0 equiv) in MeOH (1 mL) was added a solution of LiOH·H2O (6.32 mg, 151 μmol, 1.2 equiv) in water (0.1 mL). The mixture was stirred at 25 °C for 10 min. The mixture was concentrated in vacuo to give the title compound as a white solid, which was used in the next step without further purification. LCMS [M+H]+ = 186.1.

[0264] 2-[(5S)-3-(Cyclopropylmethyl)-2-oxo-1,3-oxazolidin-5-yl]-1-[(2R,4R)-2-methyloxan-4-yl]-1H-imidazo[4,5-c]quinoline-8-carbonitrile (Compound 37): To a solution of (S)-3-(cyclopropylmethyl)-2-oxooxazolidine-5-carboxylic acid (23 mg, 124.21 μmol, 1.0 equiv), Intermediate 3 (36 mg, 128 μmol, 1.03 equiv), and DIPEA (65 μL, 373 μmol, 3.0 equiv) in toluene (1 mL) was added T3P (50% in EtOAc, 177 μL, 298 μmol, 2.4 equiv), and the mixture was stirred under microwave irradiation (2 bar) at 110 °C for 6 h. The mixture was washed with water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (acidic conditions) and lyophilized to give Example 9 as a yellow solid. LCMS [M+H]+ = 432.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.02 (br s, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 6.32 (dd, J = 6.0, 8.4 Hz, 1H), 5.61 - 5.23 (m, 1H), 4.60 (br s, 1H), 4.27 - 4.10 (m, 2H), 3.94 - 3.69 (m, 2H), 3.17 (d, J = 7.2 Hz, 2H), 2.20 (br s, 2H), 2.07 (br s, 1H), 1.25 (d, J = 6.0 Hz, 3H), 1.05 (br s, 1H), 0.58 - 0.53 (m, 2H), 0.31 - 0.27 (m, 2H).

[0265] Example 10. Procedure J: Synthesis of Compound 56

Chemical Structure

[0266] 2-(Azetidin-3-ylmethyl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile: To a mixture of tert-butyl 3-((8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)methyl)azetidine-1-carboxylate (15 mg, 32.5 μmol, 1.0 equiv) in DCM (2 mL, 0.02 M) was added TFA (0.2 mL, 2.70 mmol, 83 equiv). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated in vacuo and the resulting crude material was purified by preparative HPLC (acidic conditions) and lyophilized to afford the title compound as a white solid. LCMS [M+H]+ = 362.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.98 (s, 1H), 8.37 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.00 (dd, J = 1.6, 8.4 Hz, 1H), 5.30 (s, 2H), 4.20 - 4.14 (m, 3H), 3.95 - 3.73 (m, 2H), 3.49 - 3.37 (m, 4H), 2.27 - 1.99 (m, 4H), 1.28 (d, J = 6.2 Hz, 3H).

[0267] 1-[(2R,4R)-2-Methyloxan-4-yl]-2-{[1-(pyridine-2-carbonyl)azetidin-3-yl]methyl}-1H-imidazo[4,5-c]quinoline-8-carbonitrile (Compound 56): A mixture of 2-(azetidin-3-ylmethyl)-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (80 mg, 221 μmol, 1.0 equiv), picolinic acid (32.7 mg, 266 μmol, 1.2 equiv), DIPEA (116 μL, 664 μmol, 3.0 equiv), and HATU (84.2 mg, 221 μmol, 1.0 equiv) in DMF (1 mL, 0.2 M) was stirred at 25 °C for 4 h. The mixture was poured into MeOH (1 mL). The resulting crude material was purified by preparative HPLC (acidic conditions) and lyophilized to give Example 10 (Compound 56) as a white solid. LCMS [M+H]+ = 467.3. 1 H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.98 (s, 1H), 8.61 (d, J = 4.5 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.03 (dd, J = 1.5, 8.5 Hz, 1H), 7.93 - 8.00 (m, 2H), 7.52 (ddd, J = 2.5, 4.5, 6.5 Hz, 1H), 5.10 - 5.50 (m, 1H), 4.88 (t, J = 9.5 Hz, 1H), 4.42 - 4.49 (m, 1H), 4.35 (t, J = 9.5 Hz, 1H), 4.16 (s, 1H), 3.96 (s, 1H), 3.69 - 3.87 (m, 2H), 3.56 (d, J = 7.5 Hz, 2H), 2.52 (d, J = 1.5 Hz, 2H), 2.16 (s, 2H), 1.98 - 2.09 (m, 1H), 1.24 (d, J = 6.0 Hz, 3H).

[0268] Example 11. Procedure K: Synthesis of Compound 1

Chemical Structure

[0269] (R)-1-(Benzyloxy)-3-(N-(cyclopropylmethyl)methylsulfonamido)propan-2-yl 4-methylbenzenesulfonate: To a solution of (R)-N-(3-(benzyloxy)-2-hydroxypropyl)-N-(cyclopropylmethyl)methanesulfonamide (2.5 g, 7.18 mmol, 1.0 equiv) in DCM (8 mL) were added pyridine (8 mL, 99.12 mmol, 13.8 equiv) and TsCl (2.05 g, 10.8 mmol, 1.5 equiv). The mixture was stirred at 50 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by flash silica gel chromatography (0 - 30% EtOAc in petroleum ether) to afford the title compound as a pale yellow oil. 11H NMR (400 MHz, DMSO-d6) δ = 7.78 (d, J = 8.3 Hz, 2H), 7.37 - 7.27 (m, 4H), 7.26 (br s, 3H), 4.91 - 4.81 (m, 1H), 4.46 - 4.35 (m, 2H), 3.67 - 3.53 (m, 4H), 3.20 - 3.12 (m, 1H), 3.08 - 2.99 (m, 1H), 2.91 (s, 3H), 2.42 (s, 3H), 1.06 - 0.87 (m, 1H), 0.64 - 0.48 (m, 2H), 0.33 - 0.18 (m, 2H).

[0270] (S)-4-((Benzyloxy)methyl)-2-(cyclopropylmethyl)isothiazolidine 1,1-dioxide: To a solution of (R)-1-(benzyloxy)-3-(N-(cyclopropylmethyl)methylsulfonamido)propan-2-yl 4-methylbenzenesulfonate (1 g, 1.92 mmol, 1.0 equiv) in THF (25 mL) was added n-BuLi (2.5 M in hexanes, 1.92 mL, 2.5 equiv) dropwise over 2 h at -70 °C under a N2 atmosphere. The mixture was warmed to room temperature and stirred at 25 °C for 12 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (20 mL) at 0 °C and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by preparative TLC (3:1 petroleum ether:EtOAc) to give the title compound as a yellow oil. LCMS [M+H]+ = 296.1. 1 1H NMR (400 MHz, DMSO-d6) δ = 7.41 - 7.29 (m, 5H), 4.55 (s, 2H), 3.61 - 3.50 (m, 2H), 3.45 (dd, J = 7.4, 9.3 Hz, 1H), 3.32 - 3.24 (m, 1H), 3.11 (dd, J = 6.3, 9.4 Hz, 1H), 3.05 - 2.83 (m, 4H), 1.02 - 0.91 (m, 1H), 0.62 - 0.54 (m, 2H), 0.22 (q, J = 4.9 Hz, 2H).

[0271] (S)-2-(Cyclopropylmethyl)-4-(hydroxymethyl)isothiazolidine 1,1-dioxide: To a solution of (S)-4-((benzyloxy)methyl)-2-(cyclopropylmethyl)isothiazolidine 1,1-dioxide (65 mg, 198 μmol, 1.0 equiv) in MeOH (3 mL, 0.07 M) was added Pd / C (5 wt%, 20 mg, 198 μmol, 1.0 equiv) under an N2 atmosphere. The mixture was purged three times with H2 (15 psi) and stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The resulting crude material was used in the next step without further purification. LCMS [M+H]+ = 205.1. 1 H NMR (400 MHz, DMSO-d6) δ 3.82 - 3.76 (m, 2H), 3.47 - 3.44 (m, 1H), 3.30 (dd, J = 9.0, 13.0 Hz, 1H), 3.16 (dd, J = 6.2, 9.6 Hz, 1H), 3.05 (dd, J = 7.0, 12.9 Hz, 1H), 2.99 - 2.82 (m, 3H), 1.70 (br s, 1H), 1.03 - 0.97 (m, 1H), 0.65 - 0.53 (m, 2H), 0.29 - 0.17 (m, 2H).

[0272] (S)-2-(Cyclopropylmethyl)isothiazolidine-4-carboxylic acid 1,1-dioxide: To a solution of (S)-2-(cyclopropylmethyl)-4-(hydroxymethyl)isothiazolidine 1,1-dioxide (40 mg, 195 μmol, 1.0 equiv) in CCl4 (3 mL), CH3CN (3 mL), and H2O (4 mL) was added RuCl3 (0.39 μL, 5.85 μmol, 0.03 equiv). The mixture was stirred vigorously at 25 °C and NaIO4 (443.2 μL, 780 μmol, 4.0 equiv) was added all at once. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (20 mL). The reaction mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with H2O (10 mL) and saturated aqueous K2CO3 (2 × 10 mL). The combined aqueous layers were cooled to 0 °C and acidified to pH = 3. The resulting acidic solution was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as a residue, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 6.32 - 5.96 (m, 1H), 3.70 - 3.59 (m, 2H), 3.58 - 3.50 (m, 2H), 3.48 - 3.36 (m, 1H), 3.00 - 2.86 (m, 2H), 1.11 - 0.85 (m, 1H), 0.69 - 0.51 (m, 2H), 0.32 - 0.16 (m, 2H).

[0273] 2-[(4S)-2-(Cyclopropylmethyl)-1,1-dioxo-1λ 6,2-Thiazolidin-4-yl]-1-[(2R,4R)-2-methyloxan-4-yl]-1H-imidazo[4,5-c]quinoline-8-carbonitrile (Compound 1): To a solution of Intermediate 3 (20 mg, 63.8 μmol, 1 equiv) and (S)-2-(cyclopropylmethyl)isothiazolidine-4-carboxylic acid 1,1-dioxide (19.22 mg, 70.1 μmol, 1.1 equiv) in toluene (2 mL) were added DIPEA (33.3 μL, 191.25 μmol, 3.0 equiv) and T3P (50% in EtOAc, 56.9 μL, 95.6 μmol, 1.5 equiv). The mixture was stirred at 120 °C for 3 h. The mixture was stirred at 120 °C for 3 h under microwave irradiation (2 bar). The reaction mixture was quenched by adding saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (acidic conditions) and lyophilized to give Example 11 (Compound 1) as a brown solid. LCMS [M+H]+ = 466.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.07 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.08 (dd, J = 1.6, 8.8 Hz, 1H), 5.38 - 5.16 (m, 1H), 4.78 - 4.58 (m, 1H), 4.30 - 4.12 (m, 1H), 4.10 - 3.98 (m, 1H), 3.98 - 3.90 (m, 1H), 3.72 - 3.62 (m, 2H), 3.40 - 3.38 (m, 2H), 2.94 (dd, J = 2.8, 6.8 Hz, 2H), 2.42 - 2.40 (m, 1H), 2.18 - 1.94 (m, 3H), 1.32 - 1.20 (m, 3H), 1.10 - 0.98 (m, 1H), 0.58 - 0.48 (m, 2H), 0.32 - 0.20 (m, 2H).

[0274] Example 12. Procedure L: Synthesis of Compound 50

Chemical formula

[0275] 2-[1-(Cyclopropylmethyl)-6-oxopiperidin-3-yl]-1-[(2R,4R)-2-methyloxan-4-yl]-1H-imidazo[4,5-c]quinoline-8-carbonitrile (Compound 50): To a microwave vessel containing a solution of Intermediate 3 (30 mg, 96 μmol, 1.0 equiv), 1-(cyclopropylmethyl)-6-oxopiperidine-3-carboxylic acid (29.8 mg, 143 μmol, 1.5 equiv), and DIPEA (50.0 μL, 287 μmol, 3.0 equiv) in toluene (2 mL, 0.05 M), T3P (50% in EtOAc, 136.5 μL, 230 μmol, 2.4 equiv) was added at 0 °C under a N2 atmosphere. The reaction mixture was heated to 120 °C for 4 h under microwave irradiation (2 bar). The mixture was slowly poured into ice water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (acidic conditions) and lyophilized to give Example 12 (Compound 50) as a white solid. LCMS [M+H]+ = 444.2. 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 9.06 (br s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.04 (dd, J = 1.6, 8.8 Hz, 1H), 5.41 - 5.25 (m, 1H), 4.24 - 4.14 (m, 1H), 3.99 - 3.72 (m, 3H), 3.64 - 3.53 (m, 1H), 3.42 - 3.37 (m, 2H), 3.21 - 3.10 (m, 1H), 2.79 - 2.67 (m, 2H), 2.53 - 2.52 (m, 1H), 2.29 - 2.06 (m, 4H), 2.05 - 1.93 (m, 1H), 1.25 (d, J = 6.0 Hz, 3H), 1.05 - 0.95 (m, 1H), 0.47 (d, J = 8.0 Hz, 2H), 0.30 - 0.20 (m, 2H).

[0276] Example 13. Procedure M: Synthesis of Compound 327

Chemical Structure

[0277] Example 14. Procedure N: Synthesis of Compound 334

Chemical Structure

[0278] 3-((6-Cyano-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)quinolin-3-yl)amino)-2,2-difluoro-3-oxopropanoic acid: To a solution of intermediate 3 (264.70 mg, 843.78 μmol, 1.3 equiv) and 2,2-difluoro-3-methoxy-3-oxopropanoic acid (100.00 mg, 649.06 μmol, 1 equiv) in MeCN (5 mL) were added TCFH (218.54 mg, 778.87 μmol, 1.2 equiv) and NMI (181.08 μL, 2.27 mmol, 3.5 equiv) at 0 °C. After the addition, the mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to give the title compound. LCMS [M+H]+ = 404.7.

[0279] Methyl 3-((6-cyano-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)quinolin-3-yl)amino)-2,2-difluoro-3-oxopropanoate: To a solution of 3-((6-cyano-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)quinolin-3-yl)amino)-2,2-difluoro-3-oxopropanoic acid (200 mg, 455.03 μmol, 1 equiv) in MeOH (1 mL), SOCl2 (330 μL, 4.55 mmol, 10 equiv) was added at 0 °C. After the addition, the mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. LCMS [M+H]+ = 419.1.

[0280] Methyl 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-2,2-difluoroacetate: A solution of methyl 3-((6-cyano-4-(((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)amino)quinolin-3-yl)amino)-2,2-difluoro-3-oxopropanoate (370 mg, 884.34 μmol, 1 equiv) in BSA (10 mL) was degassed and purged with N2 (3×). The reaction mixture was stirred at 90 °C for 3 h under a N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 0 / 1) to give the title compound. LCMS [M+H]+ = 401.0. 11H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 9.17 - 9.00 (m, 1H), 8.44 (d, J = 8.8 Hz, 1H), 7.95 (dd, J = 1.6, 8.8 Hz, 1H), 5.44 - 5.28 (m, 1H), 4.39 (dd, J = 5.5, 11.6 Hz, 1H), 4.12 (s, 3H), 3.87 - 3.67 (m, 2H), 2.80 - 2.65 (m, 1H), 2.45 - 2.35 (m, 1H), 2.25 - 1.99 (m, 3H), 1.40 (d, J = 6.0 Hz, 3H).

[0281] 2-(8-Cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-2,2-difluoroacetic acid: To a solution of methyl 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-2,2-difluoroacetate (36 mg, 80.92 μmol, 1 equiv) in THF (3 mL) and H2O (0.6 mL) was added LiOH·H2O (6.79 mg, 161.85 μmol, 2 equiv). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted by the addition of water (10 mL) and then the pH was adjusted to about 3 with 2N HCl. The resulting aqueous solution was extracted with EtOAc (6 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound, which was used in the next step without further purification. LCMS [M+H]+ = 387.0.

[0282] Compound 334 (Example 14): To a solution of 2-(8-cyano-1-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-2-yl)-2,2-difluoroacetic acid (25 mg, 64.71 μmol, 1 equiv) in DCM (0.5 mL) were added (COCl)2 (7.75 μL, 84.12 μmol, 1.3 equiv) and DMF (0.5 μL, 6.47 μmol, 0.1 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h. (Aminomethyl)cyclopropane was added to the above solution and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo and the resulting crude material was purified by preparative HPLC (neutral conditions) to give Example 14. LCMS [M+H]+ = 440.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 9.49 - 9.36 (m, 1H), 9.07 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.18 (dd, J = 1.2, 8.6 Hz, 1H), 5.55 - 5.19 (m, 1H), 4.24 (d, J = 7.6 Hz, 1H), 3.86 - 3.60 (m, 2H), 3.13 (t, J = 6.4 Hz, 2H), 2.31 - 2.19 (m, 1H), 2.17 - 2.02 (m, 1H), 2.04 - 1.93 (m, 1H), 1.26 (d, J = 6.4 Hz, 3H), 1.09 - 0.95 (m, 1H), 0.51 - 0.42 (m, 2H), 0.29 - 0.20 (m, 2H).

[0283] Example 15. Procedure O: Synthesis of Compound 343

Chemical Structure

[0284] Compound 343 (Example 15): LCMS [M+H]+ = 390.1. 11H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.01 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 5.31 - 5.09 (m, 1H), 4.20 (s, 4H), 3.73 - 3.51 (m, 2H), 3.00 (t, J = 6.2 Hz, 2H), 2.63 - 2.55 (m, 2H), 2.13 - 2.00 (m, 2H), 1.01 - 0.86 (m, 1H), 0.57 - 0.37 (m, 2H), 0.28 - 0.11 (m, 2H).

[0285] Example 16. Synthesis of Compound 5

Chemical Structure

[0286] Lithium 3-(cyclopropylamino)-3-oxopropanoate: To a solution of methyl 3-(cyclopropylamino)-3-oxopropanoate (11 g, 62.99 mmol, 1 equiv) in THF (55 mL) and H2O (13.75 mL) was added LiOH (2.26 g, 94.49 mmol, 1.5 equiv) at 0 °C. The mixture was stirred at 20 °C for 4 h. The reaction mixture was concentrated in vacuo. The resulting crude material was purified by preparative HPLC (a (neutral conditions)) to give the title compound as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 3.6 Hz, 1H), 2.73 (s, 2H), 2.73 - 2.58 (m, 2H), 0.63 - 0.56 (m, 2H), 0.40 - 0.34 (m, 2H).

[0287] Example 16 (Compound 5): To a solution of Intermediate 3 (1 g, 3.36 mmol, 1 equiv) in toluene (50 mL) were added DIEA (2.34 mL, 13.46 mmol, 4 equiv) and T3P (50% in EtOAc, 9.01 mL, 15.14 mmol, 4.5 equiv). The mixture was stirred at 110 °C for 0.5 h. After 0.5 h, lithium 3-(cyclopropylamino)-3-oxopropanoate (1.59 g, 10.09 mmol, 3 equiv) was added and the resulting reaction mixture was stirred at 110 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with brine (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (1:0 to 10:1 CH2Cl2:MeOH), followed by preparative HPLC (neutral conditions) to give the desired product. LCMS (ESI) [M+H]+ = 389.9. 11H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.02 (br s, 1H), 8.48 (br s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 5.34 - 5.14 (m, 1H), 4.21 - 4.16 (m, 1H), 4.11 (s, 2H), 3.74 - 3.66 (m, 2H), 2.69 - 2.65 (m, 1H), 2.55 - 2.50 (m, 1H), 2.17 - 2.04 (m, 3H), 1.25 - 1.23 (m, 3H), 0.66 - 0.63 (m, 2H), 0.48 - 0.45 (m, 2H).

[0288] Example 17. Synthesis of Compound 261

Chemical Structure

[0289] Example 18. Synthesis of Compound 290 [Chemical formula] Example 18 (Compound 290): To a solution of Intermediate 10 (500 mg, 1.26 mmol, 1 equiv) of Example 1 in pyridine (4 mL) were added EDCI (605.28 mg, 3.16 mmol, 2.5 equiv) and (1S,2R)-2-fluorocyclopropan-1-amine (1.87 g, 7.58 mmol, 6 equiv). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was partitioned between ethyl acetate (60 mL) and H2O (20 mL). The organic phase was separated, washed with brine (3 × 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (0 - 10% MeOH in DCM), followed by preparative HPLC (acidic conditions) to obtain the title compound. LCMS [M+H]+ = 408.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.03 (br s, 1H), 8.63 (br s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 5.29 - 5.10 (m, 1H), 4.82 - 4.65 (m, 1H), 4.23 (s, 2H), 3.77 - 3.61 (m, 2H), 2.73 - 2.70 (m, 1H), 2.49 - 2.37 (m, 1H), 2.30 - 1.92 (m, 3H), 1.25 - 1.23 (m, 3H), 1.14 - 1.04 (m, 2H), 0.99 - 0.87 (m, 2H).

[0290] Example 19. Synthesis of Compound 243 [Chemical formula] Example 19 (Compound 243): To a solution of Intermediate 10 of Example 1 (130 mg, 328.37 μmol, 1 equiv) in pyridine (3 mL) were added EDCI (157.37 mg, 820.93 μmol, 2.5 equiv) and 2-methoxy-4-methylpyrimidin-5-amine (228.47 mg, 1.64 mmol, 5 equiv). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The obtained crude material was purified by preparative HPLC (neutral conditions) to give the title compound. LCMS [M+H]+ = 472.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.36 (s, 1H), 9.04 (s, 1H), 8.47 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 5.43 - 5.08 (m, 1H), 4.49 (s, 2H), 4.26 - 4.14 (m, 1H), 3.88 (s, 3H), 3.81 - 3.65 (m, 2H), 2.40 (s, 3H), 2.28 - 2.02 (m, 4H), 1.24 (d, J = 6.0 Hz, 3H).

[0291] Example 20. Synthesis of Compound 201

Chemical Structure

[0292] Example 21. Synthesis of Compound 311

Chemical Structure

[0293] Example 22. Synthesis of Compound 231

Chemical Structure

[0294] Example 23. Synthesis of Compound 247

Chemical formula

[0295] Example 24. Synthesis of Additional Compounds of Formula (I) The compounds of the present invention were synthesized according to Procedures A - O described in Tables 3 and 4. [Table 4 - 1] [Table 4 - 2] [Table 4 - 3] [Table 4 - 4] [Table 4 - 5] [Table 4 - 6] [Table 4 - 7] [Table 4 - 8] [Table 4 - 9] [Table 4 - 10] [Table 4 - 11] [Table 4 - 12]

Table 4-13

Table 4-14

Table 4-15

Table 4-16

Table 4-17

Table 4-18

Table 4-19

Table 4-20

Table 4-21

Table 4-22

Table 4-23

Table 4-24

Table 4-25

Table 4-26

Table 4-27

Table 4-28

Table 4-29

Table 4-30

Table 4-31

Table 4-32

Table 4-33

Table 4-34

Table 4-35

Table 4-36

Table 4-37

Table 4-38

Table 4-39

Table 4-40

Table 4-41

Table 4-42

Table 4-43

Table 4-44

Table 4-45

Table 4-46

Table 4-47

Table 4-48

Table 4-49

Table 4-50

Table 4-51

Table 4-52

Table 4-53

Table 4-54

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

Table 5-14

Table 5-15

Table 5-16

Table 5-17

Table 5-18

Table 5-19

Table 5-20

Table 5-21

Table 5-22

Table 5-23

Table 5-24

Table 5-25

Table 5-26

Table 5-27

Table 5-28

Table 5-29

Table 5-30

Table 5-31

Table 5-32

Table 5-33

Table 5-34

Table 5-35

Table 5-36

Table 5-37

Table 5-38

Table 5-39

Table 5-40

Table 5-41

Table 5-42

Table 5-43

Table 5-44

Table 5-45

Table 5-46

Table 5-47

Table 5-48

Table 5-49

Table 5-50

Table 5-51

Table 5-52

Table 5-53

Table 5-54

Table 5-55

Table 5-56

Table 5-57

[0296] The characterization of the exemplary compounds of the present disclosure is shown in Tables 5 and 6.

Table 6-1

Table 6-2

Table 6-3

Table 6-4

Table 6-5

Table 6-6

Table 6-7

Table 6-8

Table 6-9

Table 6-10

Table 6-11

Table 6-12

Table 6-13

Table 6-14

Table 6-15

Table 6-16

Table 6-17

Table 6-18

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

Table 7-7

Table 7-8

Table 7-9

Table 7-10

Table 7-11

Table 7-12

Table 7-13

Table 7-14

Table 7-15

Table 7-16

Table 7-17

[0297] 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 (Labcyte 384-well PP 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 -4 mM, which was prepared by transferring 2.5 nL of the 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 backfilled to a total volume of 100 nL.

[0298] 2X LRRK2 enzyme solution (final concentration 3 nM) was prepared in assay buffer (Tris-HCl pH 8.0: 50 mM, MgCl2: 5 mM, EDTA: 1 mM, Brij-35: 0.01%, 2 mM DTT). A 2X substrate solution of LRRK2 tide substrate (final concentration 400 nM) and ATP (final concentration 25 μM) in the assay buffer was prepared. 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.

[0299] A 2X detection solution of Tb-pERM(pLRRKtide) antibody (final concentration 0.25 nM) and EDTA (final concentration 10 mM) in the TR-FRET dilution buffer was prepared. 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 with Envision configured for LanthaScreen (registered trademark) TR-FRET.

[0300] 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 Eu3+-cryptate (donor) and the other 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 9

[0301] Protocol: Day 0: Plasmid transient transfection: DMEM medium, FBS, DPBS, Trans-IT, 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. The cells were then washed with 10 mL of PBS and detached with 3 mL of 0.25% trypsin. 30×10 6 HEK293T cells were seeded into a 15 cm dish in DMEM + 10% FBS complete medium.

[0302] 2000 μL of OPTI-MEM was placed into a 15 mL conical tube, then 20 μg of plasmid was added to the OPTI-MEM and mixed. Subsequently, 60 μL of TransIT-LT1 was added to the plasmid OPTI-MEM mixture and mixed to prepare a DNA, TransIT-LT1, OPTI-MEM complex. The resulting mixture was cultured for 15 hours.

[0303] The above plasmid, DNA, and OPTI-MEM mixture was added dropwise to a 15 cm dish, ensuring that the droplets were evenly distributed. The culture dish was gently rocked back and forth and from left to right to evenly distribute the complex. The transfected dish was incubated at 37 °C with 5% CO2 for 24 hours.

[0304] Day 1: The transfected HEK293T cells were collected in a 15 cm dish. The medium was aspirated from the tissue culture dish and washed by dispensing 10 mL of 1×DPBS into the 15 cm dish. The 1×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 thoroughly triturated to ensure a homogeneous cell suspension.

[0305] 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 resuspended in 20 mL of complete medium. 1 mL of the cell suspension was transferred for cell counting. The cell suspension was diluted to 2×10 5 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 with 5% CO2.

[0306] Day 2: Dispensing of compounds: The compounds were diluted (10 mM DMSO stock solution) and added to the assay plates in duplicate by a Tecan liquid handler (maximum concentration: 10 μM, 3-fold serial dilution, 9 doses). The DMSO concentration in each well was normalized to 0.2%. The plates were spun rapidly at 1,000 rpm for 1 minute. The plates were incubated at 37 °C with 5% CO2 for 2 hours.

[0307] 1X lysis buffer supplemented with a blocking reagent was prepared (e.g., 1 mL of 4X lysis buffer + 3 mL of water + 40 μL of 100X stock blocking reagent). The antibody working solution was prepared by diluting 40-fold with detection buffer (e.g., 1520 μL of detection buffer + 40 μL of d2 antibody stock solution + 40 μL of cryptate antibody stock solution).

[0308] After 2 hours of incubation, the cell plates were removed from the incubator. The medium was removed by a plate washer, and then 16 μL of supplemented lysis buffer was added to each well once, and incubated at room temperature for 30 minutes with shaking (800 rpm / min). 4 μL of the antibody working solution was added to each well, covered with a top seal, and incubated overnight in an incubator at 23 °C.

[0309] Day 3: The HTRF signal was read with a Wallac 2104 EnVision® multilabel reader (665 nm and 615 nm). The data were analyzed by XL fit software.

[0310] Biochemical data for exemplary compounds of the present disclosure are shown in Table 8.

Table 10-1

Table 10-2

Table 10-3

Table 10-4

[0311] Although the above invention has been described in some detail by way of illustration and example for the purpose of a clear understanding, those skilled in the art will understand that certain changes and modifications within the scope of the appended claims are possible. Further, 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. In the event of any conflict between this application and the references provided in this specification, this application shall prevail.

Claims

1. Formula (I): 【Chemical 1】 a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ring A is C ３～８ cycloalkyl, or 3- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms each independently being N, O or S, or 5- to 6-membered heteroaryl having 1 or 2 heteroatoms each independently being N, O or S; Each R １ is independently C １～６ alkyl, -CN, or =O; R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)R ２ｂ ), -C(O)OR ２ｂ ), -OC(O)R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ C(O)R ２ｂ 、-OC(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )C(O)OR ２ｂ , -S(O)R ２ｂ , -S(O) ２ R ２ｂ , -S(O) ２ N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(R ２ R ２ｂ , -S(O)(NH)N(R ２ａ )(R ２ｂ ), or -N(R ２ａ ), S(O)(NH)R ２ｂ wherein; R ２ａ is hydrogen or C １～６ alkyl; R ２ｂ is hydrogen, C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, C １～６ haloalkyl, C ３～８ cycloalkyl, C １～６ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, C １～６ alkyl-heterocycloalkyl, C ６～１０ aryl, C １～６ alkyl-C ６～１０ aryl, heteroaryl or C １～６ alkyl-heteroaryl, and each heterocycloalkyl has 3 to 10 ring members and has 1 to 3 heteroatoms each independently being N, O or S; each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S; Each cycloalkyl, heterocycloalkyl, and heteroaryl is substituted with 0 to 3 R ２ｂ１ groups; Each alkyl is substituted with 0 to 6 R ２ｂ３ groups; Alternatively, R ２ａ and R ２ｂ combine with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms, each independently N, O or S, The heterocycloalkyl is substituted with 0 to 3 R ２ｃ groups; Each R ２ｂ１ and R ２ｃ is independently C １～６ alkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, halogen, C １～６ haloalkyl, C １～６ haloalkoxy, -CN, =O, -C(O)R ２ｄ , -C(O)OR ２ｄ 、-OC(O)R ２ｄ 、-C(O)N(R ２ｄ )(R ２ｅ )、-N(R ２ｄ )C(O)R ２ｅ 、 -OC(O)N(R ２ｄ )(R ２ｅ ), -N(R ２ｄ )(C(O)OR ２ｅ ), -P(O)(OR ２ｄ )(OR ２ｅ ), -S(O)R ２ｄ , -S(O) ２ R ２ｄ 、 -S(O) ２ OR ２ｄ 、 -S(O) ２ N(R ２ｄ )(R ２ｅ )、 -N(R ２ｄ )S(O) ２ R ２ｅ 、 -S(O)(NH)N(R ２ｄ )(R ２ｅ ), -N(R ２ｄ )(SO)(NH)R ２ｅ , C ３～８ cycloalkyl, heterocycloalkyl, C ６～１０ aryl, or heteroaryl, each alkoxy being substituted with 0 to 3 heteroaryls, each heterocycloalkyl has 3 to 10 ring members and has 1 to 3 heteroatoms each independently being N, O or S; each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S; Each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with 0 to 3 R ２ｆ groups; Each R ２ｂ３ is independently C １～６ alkoxy, halogen, C １～６ haloalkoxy, -N(R ２ｂ２ ) ２ , OH, or -CN; Each R ２ｂ２ is independently hydrogen or C １～６ alkyl; Each R ２ｄ and R ２ｅ is independently hydrogen or C １～６ alkyl; Each R ２ｆ is C １～６ alkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, C １～６ alkoxyalkyl, halogen, C １～６ haloalkyl, C １～６ haloalkoxy, -CN, or =O; Each R ２ｙ is independently hydrogen or C １～６ alkyl; R ２ｘ and R ２ｚ are each independently hydrogen, C １～６ alkyl, halogen, or C １～６ haloalkyl; Alternatively, R ２ｘ and R ２ｚ combine with the atoms to which they are attached to form a C ３～８ cycloalkyl; Alternatively, R ２ａ and R ２ｘ , or R ２ａ and one R ２ｙ are combined with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms, each independently N, O or S, substituted with 0 to 3 C １～６ alkyl; Each R ３ and R ４ is independently hydrogen, C １～６ alkyl, C １～６ alkoxy, halogen, C １～６ haloalkyl, C １～６ haloalkoxy, -CN, -N(R ３ａ )(R ３ｂ ), -C(O)N(R ３ａ )(R ３ｂ ), C ３～８ cycloalkyl or C １～６ alkyl-C ３～８ cycloalkyl; Each R ３ａ and R ３ｂ is, independently, hydrogen, C １～６ alkyl, C ３～８ cycloalkyl, or C １～６ alkyl-C ３～８ cycloalkyl; subscript n is 0, 1 or 2; subscripts m and p are each independently 0, 1, 2, 3 or 4; a compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. Ring A is C ３～８ cycloalkyl, or 3- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms each independently being N, O or S, or 5- to 6-membered heteroaryl having 1 or 2 heteroatoms each independently being N, O or S; Each R １ is independently C １～６ alkyl, -CN, or =O; R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)R ２ｂ , -C(O)OR ２ｂ , -OC(O)R ２ｂ , -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ C(O)R ２ｂ 、-OC(O)N(R ２ａ )(R ２ｂ )、-N(R ２ａ )C(O)OR ２ｂ 、-S(O) ２ R ２ｂ 、 -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(R ２ R ２ｂ wherein; R ２ａ is hydrogen or C １～６ alkyl; R ２ｂ is hydrogen, C １～６ alkyl, C １～６ alkyl-N(R ２ｂ２ ) ２ , C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, C １～６ haloalkyl, C ３～８ cycloalkyl, C １～６ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, C １～６ alkyl-heterocycloalkyl, C ６～１０ aryl, C １～６ alkyl-C ６～１０ aryl, heteroaryl or C １～６ alkyl-heteroaryl, and each heterocycloalkyl has 3 to 10 ring members and has 1 to 3 heteroatoms each independently being N, O or S; each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S; Each cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with 0 - 3 R ２ｂ１ groups; Alternatively, R ２ａ and R ２ｂ combine with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having from 0 to 2 additional heteroatoms each independently being N, O or S, The heterocycloalkyl is substituted with 0 to 3 R ２ｃ groups; Each R ２ｂ１ and R ２ｃ is independently C １～６ alkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, =O, -C(O)OH, -P(O)(OH) ２ , -S(O) ２ OH, or C ３～８ cycloalkyl, wherein the alkoxy is substituted with 0 to 3 heteroaryls, each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S; Each R ２ｂ２ is independently hydrogen or C １～６ alkyl; Each R ２ｙ is independently hydrogen or C １～６ alkyl; R ２ｘ and R ２ｚ are each independently hydrogen, C １～６ alkyl, halogen, or C １～６ haloalkyl; Alternatively, R ２ｘ and R ２ｚ are combined with the atoms to which they are attached to form a C ３～８ cycloalkyl; Alternatively, R ２ａ and R ２ｘ or R ２ａ and one R ２ｙ combine with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms, each independently N, O or S, substituted with 0 to 3 C １～６ alkyl; Each R ３ and R ４ is, independently, hydrogen, C １～６ alkyl, C １～６ alkoxy, halogen, C １～６ haloalkyl, C １～６ haloalkoxy, -CN, -N(R ３ａ )(R ３ｂ ), -C(O)N(R ３ａ )(R ３ｂ ), C ３～８ cycloalkyl or C １～６ alkyl-C ３～８ cycloalkyl; Each R ３ａ and R ３ｂ is, independently, hydrogen, C １～６ alkyl, C ３～８ cycloalkyl, or C １～６ alkyl-C ３～８ cycloalkyl; subscript n is 0, 1 or 2; subscripts m and p are each independently 0, 1, 2, 3 or 4; a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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

4. Formula Ia: 【Chemical 2】 a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, having the structure of formula (Ia).

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

6. a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein ring A is cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or pyridyl.

7. Each R １ is independently C １～３ alkyl, -CN, or =O, the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. Each R １ is independently Me, -CN, or =O, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. group 【Chemical Formula 3】 a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(C(O)R ２ｂ ), -OC(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(C(O)OR ２ｂ ), -S(O) ２ R ２ｂ ), -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(S(O) ２ R ２ｂ ); R ２ａ is hydrogen or C １～６ alkyl; R ２ｂ is hydrogen, C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, C １～６ haloalkyl, C ３～８ cycloalkyl, C １～６ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, C １～６ alkyl-heterocycloalkyl, heteroaryl or C １～６ alkyl-heteroaryl, where each heterocycloalkyl has 3 to 10 ring members and has 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S, and each heterocycloalkyl and heteroaryl is substituted with 0 to 3 R ２ｂ１ groups; Alternatively, R ２ａ and R ２ｂ combine with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms each independently being N, O or S, wherein said heterocycloalkyl is substituted with 0 to 3 R ２ｃ groups; Each R ２ｂ１ is independently C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, or C ３～８ cycloalkyl; R ２ｃ is -C(O)OH; Each R ２ｙ is hydrogen; R ２ｘ and R ２ｚ are each hydrogen; Alternatively, R ２ａ and R ２ｘ , or R ２ａ and one R ２ｙ combine with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms, each independently N, O, or S, substituted with 0 to 3 C １～６ alkyl; subscript n is 0, 1 or 2; a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)R ２ｂ , -OC(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(C(O)OR ２ｂ ), -S(O) ２ R ２ｂ ), -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(S(O) ２ R ２ｂ ); R ２ａ is hydrogen or C １～６ alkyl; R ２ｂ is hydrogen, C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, C １～６ haloalkyl, C ３～８ cycloalkyl, C １～６ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, C １～６ alkyl-heterocycloalkyl, heteroaryl or C １～６ alkyl-heteroaryl, each heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and 1 to 4 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 3 R ２ｂ１ groups; Each R ２ｂ１ is independently C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, or C ３～８ cycloalkyl; Each R ２ｙ is hydrogen; R ２ｘ and R ２ｚ are each hydrogen; The subscript n is 0, 1, or 2, a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)R ２ｂ ), -N(R ２ａ )(O)OR ２ｂ ), -S(O) ２ R ２ｂ ), -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(O)R ２ R ２ｂ ; R ２ａ is hydrogen or C １～３ alkyl; R ２ｂ is hydrogen, C １～３ alkyl, C １～３ hydroxyalkyl, C ２～４ alkoxyalkyl, C １～３ haloalkyl, C ３～６ cycloalkyl, C １～３ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, C １～３ alkyl-heterocycloalkyl, heteroaryl or C １～６ alkyl-heteroaryl, each heterocycloalkyl having 4 to 6 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 6 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 2 R ２ｂ１ groups; Each R ２ｂ１ is independently C １～３ alkyl, C １～３ hydroxyalkyl, or C ２～４ alkoxyalkyl; Each R ２ｙ is hydrogen; R ２ｘ and R ２ｚ is hydrogen; The subscript n is 0 or 1, a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)R ２ｂ , -OC(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)OR ２ｂ , -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(O)R ２ R ２ｂ ; R ２ｂ is hydrogen, C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, C １～６ haloalkyl, C ３～８ cycloalkyl, C １～６ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, heteroaryl or C １～６ alkyl-heteroaryl, each heterocycloalkyl having 3 to 10 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and having 1 to 4 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 3 R ２ｂ１ groups; Each R ２ｂ１ is independently C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, or C ３～８ cycloalkyl; R ２ａ and R ２ｘ or R ２ａ and one R ２ｙ is combined with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having from 0 to 2 additional heteroatoms, each independently N, O or S, substituted with from 0 to 3 C １～６ alkyl; Each R ２ｘ and R ２ｙ when not combined with R ２ａ is hydrogen; R ２ｚ is hydrogen; The subscript n is 0, 1, or 2, a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

14. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)R ２ｂ , -OC(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)OR ２ｂ , -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(O)R ２ R ２ｂ ; R ２ｂ is hydrogen, C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, C １～６ haloalkyl, C ３～８ cycloalkyl, C １～６ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, heteroaryl or C １～６ alkyl-heteroaryl, each heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and 1 to 4 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 3 R ２ｂ１ groups; Each R ２ｂ１ is independently C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, or C ３～８ cycloalkyl; R ２ａ and R ２ｘ are combined with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having from 0 to 2 additional heteroatoms each independently being N, O or S, substituted with from 0 to 3 C １～６ alkyl; Each R ２ｙ is hydrogen; R ２ｚ is hydrogen; The subscript n is 0, 1, or 2, a compound according to claim 13 or a pharmaceutically acceptable salt thereof.

15. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)R ２ｂ , -OC(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)OR ２ｂ , -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(O)R ２ R ２ｂ ; R ２ｂ is hydrogen, C １～３ alkyl, C １～３ hydroxyalkyl, C ２～４ alkoxyalkyl, C １～３ haloalkyl, C ３～６ cycloalkyl, C １～３ alkyl-C ３～６ cycloalkyl, heterocycloalkyl, heteroaryl or C １～３ alkyl-heteroaryl, each heterocycloalkyl having 4 to 6 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 6 ring members and having 1 to 3 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 2 R ２ｂ１ groups; Each R ２ｂ１ is independently C １～３ alkyl, C １～３ hydroxyalkyl, C ２～４ alkoxyalkyl, or C ３～６ cycloalkyl; R ２ａ and R ２ｘ combine with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having from 0 to 2 additional heteroatoms, each independently N, O, or S, Each R ２ｙ is hydrogen; R ２ｚ is hydrogen; The subscript n is 0, 1, or 2, a compound according to claim 13 or 14 or a pharmaceutically acceptable salt thereof.

16. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)R ２ｂ , -OC(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)OR ２ｂ , -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(O)R ２ R ２ｂ ; R ２ｂ is hydrogen, C １～６ alkyl, C １～６ haloalkyl, C ３～８ cycloalkyl, C １～６ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, heteroaryl or C １～６ alkyl-heteroaryl, each heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 10 ring members and 1 to 4 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 3 R ２ｂ１ groups; Each R ２ｂ１ is independently C １～６ alkyl, C １～６ hydroxyalkyl, or C ３～８ cycloalkyl; R ２ａ and one R ２ｙ are combined with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having from 0 to 2 additional heteroatoms each independently selected from N, O or S and substituted with from 0 to 3 C １～６ alkyl; R ２ｙ is hydrogen when not combined with ２ａ R; R ２ｘ and R ２ｚ are each hydrogen; The subscript n is 1 or 2, a compound according to claim 13 or a pharmaceutically acceptable salt thereof.

17. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)R ２ｂ , -OC(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(O)OR ２ｂ , -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(O)R ２ R ２ｂ ; R ２ｂ is hydrogen, C １～３ alkyl, C １～３ haloalkyl, C ３～６ cycloalkyl, C １～３ alkyl-C ３～６ cycloalkyl, heterocycloalkyl, heteroaryl or C １～３ alkyl-heteroaryl, each heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms each independently being N, O or S, each heterocycloalkyl and heteroaryl being substituted with 0 to 2 R ２ｂ１ groups; Each R ２ｂ１ is independently C １～３ alkyl, C １～３ hydroxyalkyl, or C ３～６ cycloalkyl; R ２ａ and R ２ｙ combine with the atoms to which they are attached to form a 4- to 6-membered heterocycloalkyl having from 0 to 2 additional heteroatoms each independently being N, O or S, R ２ｘ and R ２ｚ are each hydrogen; The subscript n is 1, a compound according to claim 16 or a pharmaceutically acceptable salt thereof.

18. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(C(O)R ２ｂ ), -OC(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(C(O)OR ２ｂ ), -S(O) ２ N(R ２ａ )(R ２ｂ ), or -N(R ２ａ )(S(O) ２ R ２ｂ ; R ２ａ and R ２ｂ are combined with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having from 0 to 2 additional heteroatoms, each independently N, O or S, said heterocycloalkyl being substituted with from 0 to 3 R ２ｃ groups; R ２ｃ is -C(O)OH; Each R ２ｙ is hydrogen; R ２ｘ and R ２ｚ are each hydrogen; The subscript n is 0, 1, or 2, a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

19. R ２ is -N(R ２ａ )(R ２ｂ ), -C(O)N(R ２ａ )(R ２ｂ ), -N(R ２ａ )(C(O)R ２ｂ ), or -N(R ２ａ )(S(O) ２ R ２ｂ ); R ２ａ and R ２ｂ combine with the atoms to which they are attached to form a 3- to 6-membered heterocycloalkyl having 0 to 2 additional heteroatoms, each independently N, O, or S, and the heterocycloalkyl is substituted with 0 to 3 R ２ｃ groups; R ２ｃ is -C(O)OH; R ２ｘ and R ２ｚ are each hydrogen; The subscript n is 0, a compound according to claim 18 or a pharmaceutically acceptable salt thereof.

20. R ３ is hydrogen, C １～６ alkyl, C １～６ alkoxy, halogen, C １～６ haloalkyl, C １～６ haloalkoxy, or -CN, a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

21. R ３ is hydrogen, C １～３ alkyl, halogen, C １～３ haloalkyl, or -CN, the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

22. R ３ The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

23. Each R ４ is independently C １～６ alkyl, C １～６ alkoxy, halogen, C １～６ haloalkoxy, -CN, -(C=O)N(R ３ａ )(R ３ｂ ), or C ３～８ cycloalkyl, a compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

24. R ４ is C １～３ alkyl, C １～３ alkoxy, halogen, C １～３ haloalkoxy, -CN, -(C=O)N(R ３ａ )(R ３ｂ ), or C ３～６ cycloalkyl, the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

25. R ４ is -CH ３ , -OCH ３ , Cl, -OCF ３ , -CN, -(C=O)N(CH ３ ), ２ or cyclopropyl, the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof.

26. The subscript m is 1 or 2, a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

27. The subscript n is 0 or 1, a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof.

28. Formula Ib: 【Chemical Formula 4】 having the structure of, a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

29. Formula Ic: 【Chemical Formula 5】 having the structure of, a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

30. Formula Ic-1: 【Chemical Formula 6】 having the structure of, a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

31. The group 【Chemical Formula 7】 【Chemical 8】 【Chemical Formula 9】 【Chemical Formula 10】 【Chemical 11】 【Chemical Formula 12】 【Chemical 13】 being, a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

32. The group 【Chemical Formula 14】 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】 【Chemical 18】 being, a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

33. The group 【Chemical 19】 【Chemical 20】 being, a compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

34. The group 【Chemical 21】 The compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

35. Group 【Chemical 22】 The compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

36. Group 【Chemical 23】 The compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

37. Formula Id: 【Chemical 24】 The compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof having the structure of.

38. Formula Id-1: 【Chemical 25】 The compound according to any one of claims 1 to 37 having the structure of.

39. R ２ｂ is hydrogen, C １～６ alkyl, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, C １～６ haloalkyl, C ３～８ cycloalkyl, C １～６ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, C １～６ alkyl-heterocycloalkyl, C ６～１０ aryl, heteroaryl or C １～６ alkyl-heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and has 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S, and each heterocycloalkyl and heteroaryl is substituted with 0 to 3 R ２ｂ１ groups, a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof.

40. R ２ｂ is C ３～８ cycloalkyl, C １～６ alkyl-C ３～８ cycloalkyl, heterocycloalkyl, C １～６ alkyl-heterocycloalkyl, heteroaryl or C １～６ alkyl-heteroaryl, wherein each heterocycloalkyl has 3 to 10 ring members and has 1 to 3 heteroatoms each independently being N, O or S, each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S, and each heterocycloalkyl and heteroaryl is substituted with 0 to 3 R ２ｂ１ groups, a compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof.

41. R ２ｂ is C ３～８ cycloalkyl or heteroaryl, each heteroaryl having 5 to 6 ring members and having 1 to 3 heteroatoms each independently being N, O or S, and 0 to 3 R ２ｂ１ groups, the compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof.

42. R ２ｂ is cyclopropyl, cyclobutyl, cyclopentenyl, cyclopentyl, spiro[2.2]pentyl, cyclohexyl, pyrazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and the pyrazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl are substituted with 0 to 3 R ２ｂ１ groups, a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof.

43. Each R ２ｂ１ is independently C １～６ alkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, halogen, C １～６ haloalkyl, C １～６ haloalkoxy, -CN, =O, C ３～８ cycloalkyl, heterocycloalkyl, C ６～１０ aryl, or heteroaryl, wherein the alkoxy is substituted with 0 to 3 heteroaryls, Each heterocycloalkyl has 3 to 10 ring members and has 1 to 3 heteroatoms each independently being N, O or S. Each heteroaryl has 5 to 10 ring members and has 1 to 4 heteroatoms each independently being N, O or S. The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with 0 to 3 C １～６ alkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, halogen, C １～６ haloalkyl, C １～６ haloalkoxy, -CN, or =O, and the compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof.

44. Each R ２ｂ１ is independently C １～６ alkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, C ２～６ alkoxyalkyl, halogen, or C ３～８ cycloalkyl, a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof.

45. Each R ２ｂ１ is independently C １～６ alkyl or C １～６ alkoxy, the compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof.

46. Each R ２ｂ１ is independently C １～３ alkyl or C １～３ alkoxy, a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof.

47. Each R ２ｂ１ is independently, -CH ３ -, -CH ２ CH ３ -, -CH(CH ３ ) ２ -, -OCH ３ -, -OCH ２ CH ３ -, -OCH(CH ３ ) ２ -, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ C(CH ３ ) ２ OH, -CH ２ OCH ３ -, -CH ２ CH ２ OCH ３ , cyclopropyl, cyclobutyl, oxetan-2-yl, F, Cl, CH ２ F, CHF ２ , C(CH ３ ) ２ F, CF ３ -, -OCHF ２ , 【Chemical 26】 -CN, or =O, the compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof.

48. Each R ２ｂ１ is independently —CH ３ or —OCH ３ and the compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof.

49. R ２ｂ is H, -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CH ２ CH ２ OH, -CH ２ CH ２ CH ２ OH, -CH ２ C(CH ３ ) ２ CH ２ OH, -CH ２ CH ２ OCH ３ -CH ２ CH ２ CH ２ OCH ３ , -CH ２ C(CH ３ ) ２ CH ２ OCH ３ , -CH ２ CF ３ , -CH ２ CH ２ CF ３ , -CH ２ CF ２ CH ２ OH, -CH ２ C(CH ３ ) ２ CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 【Chemical 27】 【Chemical formula 28】 【Chemical 29】 The compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof.

50. R ２ｂ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 【Chemical 30】 The compound according to any one of claims 1 to 49 or a pharmaceutically acceptable salt thereof.

51. The compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of the compound in Table 1A or Table 1B.

52. The compound has the structure: 【Chemical 31】 The compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof having.

53. The compound has the structure: 【Chemical 32】 The compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof having.

54. The compound has the structure: 【Chemical 33】 The compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof having.

55. The compound has the structure: 【Chemical 34】 The compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof having.

56. The compound has the structure: 【Chemical 35】 The compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof having.

57. The compound has the structure: 【Chemical 36】 The compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof having.

58. The compound has the structure: 【Chemical 37】 The compound according to any one of claims 1 to 51 having the following, or a pharmaceutically acceptable salt thereof.

59. The compound having the structure: 【Chemical 38】 The compound according to any one of claims 1 to 51 having the following, or a pharmaceutically acceptable salt thereof.

60. The compound having the structure: 【Chemical Formula 39】 The compound according to any one of claims 1 to 51 having the following, or a pharmaceutically acceptable salt thereof.

61. A pharmaceutical composition comprising the compound according to any one of claims 1 to 60 having the following, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

62. 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 60 having the following, or a pharmaceutically acceptable salt thereof.

63. 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 60 having the following, or a pharmaceutically acceptable salt thereof.

64. The method according to claim 63, 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, or alpha-synucleinopathy.

65. The method according to claim 63, wherein the LRRK2-related disease or condition is inflammatory bowel disease.

66. The method according to claim 63, wherein the LRRK2-related disease or condition is an autophagy-related disease or condition.

67. The method according to claim 66, wherein the autophagy-related disease or condition is alpha1-antitrypsin deficiency (AATD).

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