Inhibitors of LRRK2

Abstract

Indazole-and azaindazole-substituted octahydrocyclopenta [c] pyrrole and hexahydrocyclopenta [c] pyrrole compounds are inhibitors of LRRK2 (Leukocyte Receptor Receptor K2). The compounds and pharmaceutical compositions thereof are useful for the treatment of CNS disorders, such as familial / hereditary and / or accidental Parkinson's disease, tauopathy or Alzheimer's disease.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 487,792, filed March 1, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to selective inhibitory compounds of the G2019S mutant LRRK2 (as opposed to wild-type LRRK2), which can be used to treat CNS disorders such as familial / hereditary and / or sporadic Parkinson's disease, as well as certain cancers, Crohn's disease, Alzheimer's disease, and leprosy. Background Technology

[0003] Parkinson's disease ("PD") is a chronic, progressive movement disorder (with a prevalence of 1%-2% in people over 65 years of age) characterized by tremor, bradykinesia, speech impairment, postural abnormalities, and poor quality of life. Currently, there is no cure to improve the disease; only palliative treatment of the motor dysfunction is available through dopamine replacement therapy. However, these treatments are plagued by an "on" / "off" cycle and adverse events associated with dopaminergic states. Therefore, novel non-dopaminergic approaches to treating PD represent an unmet medical need.

[0004] Leucine-rich repeat kinase 2 (LRRK2) is a key contributor to PD, and recently genome-wide association studies have implicated it in PD. In addition, dysfunction of LRRK2 can affect alpha-synuclein accumulation and signaling pathways through kinase activation of LRRK2, and LRRK2 accumulates in Lewy bodies (Curr Neuropharmacol. Nov 2018; 16(9): 1348-1357; (Eur. J Neurosci. 2006, 23(3):659). Many PD cases are sporadic, while up to 10% of cases are genetic, and several genes have been identified to have mutations in families, such as LRRK2 and G2019S mutations. Patients with point mutations, such as G2019S LRRK2, exhibit PD pathology that is indistinguishable from idiopathic patients. Although more than 20 LRRK2 mutations have been identified that are associated with autosomal dominant Parkinson’s disease, the G2019S mutation found within the LRRK2 kinase domain accounts for >85% of LRRK2-associated PD patients. In addition, G2019S is an activating mutation, so inhibitors of G2019S LRRK2 are a therapeutic approach for treating PD patients carrying the G2019S mutation. In addition, LRRK2 is implicated in many other diseases, such as tauopathies, certain cancers, Crohn’s disease, Alzheimer’s disease, and leprosy (BMB Rep 2015 May; 48(5):243-8).

[0005] LRRK2 mutations are associated with Alzheimer’s disease-like pathology (Zimprach et al., Neuron. 2004 Nov 18; 44(4):601-7). The LRRK2 R1628P variant is associated with an increased risk of developing Alzheimer’s disease (AD) (Zhao et al., Neurobiol Aging. 2011 Nov; 32(11): 1990-3). LRRK2 mutations have been found to be clinically associated with the transition from mild cognitive impairment to AD (see WO 2007149798). These data suggest that LRRK2 inhibitors can be useful in treating AD and other dementias as well as related neurodegenerative diseases.

[0006] LRRK2 has been reported to phosphorylate microtubule-associated tau, and the kinase-activating LRRK2 mutation G2019S can enhance phosphorylation (Kawakami et al., PLoS One. 2012; 7(1): e30834; Bailey et al., Acta Neuropathol. 2013 Dec; 126(6): 809-27). Overexpression of LRRK2 in a tau transgenic mouse model resulted in insoluble tau aggregation and its phosphorylation at multiple epitopes (Bailey et al., 2013). Hyperphosphorylation of tau was observed in LRRK2 Rl441G overexpression transgenic mice (Li et al., Nat Neurosci. 2009 Jul; 12(7): 826-8). Thus, inhibition of LRRK2 kinase activity can be useful in treating tauopathies characterized by hyperphosphorylation of tau, such as argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia linked to chromosome 17, and Parkinson's disease associated with chromosome 17 (Goedert and Jakes, Biochim Biophys Acta. 1739, (2005) 240-250).

[0007] There is evidence that LRRK2 plays a role in brain immune cell function, and LRRK2 inhibitors have been shown to reduce the inflammatory response of microglia (Moehle et al., J Neurosci. 2012 Feb 1; 32(5): 1602-11). A significant increase in LRRK2 mRNA levels was observed in muscle biopsy samples taken from patients with ALS (Shtilbans et al., Amyotroph Lateral Scler. 2011 Jul; 12(4): 250-6). Because neuroinflammation is a hallmark of some neurodegenerative diseases such as PD, AD, MS, HIV-induced dementia, ALS, ischemic stroke, traumatic brain injury, and spinal cord injury, LRRK2 kinase inhibitors can be useful in treating neuroinflammation in these conditions.

[0008] LRRK2 is expressed in cells of the immune system and studies suggest that LRRK2 can play a role in modulating the immune system and modulating inflammatory responses. Thus, LRRK2 kinase inhibitors can be useful in treating a variety of immune system diseases, such as lymphoma, leukemia, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disease, type I diabetes, Sjogren's syndrome, Delvic's disease, inflammatory myopathy (Engel et al., Pharmacol Rev. 2011 Mar; 63(1): 127-56; Homann et al., Clin Neuromuscular disease, 2010), and ankylosing spondylitis (Danoy et al., PLoS Genet. 2010 Dec 2; 6(12)).

[0009] Patients with the LRRK2 G2019S mutation have been reported to have an increased incidence of certain types of non-skin cancer (e.g., kidney cancer, breast cancer, lung cancer, prostate cancer, and acute myeloid leukemia (AML)) (Agalliu et al., JAMA Neurol. 2015 Jan; 72(1); Saunders-Pullman et al., Mov Disord. 2010 Nov 15; 25(15):2536-41). LRRK2 amplification and overexpression have been reported in papillary renal carcinoma and thyroid cancer. LRRK2 has also been significantly associated with increased risk of low-grade glioma (Yan et al., Genomics 2022, 114: 316-327). Thus, inhibiting LRRK2 kinase activity can be useful in treating cancer (Looyenga et al., Proc Natl Acad Sci USA 2011 Jan 25; 108(4):1439-44).

[0010] Genome-wide association studies have also highlighted the role of LRRK2 in modifying susceptibility to chronic autoimmune Crohn's disease and leprosy (Zhang et al., The New England Journal of Medicine, Volume 361, 2009, Pages 2609-2618; Umeno et al., Inflammatory Bowel Disease, Volume 17, 2011, Pages 2407-2415).

[0011] A challenge in the field is to develop selective inhibitors for G2019S mutant LRRK2 over wild type LRRK2. A number of preclinical and clinical studies have shown that inhibition of peripheral WT LRRK2 induces pulmonary and other tissue fibrosis, reducing the therapeutic index. Non-selective LRRK2 inhibitors can induce reversible changes in the lungs of non-human primates without causing measurable pulmonary function deficits (Sci Transl Med. 2020 Apr 22; 12(540)), which indicates that high selectivity for G2019S mutant LRRK2 is needed for chronic treatment of PD patients and other chronic indications. To date, there have been few reports of inhibitors with high selectivity for G2019S mutant LRRK2, so the development of selective G2019S LRRK2 inhibitors remains critical. SUMMARY

[0012] One aspect of the present application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: " represents a single or double bond; R 1 is R 1a is G 1 , -L 1 -G 1 , -C 2-4 alkylene-OR A , -C 2-4 alkylene-NR A R B , C 1-6 alkyl, C 1-6 fluoroalkyl, or H; R A is G 1 , -L 1 -G 1 , C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-6 cycloalkyl, or -C 1-3 alkylene-C 3-6 cycloalkyl; R B is H, C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-6 cycloalkyl, or -C 1-3 alkylene-C3-6 cycloalkyl; R 1b It is halogen, C 1-4 Alkyl, C 1-2 Fluoroalkyl, CN, C 3-4 cycloalkyl, –OC 1-3 Alkyl, –OC 1-2 Fluoroalkyl or H; R 1c It is H, halogen, C 1-4 Alkyl, C 1-2 Fluoroalkyl, CN, phenyl, C 3-4 cycloalkyl, –OR 1d or –N(R) 1d )2; R 1d Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively used 1d Together with these two Rs 1d The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; L 1 It is C 1-5 Alkylene or C 2-5 alkenyl; G 1 It is a 5- or 6-membered aromatic or partially unsaturated heterocycle containing a first nitrogen atom and optionally 1-2 other heteroatoms, which are independently nitrogen, oxygen, or sulfur, attached to an unsaturated carbon atom in the heterocycle, or G. 1 It is phenyl, G 1 The first substituent may be optionally substituted by a group consisting of: halogen, C 1-4 Alkyl, cyano, C 1-2 fluoroalkyl, oxo, –OR 10 –N(R) 10 )2、–C 1-3 Alkylene – OR 10 C 3-5 cycloalkyl and –C 1-3 alkylene–C 3-5 Cycloalkyl, and optionally further substituted by 1-2 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl, cyano and C 1-2 fluoroalkyl; R 10Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively used 10 Together with these two Rs 10 The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; R 2 It is G 2 –L 2 –G 2 –L 3 –C 1-6 Alkyl, –C 2-6 Alkylene–R 2a C 1-6 Alkyl, C 1-6 Fluoroalkyl or H; L 2 It is C 1-3 alkylene or L 3 ; L 3 It is C(O), SO2, S(O)(NH), C(O)NH or C(O)O; G 2 It is a 4- to 12-membered heterocyclic group, C 3-12 Carbocyclic, 5- to 12-membered heteroaryl or 6- to 12-membered aryl, wherein G 2 The first substituent may be optionally substituted by a group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-2 fluoroalkyl, G 2a Oxygenation, –OR 13 –N(R) 13 )2、–C 1-3 Alkylene – OR 13 –C 1-3 alkylene–N(R) 13 )2、–C(O)N(R 13 )2、–C(O)OR 13 –SO2R 13 and S(O)(NH)R 13 Optionally further substituted with oxygen, and optionally further substituted with 1-3 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl and C 1-2 fluoroalkyl; G 2a It is C 3-4cycloalkyl; R 13 Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively used 13 Together with these two Rs 13 The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; R 2a Yes – OR 14 –N(R) 14 )2、–SO2R 14 S(O)(NH)R 14 –NR 14 C(O)N(R 14 )2 or –NR 14 C(O)OR 14 ; R 14 Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively used 14 Together with these two Rs 14 The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; R 3 Each time it appears, it is independently either fluorine or carbon. 1-4 Alkyl; and n is 0, 1, or 2.

[0013] In another aspect, the present invention provides a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0014] In another aspect, the present invention provides a method for treating a disease or condition of a subject, wherein the subject will benefit from the inhibition of LRRK2, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt or composition thereof.

[0015] In another aspect, the application provides a method for inhibiting LRRK2 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition.

[0016] In another aspect, the application provides a method for treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition, wherein the disease or disorder is a CNS disorder, an immune disorder, a cancer, or leprosy.

[0017] In another aspect, the application provides a method for treating a CNS disease or disorder (e.g., familial / genetic and / or sporadic Parkinson’s disease, a tauopathy, or Alzheimer’s disease), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition.

[0018] In another aspect, the application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition for use in treating a disease or disorder selected from the group consisting of a CNS disorder, an immune disorder, a cancer, and leprosy.

[0019] In another aspect, the application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition for use in treating a CNS disease or disorder (e.g., familial / genetic and / or sporadic Parkinson’s disease, a tauopathy, or Alzheimer’s disease).

[0020] In another aspect, the application provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition for use in inhibiting LRRK2 in a subject.

[0021] In another aspect, the application provides use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition, in the manufacture of a medicament for treating a disease or disorder selected from the group consisting of a CNS disorder, an immune disorder, a cancer, and leprosy.

[0022] In another aspect, the application provides use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition, in the manufacture of a medicament for treating a CNS disease or disorder (e.g., familial / genetic and / or sporadic Parkinson’s disease, a tauopathy, or Alzheimer’s disease).

[0023] In another aspect, the application provides use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a composition, in the manufacture of a medicament for inhibiting LRRK2 in a subject.

[0024] In another aspect, the present application provides a kit comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a composition and instructions for use. DETAILED DESCRIPTION

[0025] 1. DEFINITIONS Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the application belongs. In the case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0026] As used herein, the terms "comprise(s)," "include(s)," "having," "can," "contain(s)," and variants thereof, are open-ended transitional phrases, terms, or words that are intended to be synonymous with the phrases "comprising," "including," "having," and "consisting of" and are not intended to (and should not be construed as) limiting the possible meanings of the phrases "comprising," "including," "having," and "consisting of." The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments "comprising," "consisting of," and "consisting essentially of," the embodiments or elements presented herein, whether explicitly set forth or not.

[0027] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., it includes the degree of error associated with the measurement of the particular quantity). The modifier "about" should also be considered in its normal sense as disclosing a range that is near to the end point of the range. For example, the expression "about 2 to about 4" also discloses the range "2 to 4." The term "about" can mean plus or minus 10% of the indicated number. For example, "about 10%" can mean a range of 9% to 11%, and "about 1" can mean 0.9-1.1. Other meanings of "about" can be apparent from the context, such as rounding, thus, for example, "about 1" can also mean 0.5 to 1.4.

[0028] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, and specific functional moieties and reactivity are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5thEd., John Wiley & Sons, New York, 2001; and Carruthers, Organic Synthesis: Active Methods, 2ndEd., Oxford, 2004.Organic Chemistry [Organic Chemistry], Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, [March's Advanced Organic Chemistry], 5th Ed., John Wiley & Sons, Inc., New York, 2001; Larock, [Comprehensive Organic Transformations], VCH Publishers, Inc., New York, 1989; Carruthers, [Some Modern Methods of Organic Synthesis], 3rd Ed., Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. March's Advanced Organic Chemistry Comprehensive Organic Transformations [Organic Chemistry], Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, [March's Advanced Organic Chemistry], 5th Ed., John Wiley & Sons, Inc., New York, 2001; Larock, [Comprehensive Organic Transformations], VCH Publishers, Inc., New York, 1989; Carruthers, [Some Modern Methods of Organic Synthesis], 3rd Ed., Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. Some Modern Methods of Organic Synthesis [Organic Chemistry], Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, [March's Advanced Organic Chemistry], 5th Ed., John Wiley & Sons, Inc., New York, 2001; Larock, [Comprehensive Organic Transformations], VCH Publishers, Inc., New York, 1989; Carruthers, [Some Modern Methods of Organic Synthesis], 3rd Ed., Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0029] As used herein, the term "alkoxy" refers to the group -O-alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propyloxy, 2-propyloxy, butoxy, and t-butoxy.

[0030] As used herein, the term "alkyl" means a straight or branched chain saturated hydrocarbon. The term "lower alkyl" or "C 1-6 As used herein, the term "alkyl" means a straight or branched chain saturated hydrocarbon. The term "lower alkyl" or "C 1-4 As used herein, the term "alkyl" means a straight or branched chain saturated hydrocarbon. The term "lower alkyl" or "C

[0031] As used herein, the term "alkenyl" means a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond.

[0032] As used herein, the term "alkoxyalkyl" refers to an alkoxy group as defined herein attached to the parent molecular moiety through an alkyl group as defined herein.

[0033] As used herein, the term "alkoxyalkyl" refers to an alkoxy group as defined herein attached to the parent molecular moiety through an alkyl group as defined herein.

[0034] ​As used herein, the term "alkylene" refers to a divalent group derived from a straight chain or branched saturated hydrocarbon. Representative examples of alkylene groups include, but are not limited to: -CH2-, -CD2-, -CH2CH2-, -C(CH3)(H)-, -C(CH3)(D)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0035] As used herein, the term "alkylene" refers to a divalent group derived from a straight chain or branched saturated hydrocarbon. Representative examples of alkylene groups include, but are not limited to: -CH2-, -CD2-, -CH2CH2-, -C(CH3)(H)-, -C(CH3)(D)-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0036] As used herein, the term "alkylamino" means at least one alkyl group, as defined herein, attached to the parent molecular moiety through an amino group, as defined herein.

[0037] As used herein, the term "amide" means -C(O)NR- or -NRC(O)-, where R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0038] As used herein, the term "aminoalkyl" means at least one amino group, as defined herein, attached to the parent molecular moiety through an alkylene group, as defined herein.

[0039] As used herein, the term "amino" means -NR x R y , where R x and R y may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other moiety where an amino group is attached to two other moieties together, the amino group can be -NR x , where R x may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0040] As used herein, the term "aryl" refers to a phenyl group or a phenyl group that is attached to the parent molecular moiety and is fused to a cycloalkane group (e.g., the aryl group can be indan-4-yl), fused to a 6-membered aromatic hydrocarbon group (i.e., the aryl group is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl group can be benzo[d][l,3]dioxol-5-yl). The term "phenyl" is used when referring to a substituent group and the term 6-membered aromatic hydrocarbon is used when referring to a fused ring. The 6-membered aromatic hydrocarbon is monocyclic (e.g., benzene or benzo). The aryl group can be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic ring system).

[0041] As used herein, the term "cyanoalkyl" means at least one -CN group attached to the parent molecular moiety through an alkylene group, as defined herein.

[0042] As used herein, the term "cyanoalkyl" means at least one -CN group attached to the parent molecular moiety through an alkyl group, as defined herein.

[0043] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom.

[0044] As used herein, the term "cycloalkyl" or "cycloalkane" refers to a saturated ring system containing all carbon atoms as ring members and no double bonds. As used herein, the term "cycloalkyl" refers to a cycloalkane when present as a substituent. Cycloalkyl groups can be monocyclic cycloalkyl groups (e.g., cyclopropyl), fused bicyclic cycloalkyl groups (e.g., decalinyl), or bridged cycloalkyl groups, in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[l. l. l]pentanyl.

[0045] As used herein, the term "cycloalkenyl" or "cycloalkene" means a non-aromatic monocyclic or polycyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond, and preferably each ring has 5-10 carbon atoms. As used herein, the term "cycloalkenyl" refers to a cycloalkene when present as a substituent. Cycloalkenyl groups can be monocyclic cycloalkenyl groups (e.g., cyclopentenyl), fused bicyclic cycloalkenyl groups (e.g., octahydronaphthyl), or bridged cycloalkenyl groups, in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0046] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl". The term "carbocycle" means "cycloalkane" or "cycloalkene". The term "carbocyclyl" refers to a "carbocycle" when present as a substituent.

[0047] The term "1,1-carbocyclylene" means a geminal bivalent radical derived from a cycloalkyl group. One representative example is 1,1-C 3-6 cycloalkylidene (i.e., ). Another example is 1,1-cyclopropylidene (i.e., ).

[0048] As used herein, the term "fluoroalkyl" means an alkyl group as defined herein in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced with fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl, such as 3,3,3-trifluoropropyl.

[0049] As used herein, the term "difluoroalkyl" means an alkyl group as defined herein in which two hydrogen atoms are replaced with fluorine. Representative examples of difluoroalkyl include difluoromethyl and difluoroethyl.

[0050] As used herein, the term "fluoroalkylene" means an alkylene group as defined herein in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced with fluorine. Representative examples of fluoroalkylene include, but are not limited to, -CF2-, -CH2CF2-, 1,2-difluoroethylene, 1,1,2,2-tetrafluoroethylene, 1,3,3,3-tetrafluoropropene, 1,1,2,3,3-pentafluoropropene, and perfluoropropene, such as 1,1,2,2,3,3-hexafluoropropene.

[0051] As used herein, the term "fluoroalkoxy" means at least one fluoroalkyl group as defined herein attached to the parent molecular moiety through an oxygen atom. Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0052] As used herein, the term "halogen" or "halo" means Cl, Br, I, or F.

[0053] As used herein, the term "haloalkyl" means an alkyl group as defined herein in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced with a halogen.

[0054] As used herein, the term "haloalkoxy" means at least one haloalkyl group as defined herein attached to the parent molecular moiety through an oxygen atom.

[0055] As used herein, the term "halocycloalkyl" means a cycloalkyl group as defined herein in which one or more hydrogen atoms are replaced with a halogen.

[0056] As used herein, the term "heteroalkyl" means an alkyl group as defined herein in which one or more carbon atoms are replaced with a heteroatom selected from S, O, P, and N. Representative examples of heteroalkyl include, but are not limited to, alkyl ethers, secondary alkyl amines, tertiary alkyl amines, amides, and alkyl sulfides.

[0057] As used herein, the term "heteroaryl" refers to a ring containing an aromatic monocyclic heteroatom (monocyclic heteroaryl) or a bicyclic system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). As present as a substituent, the term "heteroaryl" as used herein refers to a heteroarene. Monocyclic heteroaryl is a five- or six-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). A five-membered aromatic monocycle has two double bonds, and a six-membered aromatic monocycle has three double bonds. Bicyclic heteroaryl is an 8- to 12-membered ring system and includes fused bicyclic heteroaromatic ring systems (i.e., 10 pi-electron systems), such as monocyclic heteroaryl rings fused to a 6-membered arene (e.g., quinolin-4-yl, indol-1-yl), monocyclic heteroaryl rings fused to a monocyclic heteroarene (e.g., naphthyridinyl), and phenyl groups fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indol-4-yl). Bicyclic heteroaryl / heteroarene groups include 9-membered fused bicyclic heteroaromatic ring systems having four double bonds and at least one heteroatom contributing a lone pair of electrons to the fully aromatic 10 pi-electron system, such as ring systems having a nitrogen atom at the ring junction (e.g., imidazopyridine) or benzoxadiazolyl. Bicyclic heteroaryl also includes fused bicyclic systems consisting of one heteroaromatic ring and one non-aromatic ring, such as monocyclic heteroaryl rings fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl) or monocyclic heteroaryl rings fused to a monocyclic heterocyclic ring (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). Bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Other representative examples of heteroaryl include, but are not limited to: indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridyl (including pyrid-2-yl, pyrid-3-yl, pyrid-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thiophenyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothiophenyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2- a ]pyridyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridinoimidazolyl, thiazolo[5,4- b ]pyridin-2-yl, and thiazolo[5,4- dpyrimidin-2-yl.

[0058] As used herein, the term "heterocycle" or "heterocyclyl" means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. As used herein, the term "heterocyclyl" when present as a substituent refers to a heterocycle. A monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A three- or four-membered ring contains zero or one double bonds and one heteroatom selected from the group consisting of O, N, and S. A five-membered ring contains zero or one double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A six-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A seven-membered ring and an eight-membered ring contain zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclyl groups include, but are not limited to: azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dithianyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. A bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered aromatic hydrocarbon, or a monocyclic heterocycle fused to a monocyclic cycloalkane (e.g., a 7- to 12-membered fused bicyclic heterocyclyl ring system, such as hexahydro-2H-cyclopenta[b]furanyl, octahydro-3aH-cyclohepta[b]furanyl, or 3-oxabicyclo[3.1.0]hexanyl), or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocyclyl group (e.g., a 7- to 12-membered spiro heterocyclyl ring system, such as 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octanyl, or 5-oxaspiro[2.4]heptanyl), or a bridged heterocyclic ring system in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., a 6- to 10-membered bridged bicyclic heterocyclyl ring system, such as 7-oxabicyclo[2.2.1]heptanyl or 2-oxabicyclo[2.1.1]hexanyl) by or di-, tri-, or tetra-alkenylene bridges of 2, 3, or 4 carbon atoms.Bicyclic heterocyclyl is attached at a non-aromatic ring atom to the parent molecular moiety (e.g., indolin-1-yl). Representative examples of bicyclic heterocyclyl include, but are not limited to: chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothiophen-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]heptan-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1. H - indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[ c ]pyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H- cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-1-yl, and 3-oxabicyclo[3.1.0]hexan-6-yl. Tricyclic heterocycles are exemplified by bicyclic heterocycles fused to a 6-membered aromatic hydrocarbon, or bicyclic heterocycles fused to a monocyclic cycloalkane, or bicyclic heterocycles fused to a monocyclic cycloalkene, or bicyclic heterocycles fused to a monocyclic heterocycle, or bicyclic heterocycles wherein two non-adjacent atoms of the bicyclic ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms or by an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxycyclopenta[2,3-b]indenyl, hexahydro-2 H - 2,5-methylenecyclopenta[ b ]dienyl, hexahydro-1 H - 1,4-methylenecyclopenta[ c ]dienyl, azadamantine (1-azatricyclo[3.3.1.13,7]decane), and oxadamantine (2-oxatricyclo[3.3.1.13,7]decane). Monocyclic, bicyclic, and tricyclic heterocyclyl is connected at a non-aromatic ring atom to the parent molecular moiety.

[0059] As used herein, the term “hydroxyl” or “hydroxy” means an -OH group.

[0060] As used herein, the term “hydroxyalkyl” means at least one -OH group attached to the parent molecular moiety through an alkylene group as defined herein.

[0061] As used herein, the term “hydroxyfluoroalkyl” means at least one -OH group attached to the parent molecular moiety through a fluoroalkyl group as defined herein.

[0062] The terms such as "alkyl," "cycloalkyl," "alkylene," etc. can be preceded by a designation indicating the number of atoms present in the group in the particular instance (e.g., "C 1-4 "alkyl," "C 3-6 "cycloalkyl," "C 1-4 "alkylene"). These designations are used as generally understood by those skilled in the art. For example, "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, "C3 alkyl" is an alkyl group having three carbon atoms (i.e., n-propyl, iso-propyl). In the case of a given range, such as in "C 1-4 "1-4 alkyl," the members of the group that follows can have any number of carbon atoms falling within the range. For example, "C 1-4 "1-4 alkyl" is an alkyl group having from 1 to 4 carbon atoms, arranged in any manner, i.e., straight or branched.

[0063] The term "substituted" means that a group can be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =0 (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0064] For the compounds described herein, groups and substituents can be selected according to the valence of the atom and substituents allowed, such that the selection and substitution results in a stable compound, e.g., the compound does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, etc.).

[0065] For recitations of numerical ranges including endpoints, each intervening number between the endpoints is explicitly included. For example, for the range 6-9, the numbers 7 and 8 are explicitly included in addition to 6 and 9. For the range 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly included.

[0066] 2. Compounds In one aspect, the present application provides compounds having the formula (I), wherein R 1 , R 2 , R 3 , and n are as defined herein.

[0067] Unsubstituted or substituted ring (i.e., optionally substituted), such as aryl, heteroaryl, and the like, consists of a ring system and optional substituents of the ring system. Thus, the ring system can be defined independently of its substituents, such that redefining the ring system only preserves any prior optional substituents. For example, a 5- to 12-membered heteroaryl having optional substituents can be further defined by specifying the ring system of the 5- to 12-membered heteroaryl as a 5- to 6-membered heteroaryl (i.e., a 5- to 6-membered heteroaryl ring system), in which case the optional substituents of the 5- to 12-membered heteroaryl still exist on the 5- to 6-membered heteroaryl, unless otherwise explicitly stated.

[0068] In cases where a heterocyclic and heteroaromatic ring system is defined as “containing” (contain or containing) a specified heteroatom (e.g., 1-3 heteroatoms independently selected from the group consisting of O, N, and S), any ring atom of the heterocyclic and heteroaromatic ring system that is not one of the specified heteroatoms is a carbon atom.

[0069] Hereinafter, numbered embodiments of the present application are disclosed. The first embodiment is denoted E1, and subsequent embodiments are denoted E1.1, E1.2, E1.3, E1.4, E1.5, E2, E3, and so on.

[0070] E1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: " " represents a single or double bond; R 1 is R 1a is G 1 , -L 1 -G 1 , -C 2-4 alkylene-OR A , -C 2-4 alkylene-NR A R B , C 1-6 alkyl, C 1-6 fluoroalkyl, or H; R A is G 1 , -L 1 -G 1 , C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-6 cycloalkyl, or -C 1-3 alkylene-C 3-6cycloalkyl; R B It is H, C 1-6 Alkyl, C 1-6 fluoroalkyl, C 3-6 cycloalkyl or –C 1-3 Alkylene-C 3-6 cycloalkyl; R 1b It is halogen, C 1-4 Alkyl, C 1-2 Fluoroalkyl, CN, C 3-4 cycloalkyl, –OC 1-3 Alkyl, –OC 1-2 Fluoroalkyl or H; R 1c It is H, halogen, C 1-4 Alkyl, C 1-2 Fluoroalkyl, CN, phenyl, C 3-4 cycloalkyl, –OR 1d or –N(R) 1d )2; R 1d Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively used 1d Together with these two Rs 1d The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; L 1 It is C 1-5 Alkylene or C 2-5 alkenyl; G 1 It is a 5- or 6-membered aromatic or partially unsaturated heterocycle containing a first nitrogen atom and optionally 1-2 other heteroatoms, which are independently nitrogen, oxygen, or sulfur, attached to an unsaturated carbon atom in the heterocycle, or G. 1 It is phenyl, G 1 The first substituent may be optionally substituted by a group consisting of: halogen, C 1-4 Alkyl, cyano, C 1-2 fluoroalkyl, oxo, –OR 10 –N(R) 10 )2、–C 1-3 Alkylene – OR 10 C 3-5 cycloalkyl and –C 1-3 alkylene–C 3-5Cycloalkyl, and optionally further substituted by 1-2 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl, cyano and C 1-2 fluoroalkyl; R 10 Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively used 10 Together with these two Rs 10 The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; R 2 It is G 2 –L 2 –G 2 –L 3 –C 1-6 Alkyl, –C 2-6 alkylene–R 2a C 1-6 Alkyl, C 1-6 Fluoroalkyl or H; L 2 It is C 1-3 alkylene or L 3 ; L 3 It is C(O), SO2, S(O)(NH), C(O)NH or C(O)O; G 2 It is a 4- to 12-membered heterocyclic group, C 3-12 Carbocyclic, 5- to 12-membered heteroaryl or 6- to 12-membered aryl, wherein G 2 The first substituent may be optionally substituted by a group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-2 fluoroalkyl, G 2a Oxygenation, –OR 13 –N(R) 13 )2、–C 1-3 Alkylene – OR 13 –C 1-3 Alkylene–N(R) 13 )2、–C(O)N(R 13 )2、–C(O)OR 13 –SO2R 13 and S(O)(NH)R 13Optionally further substituted with oxygen, and optionally further substituted with 1-3 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl and C 1-2 fluoroalkyl; G 2a It is C 3-4 cycloalkyl; R 13 Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively used 13 Together with these two Rs 13 The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; R 2a Is – OR 14 –N(R) 14 )2、–SO2R 14 S(O)(NH)R 14 –NR 14 C(O)N(R 14 )2 or –NR 14 C(O)OR 14 ; R 14 Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively used 14 Together with these two Rs 14 The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; R 3 Each time it appears, it is independently either fluorine or carbon. 1-4 Alkyl; and n is 0, 1, or 2.

[0071] E1.1. A compound as described in E1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II): .

[0072] E1.2. The compound of E1 or E1.1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-A): .

[0073] E1.3. The compound of E1 or E1.1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-B): .

[0074] E1.4. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III-A): .

[0075] E1.5. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III-B): .

[0076] E2. The compound of any one of E1-E1.5, or a pharmaceutically acceptable salt thereof, wherein R 1a is G 1 ; and G 1 is an optionally substituted 5- to 6-membered aromatic heterocycle.

[0077] E3. The compound of any one of E1-E2, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- to 6-membered aromatic heterocycle at G 1 contains 1-2 nitrogens.

[0078] E3.1. The compound of any one of E1-E3, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- to 6-membered aromatic heterocycle at G 1 is pyridinyl or pyrazolyl.

[0079] E3.2. The compound of any one of E1-E3.1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- to 6-membered aromatic heterocycle at G 1 is pyridin-4-yl or pyrazol-4-yl.

[0080] E3.3. The compound of any one of E1-E3.2, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- to 6-membered aromatic heterocycle at G 1 is pyrazol-4-yl.

[0081] E4. The compound of any one of E1-E3.3, or a pharmaceutically acceptable salt thereof, wherein G 1optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, cyano, C 1-2 fluoroalkyl, -OR 10 , C 3-5 cycloalkyl, and -C 1-3 alkylene-C 3-5 cycloalkyl, and further optionally substituted with 1-2 substituents independently selected from the group consisting of halogen and C 1-4 alkyl.

[0082] E4.1. The compound of any one of E1-E4 or a pharmaceutically acceptable salt thereof, wherein G 1 is substituted with a first substituent selected from the group consisting of C 1-4 alkyl and -OC 1-4 alkyl.

[0083] E4.2. The compound of any one of E1-E4.1 or a pharmaceutically acceptable salt thereof, wherein G 1 is substituted with a first substituent selected from the group consisting of methyl and -OCH3.

[0084] E4.3. The compound of E4.1 or a pharmaceutically acceptable salt thereof, wherein G 1 is substituted with a first substituent which is C 1-4 alkyl.

[0085] E4.4. The compound of E4.2 or E4.3 or a pharmaceutically acceptable salt thereof, wherein G 1 is substituted with a first substituent which is methyl.

[0086] E4.5. The compound of any one of E1-E4.1 or E4.3 or a pharmaceutically acceptable salt thereof, wherein G 1 is , or .

[0087] E4.6. The compound of any one of E1-E4.5 or a pharmaceutically acceptable salt thereof, wherein G 1 is .

[0088] E4.7. The compound of E4.5 or a pharmaceutically acceptable salt thereof, wherein G 1 is .

[0089] E4.8. The compound of E4.6 or E4.7 or a pharmaceutically acceptable salt thereof, wherein G 1 is .

[0090] E5. The compound of any one of E1-E1.5 or a pharmaceutically acceptable salt thereof, wherein R 1a is G 1 ; and G 1 is an optionally substituted 5- to 6-membered partially unsaturated heterocyclic ring.

[0091] E6. The compound of any one of E1-E1.5 or E5 or a pharmaceutically acceptable salt thereof, wherein G 1 the ring system of the optionally substituted 5- to 6-membered partially unsaturated heterocyclic ring at G

[0092] E6.1. The compound of any one of E1-E1.5 or E5-E6 or a pharmaceutically acceptable salt thereof, wherein G 1 is optionally substituted with oxo.

[0093] E6.2. The compound of any one of E1-E1.5 or E5-E6.1 or a pharmaceutically acceptable salt thereof, wherein G 1 is .

[0094] E7. The compound of any one of E1-E6.2 or a pharmaceutically acceptable salt thereof, wherein G 1 is .

[0095] E8. The compound of any one of E1-E7 or a pharmaceutically acceptable salt thereof, wherein R 1b is halogen or C 1-4 alkyl.

[0096] E8.1. The compound of any one of E1-E8 or a pharmaceutically acceptable salt thereof, wherein R 1b is chloro or methyl.

[0097] E8.2. The compound of E8 or a pharmaceutically acceptable salt thereof, wherein R 1b is C 1-4 alkyl.

[0098] E8.3. The compound of any one of E8.1-E8.2 or a pharmaceutically acceptable salt thereof, wherein R 1b is methyl.

[0099] E9. The compound of any one of E1-E8.3 or a pharmaceutically acceptable salt thereof, wherein R 1c is H.

[0100] E10. The compound of any one of E1-E9, or a pharmaceutically acceptable salt thereof, wherein R 2 is G 2 .

[0101] E11. The compound of any one of E1-E9, or a pharmaceutically acceptable salt thereof, wherein R 2 is -L 2 -G 2 .

[0102] E12. The compound of any one of E1-E9 or E11, or a pharmaceutically acceptable salt thereof, wherein L 2 is C 1-3 alkylene.

[0103] E13. The compound of any one of E1-E9 or E11, or a pharmaceutically acceptable salt thereof, wherein L 2 is L 3 and L 3 is C(O).

[0104] E14. The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein G 2 is an optionally substituted 4- to 12-membered heterocyclyl.

[0105] E15. The compound of any one of E1-E14, or a pharmaceutically acceptable salt thereof, wherein G 2 the ring system of the optionally substituted 4- to 12-membered heterocyclyl at G 2 is a 4- to 8-membered heterocyclyl or an 8- to 10-membered fused bicyclic heterocyclyl, the heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur.

[0106] E15.1. The compound of E15, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl at G 2 is an optionally substituted 4- to 8-membered heterocyclyl.

[0107] E15.2. The compound of E15 or E15.1, or a pharmaceutically acceptable salt thereof, wherein the 4- to 8-membered heterocyclyl ring system at G 2 is a 4- to 8-membered monocyclic heterocyclyl ring system.

[0108] E15.3. The compound of E15.2, or a pharmaceutically acceptable salt thereof, wherein the 4- to 8-membered monocyclic heterocyclyl ring system at G 2 is a 4- to 6-membered monocyclic heterocyclyl ring system.

[0109] E15.4. The compound of E15.3 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the 4- to 6-membered monocyclic heterocyclyl ring system at the 4-position is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, or piperidinyl.

[0110] E15.5. The compound of E15.4 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the 4- to 6-membered monocyclic heterocyclyl ring system at the 4-position is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, or piperidin-3-yl.

[0111] E15.6. The compound of any one of E1-E15.5 or a pharmaceutically acceptable salt thereof, wherein G 2 is optionally substituted with a first substituent selected from the group consisting of C 1-4 alkyl, oxo, and -C(O)OR 13 , optionally further substituted with oxo, and optionally further substituted with 1-3 C 1-4 alkyl.

[0112] E15.7. The compound of E15.6 or a pharmaceutically acceptable salt thereof, wherein G 2 is optionally substituted with a first substituent selected from the group consisting of methyl, oxo, and -C(O)OCH3, optionally further substituted with oxo, and optionally further substituted with 1-3 methyl.

[0113] E15.8. The compound of E15.7 or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0114] E15.9. The compound of E15.8 or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0115] E15.10. The compound of E15 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 4- to 12-membered heterocyclyl at the 4- position is an 8- to 10-membered fused bicyclic heterocyclyl ring system (i.e., G 2 is an optionally substituted 8- to 10-membered fused bicyclic heterocyclyl).

[0116] E15.11. A compound as described in E15.10 or a pharmaceutically acceptable salt thereof, wherein G 2 The 8- to 10-membered fused bicyclic heterocyclic group system is a 5- to 6-membered monocyclic heterocyclic group fused to a 6-membered aromatic hydrocarbon, which contains sulfur, oxygen, or nitrogen atoms.

[0117] E15.12. A compound as described in E15.11 or a pharmaceutically acceptable salt thereof, wherein G 2 The 8- to 10-membered fused bicyclic heterocyclic group system is a 5- to 6-membered monocyclic heterocyclic group fused to a 6-membered aromatic hydrocarbon, which contains a sulfur atom.

[0118] E15.13. A compound as described in E15.12 or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0119] E16. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E13, wherein G 2 C is arbitrarily replaced 3-12 Carbon cyclic group.

[0120] E17. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E13 or E16, wherein G 2 The C that can be arbitrarily replaced at this location 3-12 The ring system of the carbon cyclic group is C 3-6 Cycloalkyl.

[0121] E17.1. A compound as described in E17 or a pharmaceutically acceptable salt thereof, wherein G 2 The C at that location 3-6 The cycloalkyl ring system is the cyclohexyl ring system.

[0122] E17.2. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E13 or E16-E17.1, wherein G 2 The first substituent may be optionally substituted by a group consisting of: cyano, G 2a –OR 13 and –SO2R 13 , and optionally further substituted with cyano groups.

[0123] E17.3. A compound as described in E17.2 or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0124] E17.4. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E17.3, wherein R 13 It is C 1-4alkyl.

[0125] E17.5. The compound of E17.4 or a pharmaceutically acceptable salt thereof, wherein R 13 is methyl.

[0126] E17.6. The compound of any one of E1-E17.5 or a pharmaceutically acceptable salt thereof, wherein G 2a is cyclopropyl.

[0127] E17.7. The compound of any one of E17-E17.6 or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0128] E18. The compound of any one of E1-E13 or a pharmaceutically acceptable salt thereof, wherein G 2 is an optionally substituted 5- to 12-membered heteroaryl.

[0129] E19. The compound of any one of E1-E13 or E18 or a pharmaceutically acceptable salt thereof, wherein G 2 the ring system of the optionally substituted 5- to 12-membered heteroaryl at G is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur.

[0130] E19.1. The compound of any one of E1-E13 or E18-E19 or a pharmaceutically acceptable salt thereof, wherein G 2 the ring system of the optionally substituted 5- to 12-membered heteroaryl at G is pyrazolyl, thiazolyl, or thiadiazolyl.

[0131] E19.2. The compound of E19.1 or a pharmaceutically acceptable salt thereof, wherein G 2 the ring system of the optionally substituted 5- to 12-membered heteroaryl at G is pyrazol-4-yl, thiazol-4-yl, or thiadiazol-5-yl.

[0132] E19.3. The compound of any one of E1-E13 or E18-E19.1 or a pharmaceutically acceptable salt thereof, wherein G 2 the ring system of the optionally substituted 5- to 12-membered heteroaryl at G is thiadiazolyl.

[0133] E19.4. The compound of E19.2 or E19.3 or a pharmaceutically acceptable salt thereof, wherein G 2 the ring system of the optionally substituted 5- to 12-membered heteroaryl at G is thiadiazol-5-yl.

[0134] E19.5. The compound of any one of E1-E13 or E18-E19.4, or a pharmaceutically acceptable salt thereof, wherein G 2 is optionally substituted with one substituent that is C 1-4 alkyl, and is optionally further substituted with 1-2 C 1-4 alkyl groups.

[0135] E19.6. The compound of E19.5, or a pharmaceutically acceptable salt thereof, wherein G 2 is optionally substituted with one substituent that is methyl, and is optionally further substituted with 1-2 methyl groups.

[0136] E19.7. The compound of E19.5, or a pharmaceutically acceptable salt thereof, wherein G 2 is , or .

[0137] E19.8. The compound of E19.6 or E19.7, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0138] E19.9. The compound of E19.7, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0139] E19.10. The compound of any one of E19.6-E19.9, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0140] E20. The compound of any one of E1-E13, or a pharmaceutically acceptable salt thereof, wherein G 2 is an optionally substituted 6- to 12-membered aryl.

[0141] E21. The compound of any one of E1-E19.10, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0142] E22. The compound of any one of E1-E21, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0143] E23. The compound of any one of E1-E22, or a pharmaceutically acceptable salt thereof, wherein R 1 is .

[0144] E24. The compound of any one of E1-E23, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-C): .

[0145] E24.1. The compound of E24, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-C1): .

[0146] E24.2. The compound of E24, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-C2): .

[0147] E25. The compound of any one of E1-E23, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III-C): .

[0148] E25.1. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III-C1): .

[0149] E25.2. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III-C2): .

[0150] E26. The compound of E1 selected from the group consisting of: 6-((3a R ,6a S )-1,2,3,3a,4,6a-hexahydrocyclopenta[ c ]pyrrol-5-yl)-5-methyl-1-(1-methyl-1 H - pyrazol-4-yl)-1 H - indazole; (3a R ,6a S )-5-(5-methyl-1-(1-methyl-1 H - pyrazol-4-yl)-1 H - indazole-6-yl)-3,3a,4,6a-tetrahydrocyclopenta[ c ]pyrrol-2(1 H )-carboxylic acid tert-butyl ester; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R ,6a S )-2-(tetrahydro-2 H -pyran-4-yl)-1,2,3,3a,4,6a-hexahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 4-((3a R ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)-3,3a,4,6a-tetrahydrocyclopentadien[c]pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 s ,6a S )-2-(tetrahydro-2 H -pyran-4-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 r ,6a S )-2-(tetrahydro-2 H -pyran-4-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 4-((3a R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide; 4-((3a R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1)H - pyrazol-4-yl)- 1 H - indazol-6-yl)hexahydrocyclopenta[ c ]pyrrolo-2(l H )-yl)tetrahydro-2 H - thiopyran 1,1-dioxide; (4-methyl-l,2,3-thiadiazol-5-yl)((3a R ,5 s ,6a S )-5-(5-methyl-l-(l-methyl-l H - pyrazol-4-yl)- 1 H - indazol-6-yl)hexahydrocyclopenta[ c ]pyrrolo-2(l H )-yl)ketone; (4-methyl-l,2,3-thiadiazol-5-yl)((3a R ,5 r ,6a S )-5-(5-methyl-l-(l-methyl-l H - pyrazol-4-yl)- 1 H - indazol-6-yl)hexahydrocyclopenta[ c ]pyrrolo-2(l H )-yl)ketone; 5-methyl-l-(l-methyl-l H - pyrazol-4-yl)-6-((3a R ,5 s ,6a S )-2-(tetrahydro-2 H - pyran-3-yl)octahydrocyclopenta[ c ]pyrrolo-5-yl)- 1 H - indazole; 5-methyl-l-(l-methyl-l H - pyrazol-4-yl)-6-((3a R ,5 r ,6a S )-2-(tetrahydro-2 H - pyran-3-yl)octahydrocyclopenta[ c ]pyrrolo-5-yl)- 1 H - indazole; 5-methyl-l-(l-methyl-l H - pyrazol-4-yl)-6-((3a R ,5 s ,6a S )-2-(tetrahydrofuran-3-yl)octahydrocyclopenta[ c ]pyrrolo-5-yl)- 1H - indazol-6-yl)hexahydrocyclopenta[ 5-methyl-1 -(1 -methyl-1 H- H - pyrazol-4-yl)-6-((3a R ,5 r ,6a S )-2-(tetrahydrofuran-3-yl)octahydrocyclopenta[ c ]pyrrol-5-yl)-1 H- H - indazol-6-yl)hexahydrocyclopenta[ 3-((3a R ,5 s ,6a S )-5-(5-methyl-1 -(1 -methyl-1 H- H - pyrazol-4-yl)-1 H- H - indazol-6-yl)hexahydrocyclopenta[ c ]pyrrol-2(1 H )-yl)tetrahydro-2 H - thiopyran 1,1 -dioxide; 5-methyl-1 -(1 -methyl-1 H- H - pyrazol-4-yl)-6-((3a R ,5 s ,6a S )-2-(oxetan-3-yl)octahydrocyclopenta[ c ]pyrrol-5-yl)-1 H- H - indazol-6-yl)hexahydrocyclopenta[ 5-methyl-1 -(1 -methyl-1 H- H - pyrazol-4-yl)-6-((3a R ,5 r ,6a S )-2-(oxetan-3-yl)octahydrocyclopenta[ c ]pyrrol-5-yl)-1 H- H - indazol-6-yl)hexahydrocyclopenta[ 3-((3a R ,5 s ,6a S )-5-(5-methyl-1 -(1 -methyl-1 H- H - pyrazol-4-yl)-1 H- H - indazol-6-yl)hexahydrocyclopenta[ c ]pyrrol-2(1 H )-yl)piperidine-1 -carboxylate; 3-((3a R ,5 r ,6a S )-5-(5-methyl-1 -(1 -methyl-1 H- H - pyrazol-4-yl)-1 H- H- (3aR, 6aR)-5-(5-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-2-yl)hexahydrocyclopenta[ c ]pyrrol-2(1 H )-yl)pyrrolidine-1-carboxylate; 3-((3a R ,5 r ,6a S )-5-(5-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-2-yl)hexahydrocyclopenta[ H -yl)pyrrolidine-1-carboxylate; H - (3aR, 6aR)-5-(5-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-2-yl)hexahydrocyclopenta[ c ]pyrrol-2(1 H )-yl)pyrrolidine-1-carboxylate; H - (3aR, 6aR)-5-(5-methoxy-1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-2-yl)hexahydrocyclopenta[ or a pharmaceutically acceptable salt thereof.

[0151] E27. A pharmaceutical composition comprising a compound of any one of E1-E26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0152] E28. A method of treating a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of E1-E26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E27, wherein the disease or disorder is a CNS disease or disorder, an immune disease or disorder, a cancer, or leprosy.

[0153] E29. The method of E28, wherein the disease or disorder is a CNS disease or disorder.

[0154] E29.1. The method of E29, wherein the CNS disease or disorder is selected from the group consisting of familial / hereditary and / or sporadic Parkinson’s disease, tauopathies, Alzheimer’s disease, neuroinflammation, HIV-induced dementia, ALS, ischemic stroke, traumatic brain injury, and spinal cord injury.

[0155] E29.2. The method of E29.1, wherein the CNS disease or disorder is familial / hereditary and / or sporadic Parkinson’s disease.

[0156] E30. The method of E28, wherein the disease or disorder is an immune disease or disorder.

[0157] E30.1. The method of E30, wherein the immune disease or disorder is selected from the group consisting of lymphoma, leukemia, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disease, type I diabetes, Sjogren’s syndrome, Delvecchio’s disease, inflammatory myopathy, ankylosing spondylitis, and Crohn’s disease.

[0158] E31. The method of E28, wherein the disease or disorder is cancer.

[0159] E31.1. The method of E31, wherein the cancer is selected from the group consisting of renal cancer, breast cancer, lung cancer, prostate cancer, acute myeloid leukemia (AML), papillary renal carcinoma, thyroid cancer, and low-grade glioma.

[0160] E32. The method of E28, wherein the disease or disorder is leprosy.

[0161] E33. A method of inhibiting LRRK2 in a subject, comprising administering to the subject an amount of a compound of any one of E1-E26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E27, effective to inhibit LRRK2.

[0162] E33.1. The method of E33, wherein the subject has a disease or disorder of any one of E28-E32.

[0163] E34. The method of E33 or E33.1, wherein LRRK2 is a G2019S mutant of LRRK2.

[0164] E35. The method of any one of E28-E34, wherein the subject expresses a LRRK2 G2019S mutation.

[0165] E36. The method of any one of E28-E35, wherein LRRK2 is amplified or overexpressed in the subject.

[0166] E37. A compound of any one of E1-E26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E27, for use in treating a disease or disorder selected from the group consisting of a CNS disease or disorder, an immune disease or disorder, cancer, and leprosy.

[0167] E38. Use of a compound of any one of E1-E26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E27, in the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of CNS diseases or disorders, immune diseases or disorders, cancer, and leprosy.

[0168] Compound names and / or structures can be assigned / determined by using the Struct=Name naming algorithm as part of CHEMDRAW® ULTRA.

[0169] Compounds can exist as stereoisomers having asymmetric or chiral centers, the stereochemistry of which is specified according to the R / S conventions as R ” or “ S ”. As used herein, the terms “ R ” and “ S ” are the configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry [IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry], Pure Appl. Chem., 1976, 45: 13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, and these are specifically included within the scope of the invention. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomeric or diastereomeric forms. Single enantiomeric forms of these compounds can be synthesized from commercially available starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures and subsequently resolving them by methods well known to those of ordinary skill in the art. These resolution methods are illustrated by (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and optionally releasing the optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel’s Textbook of Practical Organic Chemistry”, 5thEdition (1989), Longman Scientific & Technical [Longman Scientific & Technical], CM20 2JE, Essex, England, or (2) separating a mixture of optical enantiomers directly on a chiral chromatographic column, or (3) fractional recrystallization methods.

[0170] Compounds have the 3,3a,4,5,6,6a-hexahydro-1 H -cyclopentac ]pyrrole core structure, which core structure has a plane of symmetry, as shown in the following two representative structures.

[0171] These structures are considered meso, as A and B are superimposable with their respective mirror images. The 3a, 5 and 6a stereochemical designations are used herein for the A and B symmetry structures to designate the relative stereochemistry between the ring fusion and the 5 position. Thus, 3aR, 5s, 6aS, when drawn in the orientation above, refers to the trans relative stereochemistry between the 5 position substituent and the ring fusion, while 3aR, 5r, 6aS refers to the cis relative stereochemistry between the 5 position substituent and the ring fusion. The lower case s and r for the 5 position refer to the pseudoasymmetry described by G. P. Moss in “Basic terminology of stereochemistry [Basic terminology of stereochemistry]” Pure and Applied Chemistry (1996), 68 (12) 2193-2222. Those skilled in the art will appreciate that when structures A and B are drawn as their respective mirror images, the stereochemical designation for the 3a and 6 positions can be reversed by the chemical naming program from R to S and S to R, respectively, depending on the program, but the pseudoasymmetry for the 5 position remains the same, as R takes precedence over S according to the priority rules and the inversion of the carbon with R and S designations. Compounds of Formula (I) or any subformula thereof can have the 5 position substituent in the trans configuration or the cis configuration, or can be prepared as a mixture of the trans and cis. Pure and Applied Chemistry [Basic terminology of stereochemistry [Basic terminology of stereochemistry]” Pure and Applied Chemistry (1996), 68 (12) 2193-2222. Those skilled in the art will appreciate that when structures A and B are drawn as their respective mirror images, the stereochemical designation for the 3a and 6 positions can be reversed by the chemical naming program from R to S and S to R, respectively, depending on the program, but the pseudoasymmetry for the 5 position remains the same, as R takes precedence over S according to the priority rules and the inversion of the carbon with R and S designations. Compounds of Formula (I) or any subformula thereof can have the 5 position substituent in the trans configuration or the cis configuration, or can be prepared as a mixture of the trans and cis.

[0172] It will be understood that the compounds can have tautomeric forms as well as geometric isomers, and these are also contemplated as embodiments of the disclosure.

[0173] In compounds of Formula (I) and any subformula, any “hydrogen” or “H”, whether explicitly listed in a structure or implied, includes hydrogen isotopes 1 H (protium) and 2 H (deuterium).

[0174] The present disclosure also includes isotopically-labeled compounds (e.g., deuterium-labeled), wherein the atoms in the isotopically-labeled compound are designated by particular isotopic symbols. Examples of isotopes suitable for inclusion in the compounds of the application are hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, and chlorine, for example, and include without limitation 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32P, 35 S, 18 F, and 36 Cl. This compound may contain positron emission isotopes for medical imaging and positron emission tomography (PET) studies for determining receptor distribution. Suitable positron emission isotopes that can be incorporated into compounds having formula (I) are 11 C 13 N、 15 O, and 18 F.

[0175] Isotopically enriched compounds having formula (I) or any subform can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotopically enriching reagents instead of non-isotopically enriching reagents. The degree of isotopic enrichment can be characterized as the percentage of a particular isotope incorporated at the isotopically labeled atom (e.g., deuterium incorporation % at a deuterium label).

[0176] a. Pharmaceutically acceptable salts The disclosed compounds may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt or zwitterion of a compound that is water-soluble, oil-soluble, or dispersible, suitable for treating a condition without unusual toxicity, irritation, or allergic reactions, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. These salts may be prepared during the final separation and purification of the compound, or separately by reacting the amino group of the compound with a suitable acid. For example, the compound may be dissolved in a suitable solvent (e.g., but not limited to methanol and water) and treated with at least one equivalent of an acid (e.g., hydrochloric acid). The resulting salt may precipitate and be separated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Representative salts include: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, camphorates, camphorsulfonates, diglucose, glycerol phosphates, hemisulfates, heptahydrates, hexanoates, formates, hydroxyethyl sulfonates, fumarates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nicotinates, oxalates, dihydroxynaphthalate, pectates, persulfates, 3-phenylpropionates, picrates, oxalates, maleates, neopentanoates, propionates, succinates, tartrates, trichloroacetates, trifluoroacetates, glutamates, p-toluenesulfonates, undecanoates, hydrochlorides, hydrobromates, sulfates, phosphates, etc. The amino groups of these compounds can be quaternized using alkyl chlorides, bromides, and iodides (e.g., methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, etc.).

[0177] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reaction of the carboxyl group with a suitable base, for example, metal cations such as lithium, sodium, potassium, calcium, magnesium, or aluminum, hydroxides, carbonates, or bicarbonates, or organic primary, secondary, or tertiary amines. Quaternary amine salts can be prepared, for example, those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1- diphenyl-hydrabamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0178] b. General Synthesis Compounds of Formula (I), or any subformula thereof, can be prepared by synthetic or metabolic methods. Preparation of compounds by metabolic methods includes those occurring in the human or animal body (in vivo) or methods occurring in vitro.

[0179] Abbreviations: AcOH is acetic acid; BMS is borane dimethyl sulfide complex; Boc is tert-butoxycarbonyl; BrettPhos-Pd-G3 is [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS No. 1470372-59-8); t-BuXPhos is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; DAST is diethylaminosulfur trifluoride; DCE is 1,2-dichloroethane; DCM is dichloromethane; DIAD is diisopropyl azodicarboxylate; DIBAL is diisobutylaluminum hydride; DIEA and DIPEA both refer to N,N diisopropylethylamine; DMF is N,N-dimethylformamide; EtOH is ethanol; Et3SiCl is triethylchlorosilane; HATU is 2-(7-aza-1 N , N dimethylformamide; EtOH is ethanol; Et3SiCl is triethylchlorosilane; HATU is 2-(7-aza-1 H- benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HOBt is hydroxybenzotriazole; LiAlH(OtBu)3 is lithium tri-tert-butoxyhydroaluminate; LiHMDS is lithium bis(trimethylsilyl)amide; m-CPBA is meta-chloroperoxybenzoic acid; MeOH is methanol; MsCl is methanesulfonyl chloride; NaBH(OAc)3 and STAB both refer to sodium triacetoxyborohydride; rt or r.t. is room temperature; NMP is N-methyl-2-pyrrolidone; Pd(dppf)Cl2 is [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); PPh3 is triphenylphosphine; RuPhos-Pd-G3 is (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1 '- biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium(II) mesylate (CAS number 1445085-77-7); Selectfluor TM is 1 -chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate); t-BuOH is tert-butanol; t-BuOK is potassium tert-butoxide; TBAI is tetrabutylammonium iodide; THF is tetrahydrofuran; and TosMIC is tosylmethyl isocyanide.

[0180] Compounds of Formula (I) or any subformulae thereof can be synthesized as shown in the following schemes.

[0181] Scheme 1 As shown in Scheme 1, iodide A is coupled with 1 H - indazole B under suitable Ullmann coupling conditions to provide N - substituted indazole C.

[0182] Scheme 2 Scheme 2 illustrates the conversion of ketone D to enol triflate E by reaction with a base (e.g., LiHMDS) and a triflate-forming reagent (e.g., N - phenyl bis(trifluoromethanesulfonimide).

[0183] Scheme 3 Scheme 3 illustrates the conversion of enol triflate E to pinacol borane F by coupling enol triflate E with bis(pinacolato)diboron (B2Pin2) under suitable Miyaura borylation conditions.

[0184] Scheme 4 Scheme 4 illustrates the process of converting intermediates C and F to products G through J. Intermediate C can be coupled with pinacol borane F under suitable Suzuki reaction conditions to provide Boc-protected G, which can also be deprotected to provide deprotected H, which can be hydrogenated over a palladium catalyst to provide products I and J.

[0185] Scheme 5 Scheme 5 illustrates the process of reductive amination of deprotected compound Q and the resulting secondary amine R to provide tertiary amine compound S.

[0186] Scheme 6 As shown in Scheme 6, compound R can be reacted with an appropriate carboxylic acid to form amide compound T, which can be reduced to generate compound U, where R 4 is G 2 , -C 1-2 alkylene-G 2 , -C 1-5 alkylene-R 2a , or C 2-6 alkyl, where G 2 and R 2a are as defined herein. Amide coupling conditions are well known in the art and include treatment of the reactants with a coupling agent such as HATU in the presence of a base (e.g. DIPEA) in a solvent such as DMF or DCM. Amide reduction conditions are well known in the art and include treatment of the amide substrate with a reducing agent such as DIBAL in DCM or LiAlH4 in THF. The reaction can be run at any temperature ranging from -78 °C to room temperature. Compound T can also be reacted with LiAlD4 to introduce deuterium atoms in place of the carbonyl group.

[0187] Scheme 7 As shown in Scheme 7, a compound having the formula R can be alkylated using standard secondary amine alkylation conditions to provide tertiary amine S, where R 2 is -L 2 -G 2 , -C 2-6 alkylene-R 2a , or C 3-7 haloalkyl; L 4 is a C 2-6 alkylene group; LG is a leaving group (e.g. CI, Br, I, mesylate, tosylate, triflate); and R 2a , L2 and G 2 One set of exemplary alkylation conditions is heating the reactants to about 70 °C in the presence of a base (e.g., Cs2C03) in a solvent (e.g., DMF or DMSO). Another set of exemplary alkylation conditions is heating the reactants to about >100 °C in a sealed vessel in a microwave reactor in the presence of a tertiary amine base (such as DIPEA) using a solvent (e.g., acetonitrile, DMF or DMSO).

[0188] Scheme 8 Scheme 8 shows the process for preparing intermediate V. Compound V can be processed according to Schemes 2-7 to give compounds of the application.

[0189] Scheme 9 Scheme 9 shows the process for preparing intermediate X (in racemic form). Compound X can be processed according to Schemes 2-7 to give compounds of the application.

[0190] Scheme 10 Scheme 10 shows the process for preparing intermediate Z1 (in racemic form). Compound Z1 can be processed according to Schemes 2-7 to give compounds of the application.

[0191] Reductive amination conditions suitable for the processes outlined above are well known in the art. Representative reaction conditions for aldehyde reductive amination include treatment of the reactants with NaBH(OAc)3in a solvent such as DCM, THF, and MeOH, and mixtures thereof, optionally in the presence of a base (e.g., DIPEA). Aldehyde reductive amination can also be achieved by treatment with NaBH3CN in EtOH under heating conditions (e.g., heating to about 80 °C). Ketone reductive amination can be facilitated by the addition of an acid (such as acetic acid) to a solvent mixture (e.g., DCM-THF) and heating to 40 °C for about 1 hour. A representative solvent ratio for DCM:THF:AcOH is (3 : 3 : 0.5). Ketone reductive amination can also be achieved by treatment with Ti(OiPr)4and NaBH3CN or NaBH4in EtOH from room temperature to about 80 °C. Ketone reductive amination can also be achieved by treatment with 2-methylpyridine borane complex and acetic acid heated to about 60 °C. NaBD3CN can be used in place of NaBH3CN to incorporate deuterium and provide compounds enriched in deuterium rather than protium.

[0192] Ullmann coupling conditions suitable for the processes of Scheme 1 are well known in the art. Suitable Ullmann conditions include those generally outlined in Scheme 1 and as described in the examples herein.

[0193] The suitable Miyaura boration conditions used in Scheme 3 are well known in the art. Suitable Miyaura boration conditions include those generally outlined in Scheme 3 as well as those described in the examples herein.

[0194] The Suzuki coupling conditions applicable to the process of Scheme 4 are well known in the art. Suitable Suzuki conditions include those generally outlined in Scheme 4 as well as those described in the examples herein.

[0195] The boric acid or ester starting materials for preparing the compounds of the present invention can be purchased from commercial sources or prepared using procedures well known to those skilled in the art.

[0196] The preparation of R is shown. 1 yes Schemes 1 and 4-7 of the process for preparing the compound R can also be applied to prepare the compound R. 1 yes Compounds.

[0197] Compounds and intermediates can be separated and purified using methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for separating and purifying compounds include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derived with alkylsilyl groups, recrystallization at high or low temperatures (optionally pretreated with activated carbon), thin-layer chromatography, distillation under various pressures, sublimation under vacuum, and grinding, as described, for example, in “Vogel’s Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, Longman Scientific & Technical, Essex CM20 2JE, England.

[0198] The disclosed compound may have at least one basic nitrogen atom, thus allowing it to be treated with an acid to form a desired salt. For example, the compound may react with an acid at or above room temperature to provide the desired salt, which is then precipitated and collected by filtration upon cooling. Examples of acids suitable for this reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic acid, alpha-lactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0199] The reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. The Examples section provides specific procedures. The reactions can be worked up in the conventional manner, for example by removing the solvent from the residue and further purified according to methods generally known in the art, for example but not limited to crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise stated, the starting materials and reagents are commercially available, or can be prepared from commercially available materials by methods described in the chemical literature by one skilled in the art. Starting materials, if not commercially available, can be prepared by procedures selected from standard techniques of organic chemistry, techniques analogous to those described in the synthesis of structurally similar compounds known, or techniques analogous to the procedures described in the above schemes or the synthesis examples section.

[0200] Conventional procedures, including reaction conditions, reagents, the order of a synthesis route, protection of any chemical functionality that is incompatible with the reaction conditions, and appropriate manipulations of protecting groups performed at suitable points in the reaction sequence of the process, are included in the scope of this application. Suitable protecting groups and processes for protecting and deprotecting different substituents using such suitable protecting groups are well-known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, Greene's Book entitled Protective Groups in Organic Synthesis (4th Ed.) [Protective Groups in Organic Synthesis (4th Ed.)], John Wiley & Sons [John Wiley & Sons], New York (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the present application can be accomplished by methods analogous to those described in the above synthesis schemes and specific examples. th ed.) [Protective Groups in Organic Synthesis (4th Ed.)], John Wiley & Sons [John Wiley & Sons], New York (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the present application can be accomplished by methods analogous to those described in the above synthesis schemes and specific examples.

[0201] When an optically active form of the disclosed compounds is desired, it can be obtained by using one of the procedures described herein, or by resolving a mixture of stereoisomers of the compound or intermediate, either by using an optically active starting material (e.g., prepared by asymmetric induction of an appropriate reaction step), or by using standard procedures such as chromatographic separation, recrystallization, or enzymatic resolution.

[0202] Similarly, when a pure geometric isomer of a compound is desired, it can be obtained by using one of the above procedures, or by resolving a mixture of geometric isomers of the compound or intermediate, by using standard procedures such as chromatographic separation.

[0203] It is understood that the synthetic schemes and specific examples are illustrative and should not be construed as limiting the scope of the application as defined in the appended claims. All alternatives, modifications, and equivalents thereof are included within the scope of the claims.

[0204] 3. Pharmaceutical compositions and formulations The disclosed compounds can be incorporated into pharmaceutical compositions suitable for administration to a subject (e.g., a patient, which can be a human or non-human). The disclosed compounds can also be provided as a formulation (e.g., a spray-dried dispersion formulation).

[0205] The pharmaceutical compositions and formulations can include a "therapeutically effective amount" or a "prophylactically effective amount" of the agent. A "therapeutically effective amount" refers to the amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a composition can be determined by one of skill in the art and can vary according to factors such as the disease state, age, sex, and weight of the individual, and like factors as well as the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compounds of the present application (e.g., a compound of Formula (I) or any subformula thereof) are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, this amount will be less than the therapeutically effective amounts since the prophylactic dose is used before or at the early stages of disease in the subject.

[0206] For example, a therapeutically effective amount of a compound of Formula (I) or any subformula thereof can be about 1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg, about 35 mg / kg to about 650 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0207] The pharmaceutical compositions and formulations can include a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as, but not limited to, propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can be desirable. In addition, when desired, desiccants can be used.

[0208] Accordingly, the compounds and physiologically acceptable salts thereof can be formulated for administration by, for example, solid dosage forms, eye drops, in topical oil-based formulations, injection, inhalation (through the mouth or nose), implant administration, or for oral, buccal, parenteral, or rectal administration. Techniques and formulations generally can be found in "Remington's Pharmaceutical Sciences," (Meade Publishing Co., Easton, Pa.). Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage.

[0209] The route and form of the composition in which the disclosed compounds are administered determines the type of carrier that is used. The composition can be in various forms such as, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant, or parenteral) or for topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery system, or iontophoresis).

[0210] Carriers for systemic administration typically include at least one of a diluent, a lubricant, a binder, a disintegrant, a colorant, a flavorant, a sweetener, an antioxidant, a preservative, a glidant, a solvent, a suspending agent, a wetting agent, a surfactant, combinations thereof, and the like. All carriers are optional in the composition.

[0211] Suitable diluents include sugars such as dextrose, lactose, dextrates, and sucrose; glycols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50% to about 90%.

[0212] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and coconut oil. The amount of lubricant(s) in a systemic or topical composition is typically about 5% to about 10%.

[0213] Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and celluloses and their derivatives such as sodium carboxymethylcellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5% to about 50%.

[0214] Suitable disintegrants include agar-agar, alginic acid and its sodium salt, effervescent mixtures, crosscarmellose, crospovidone, sodium starch glycolate, starch, sodium starch glycolate, hydroxypropyl starch, clay, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1% to about 10%.

[0215] Suitable coloring agents include coloring agents such as FD&C dyes. When used, the amount of coloring agent(s) in a systemic or topical composition is typically about 0.005% to about 0.1%.

[0216] Suitable flavoring agents include menthol, peppermint, and fruit flavors. When used, the amount of flavoring agent(s) in a systemic or topical composition is typically about 0.1% to about 1.0%.

[0217] Suitable sweetening agents include aspartame and saccharin. The amount of sweetening agent(s) in a systemic or topical composition is typically about 0.001% to about 1%.

[0218] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1% to about 5%.

[0219] Suitable preservatives include benzalkonium chloride, methyl paraben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01% to about 5%.

[0220] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically from about 1% to about 5%.

[0221] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohols such as ethanol, and phosphate buffered solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0% to about 100%.

[0222] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation, Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically from about 1% to about 8%.

[0223] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, as well as TWEENS (from Atlas Powder Company, Wilmington, DE). Suitable surfactants include those described in C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in a systemic or topical composition is typically from about 0.1% to about 5%.

[0224] While the amount of components in a systemic composition can vary depending on the type of systemic composition being prepared, generally, a systemic composition includes from 0.01% to 50% of an active compound (e.g., a compound of Formula (I) or any subformula thereof) and from 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include from 0.1% to 10% of an active and from 90% to 99.9% of a carrier, including diluents and solvents.

[0225] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount (typically at least about 5%, more particularly from about 25% to about 50%) of the active ingredient. Oral dosage compositions include from about 50% to about 95% of a carrier, and more particularly, from about 50% to about 75%.

[0226] Tablets can be compressed, tablet triturates, enteric coated, sugar coated, film coated, or multiple compressed. Tablets typically include the active ingredient and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, coloring agents, flavoring agents, sweetening agents, glidants, and combinations thereof. In particular, diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. In particular, binders include starch, gelatin, and sucrose. In particular, disintegrants include alginic acid and crosscarmellose. In particular, lubricants include magnesium stearate, stearic acid, and talc. In particular, coloring agents are FD&C dyes which can be added for appearance. Chewing tablets preferably contain a sweetening agent (e.g., aspartame and saccharin), or a flavoring agent (e.g., menthol, peppermint, fruit flavors), or combinations thereof.

[0227] Capsules (including implants, timed release and sustained release formulations) typically include the active compound (e.g., a compound of Formula (I) or any subformula thereof) and a carrier comprising one or more diluents disclosed above in the capsules comprising gelatin. Granules typically contain the disclosed compound, preferably a glidant (e.g., silicon dioxide) to improve flow properties. Implants can be of the biodegradable or non-biodegradable type.

[0228] The choice of ingredients in the carrier for oral compositions depends on secondary considerations, such as taste, cost, and shelf stability, which do not materially affect the efficacy of the application.

[0229] Solid compositions can be coated by conventional methods (typically with pH or time dependent coatings) such that the disclosed compound is released in the gastrointestinal tract near the desired administration, or at different points and times, to prolong the desired action. Coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes, and shellac.

[0230] Compositions for oral administration can have a liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent formulations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid compositions for oral administration typically include the disclosed compound and a carrier, i.e., a carrier selected from diluents, coloring agents, flavoring agents, sweetening agents, preservatives, solvents, suspending agents, and surface active agents. Liquid compositions for oral administration preferably include one or more ingredients selected from coloring agents, flavoring agents, and sweetening agents.

[0231] Other compositions for achieving systemic delivery of the subject compounds include sublingual, buccal, and nasal dosage forms. Such compositions typically include one or more soluble filler substances, such as diluents, including sucrose, sorbitol, and mannitol; and binders, such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. Such compositions can further include lubricants, colorants, flavorants, sweeteners, antioxidants, and glidants.

[0232] The disclosed compounds can be administered topically. Topical compositions that can be topically administered to the skin can be in any form including a solid, a solution, an oil, a cream, an ointment, a gel, a lotion, a shampoo, a leave-in and rinse-off hair conditioner, a milk, a cleanser, a moisturizer, a spray, a skin patch, and the like. The topical composition includes a disclosed compound (e.g., a compound of Formula (I) or any subformula thereof) and a carrier. The carrier of the topical composition preferably aids in penetration of the compound into the skin. The carrier can further include one or more optional components.

[0233] The amount of carrier used in combination with the disclosed compounds is sufficient to provide the actual amount of the composition administered per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of the present application are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, Eds., (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Edition, (1976).

[0234] The carrier can include a single ingredient or a combination of two or more ingredients. In the topical composition, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from the group consisting of: phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol, symmetrical alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, the carrier for skin administration includes propylene glycol, dimethyl isosorbide, and water, even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol, and symmetrical alcohol.

[0235] The carrier of the topical composition can further include one or more ingredients selected from the group consisting of: emollients, propellants, solvents, humectants, thickening agents, powders, fragrances, pigments, and preservatives, all of which are optional.

[0236] Suitable emollients include stearyl alcohol, glycerol monoricinoleate, glycerol monostearate, propane- 1,2-diol, butane- 1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Particular emollients for use on skin include stearyl alcohol and dimethicone. The amount of emollient(s) in a skin-based topical composition is typically from about 5% to about 95%.

[0237] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically from about 0% to about 95%.

[0238] Suitable solvents include water, ethanol, dichloromethane, isopropyl alcohol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Particular solvents include ethanol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically from about 0% to about 95%.

[0239] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. A particular humectant includes glycerin. The amount of humectant(s) in a topical composition is typically from 0% to 95%.

[0240] The amount of thickening agent(s) in a topical composition is typically from about 0% to about 95%.

[0241] Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, whiting, talc, fullers earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectites, trialkylaryl ammonium smectites, chemically modified magnesium aluminum silicate, organically modified smectite clay, hydrated aluminum silicate, fumed silicon dioxide, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically from 0% to 95%.

[0242] The amount of perfume in the topical composition is typically from about 0% to about 0.5%, specifically, from about 0.001% to about 0.1%.

[0243] Suitable pH adjusting additives include HC1 or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0244] 4. Methods of use The disclosed compounds, pharmaceutical compositions, and formulations can be used in methods of treating CNS disorders, such as familial / genetic and / or sporadic Parkinson’s disease, tauopathies, or Alzheimer’s disease. The disclosed compounds and pharmaceutical compositions can also be used in methods of reducing LRRK2, including the G2019S mutant of LRRK2, activity in a mammal. These methods also include cotherapeutic methods for improving treatment outcomes. In the methods of use described herein, additional therapeutic agents can be administered simultaneously, separately, or sequentially with the disclosed compounds and compositions.

[0245] a. Treating a disorder The disclosed compounds, pharmaceutical compositions, and formulations can be used in methods of treating, preventing, ameliorating, controlling, reducing, or reducing the risk of a variety of diseases or disorders or symptoms of a disease or disorder, wherein the patient would benefit from inhibition of LRRK2. Diseases or disorders in which the patient would benefit from inhibition of LRRK2 can include CNS disorders, such as familial / genetic and / or sporadic Parkinson’s disease, tauopathies, and Alzheimer’s disease. The methods can include administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (I) or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or any subformulae thereof, or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the disclosure provides methods of treating CNS disorders, such as familial / genetic and / or sporadic Parkinson’s disease, tauopathies, and Alzheimer’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or any subformulae thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or any subformulae thereof, or a pharmaceutically acceptable salt thereof.

[0247] LRRK2 pathogenic mutations are associated with certain aspects of Parkinson's disease, including dopaminergic neuronal cell death, impaired dopamine neurotransmission and motor activity, defects in protein synthesis and degradation, inflammatory responses, and oxidative damage (BMB Rep [BMB Reports] May 2015; 48(5):243-8). Treatment of Parkinson's disease can include: treating the neurological damage associated with Parkinson's disease; or treating or improving dopaminergic tone to provide symptomatic relief (e.g., treating, alleviating, ameliorating, or controlling the motor and non-motor symptoms of Parkinson's disease). Motor symptoms of Parkinson's disease include bradykinesia, rigidity, and resting tremor. Non-motor symptoms include cognitive dysfunction, autonomic dysfunction, emotional changes, and sleep interruption.

[0248] Additional diseases or conditions that patients can benefit from inhibition of LRRK2 include Alzheimer's disease, mild cognitive impairment, transition from mild cognitive impairment to Alzheimer's disease, and tauopathies characterized by hyperphosphorylation of tau.

[0249] Tauopathies are neurodegenerative diseases characterized by abnormal tau protein deposits in the brain, including conditions characterized by hyperphosphorylation of tau, such as argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia, and Parkinson's disease linked to chromosome 17.

[0250] Additional diseases or conditions that patients can benefit from inhibition of LRRK2 include neuroinflammation, including neuroinflammation associated with microglial inflammatory responses associated with multiple sclerosis, HIV-induced dementia, ALS, ischemic stroke, traumatic brain injury, and spinal cord injury.

[0251] Additional diseases or conditions that patients can benefit from inhibition of LRRK2 include diseases of the immune system, including lymphoma, leukemia, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disease, type I diabetes, Sjogren's syndrome, Delvecchio's disease, inflammatory myopathy, and ankylosing spondylitis.

[0252] Additional diseases or conditions that patients can benefit from inhibition of LRRK2 include kidney cancer, breast cancer, lung cancer, prostate cancer, and acute myeloid leukemia (AML) in subjects expressing the LRRK2 G2019S mutation.

[0253] Additional diseases or conditions that patients can benefit from inhibition of LRRK2 include papillary renal carcinoma and thyroid cancer in subjects with LRRK2 amplification or overexpression.

[0254] Another disease or condition for which a patient can benefit from inhibition of LRRK2 is low grade glioma.

[0255] Another disease or condition for which a patient can benefit from inhibition of LRRK2 includes chronic autoimmune diseases, including Crohn's disease and leprosy.

[0256] The compounds and compositions can further be used in a method for preventing, treating, controlling, ameliorating, or reducing the risk of the diseases, disorders, and conditions described herein. The compounds and compositions can further be used in combination with other agents in a method for preventing, treating, controlling, ameliorating, or reducing the risk of the diseases, disorders, and conditions described above.

[0257] In the treatment of conditions such as would benefit from inhibition of LRRK2, a suitable dosage level is about 0.01 to 500 mg / kg patient body weight per day which could be administered in single or multiple doses. Dosage levels can be about 0.1 to about 250 mg / kg per day, or about 0.5 to about 100 mg / kg per day. A suitable dosage level can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions can be provided in the form of tablets containing 1.0 to 1000 milligrams, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. The dosing regimen can be adjusted to provide

[0258] Accordingly, in some embodiments, the disclosure relates to a method of inhibiting LRRK2 in at least one cell, the method comprising the step of contacting the at least one cell with at least one disclosed compound or at least one product of a disclosed method, in an amount effective to inhibit LRRK2 in the at least one cell. In some embodiments, the cell is mammalian, e.g., human. In some embodiments, the cell has been isolated from a subject prior to the contacting step. In some embodiments, the contacting is by administration to a subject.

[0259] In some embodiments, the disclosure relates to a method for inhibiting LRRK2 in a subject, the method comprising the step of administering to the subject at least one disclosed compound or at least one product of a disclosed method, in a dosage and amount effective to inhibit LRRK2 in the subject. In some embodiments, the subject is mammalian, e.g., human. In some embodiments, the mammal has been diagnosed as needing LRRK2 inhibition prior to the administering step. In some embodiments, the mammal has been diagnosed as needing LRRK2 inhibition prior to the administering step. In some embodiments, the method further comprises the step of identifying a subject in need of LRRK2 inhibition.

[0260] b. Inhibition of LRRK2 In some embodiments, the disclosure relates to a method for inhibiting LRRK2 in a mammal, the method comprising the step of administering to the mammal an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, the disclosure relates to a method for inhibiting G2019S mutant LRRK2 in a mammal, the method comprising the step of administering to the mammal an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the compound is administered at an IC 50 Inhibiting LRRK2 or G2019S mutant. In some embodiments, the compound is administered at an IC 50 Inhibiting LRRK2 or G2019S mutant.

[0263] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed as needing to reduce LRRK2 or G2019S mutant activity prior to the administering step. In some embodiments, the method further comprises the step of identifying a mammal in need of reducing LRRK2 or G2019S mutant activity. In some embodiments, the inhibition of LRRK2 or G2019S mutant treats a disorder associated with LRRK2 activity in the mammal.

[0264] In some embodiments, the inhibition of LRRK2 in the mammal is associated with treating a disorder associated with the G2019S mutant of LRRK2 (e.g., a disorder disclosed herein).

[0265] In some embodiments, the disclosure provides a method of inhibiting LRRK2 or G2019S mutant in a cell, the method comprising the step of contacting the cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is of a mammal (e.g., a human). In some embodiments, the cell has been isolated from a mammal prior to the contacting step. In some embodiments, the contacting is via administration to the mammal.

[0266] c. Combination therapy The disclosed compounds can be used in the treatment, prevention, control, amelioration, or reduction of risk of the above diseases, disorders and conditions for which compounds of Formula I or other drugs are useful, as a sole agent or in combination with one or more other drugs.

[0267] In one aspect, the compounds can be co-administered with anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, muscarinic agonists, muscarinic potentiators, HMG-CoA reductase inhibitors, NSAIDs, and anti-amyloid antibodies. In another aspect, the compounds can be co-administered with tranquilizers, hypnotics, anti-anxiety agents, antipsychotic agents, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), 5-HT2 antagonists, GlyTl inhibitors, and the like (e.g., but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbital, and salts thereof), and combinations thereof. In another aspect, the subject compounds can be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor), anticholinergics such as biperiden and M4 selective antagonists, COMT inhibitors such as entacapone, A2a adenosine antagonists, cholinergic agonists, NMDA receptor antagonists, and dopamine agonists.

[0268] In some embodiments, the compounds of the application can be used in combination with other agents to increase their efficacy and / or safety. The compounds can be administered in combination with, but not limited to, alpha-synuclein fibrillogenesis and / or aggregation inhibitors, MAO-B inhibitors (e.g., Rasagiline, Selegiline), antiemetics, L-DOPA, dopamine agonists (e.g., Rotigotine, Lisuride, Pramipexole), agents that increase extracellular dopamine levels (e.g., amphetamines, methylphenidate, or lisdexamfetamine), nicotinic receptor agonists (e.g., amantadine), dopaminergic agonists (e.g., Cabergoline, Ropinirole, Quinpirole, Ropinirole, Pramipexole, Pergolide, and Bromocriptine), DOPA decarboxylase inhibitors (e.g., Carbidopa and Benserazide), COMT inhibitors (e.g., Tolcapone and Entacapone), adenosine A2a antagonist co-administration, mGlu4 modulators, mGlu5 modulators, or growth factors (e.g., brain-derived neurotrophic factor (BDNF)).

[0269] In other embodiments, the compounds can be used in combination with other therapies including, but not limited to, glycoprotein Ilb / IIIa receptor inhibitors, ion channel blockers (e.g., calcium channel blockers), beta blockers, cyclooxygenase inhibitors, agents that improve lung and / or kidney function, angiotensin system inhibitors (e.g., angiotensin converting enzyme inhibitors), renin inhibitors, PARP inhibitors, Src inhibitors, cardiovascular disease related agents, anti-hypertensive agents, hypercholesterolemia and type II diabetes related agents, anti-inflammatory agents, anti-thrombotic agents, fibrinolytic agents, anti-platelet agents, lipid lowering agents, thrombin inhibitors, apoptosis inhibitors, and / or agents that bind to cell adhesion molecules and prevent leukocyte attachment thereto (e.g., polypeptides, polyclonal and monoclonal antibodies).

[0270] In the methods of use described herein, the additional therapeutic agent(s) can be administered simultaneously, separately or sequentially with the disclosed compounds and compositions. Sequential administration encompasses administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent(s) can be administered in the same composition as the disclosed compounds. In other embodiments, there can be a time interval between administration of the additional therapeutic agent(s) and the disclosed compounds. In some embodiments, administration of the additional therapeutic agent(s) with the disclosed compounds can allow for lower dosages and / or less frequent intervals of administration of the other therapeutic agent(s). When used in combination with one or more other active ingredients, the compounds of the present application, as well as the other active ingredients, can be used within the range of doses that are commonly used in each of these active ingredients. Thus, the pharmaceutical compositions of the present application include those that contain one or more other active ingredients, in addition to a compound having the formula (I) or any subformula thereof. The combinations referred to above include not only the combination of a compound of the present application with one other active compound, but also the combination of a compound of the present application with two or more other active compounds.

[0271] The disclosed compounds can be used in the treatment, prevention, control, amelioration, or reduction of risk of the diseases, disorders, and conditions for which the disclosed compounds or other drugs are useful, as described above, either as sole active agent or in combination with one or more other drugs. The drug combination can be administered together in one unit dosage form, or separately. When administered separately, the compounds of the present application and the other drugs can be administered at essentially the same time or at different times. When the disclosed compounds and one or more other drugs are administered at different times, they can be administered in any sequence. The disclosed compounds and other drugs can be administered in the same composition or separately. When administered separately, the disclosed compounds and other drugs can be administered by the same or different routes of administration and in the same or different dosage forms. The disclosed compounds and other drugs can be administered by the same or different routes of administration. The disclosed compounds and other drugs can be administered in the same or different dosage forms. The disclosed compounds and other drugs can be administered by the same or different routes of administration and in the same or different dosage forms.

[0272] The pharmaceutical compositions and methods of the present application can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.

[0273] The combinations described above include not only combinations of the disclosed compounds with one other active compound, but also combinations with two or more other active compounds. Similarly, the disclosed compounds can be combined with other pharmaceuticals for the prevention, treatment, control, improvement of diseases or conditions for which the disclosed compounds can be used, or reduction of the risk of such diseases or conditions. Such other pharmaceuticals may be administered simultaneously or sequentially with the compounds of the present invention via a route and in amounts typically used. When the compounds of the present invention are used simultaneously with one or more other pharmaceuticals, pharmaceutical compositions containing these other pharmaceuticals besides the disclosed compounds are preferred. Accordingly, pharmaceutical compositions include those containing one or more other active ingredients in addition to the compounds of the present invention.

[0274] The weight ratio of the disclosed compound to the second active ingredient can vary and will depend on the effective dosage of each ingredient. Typically, the effective dosage of each ingredient will be used. Therefore, for example, when the compound of the present invention is combined with another pharmaceutical agent, the weight ratio of the disclosed compound to that other pharmaceutical agent will generally be in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of the compound of the present invention with other active ingredients will also generally be within the above range, but in each case, the effective dosage of each active ingredient should be used.

[0275] In such combinations, the disclosed compounds and other active agents can be administered alone or in combination. Furthermore, the administration of one element can be performed before, simultaneously with, or subsequently of one or more other agents.

[0276] Therefore, the disclosed compound may be used alone or in combination with other agents known to be beneficial in the subject's indication or with other drugs that affect receptors or enzymes, which may increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compound. The subject compound and other agents may be administered together as concomitant therapy or in a fixed combination.

[0277] d. Application method The methods of treatment can include any number of ways of administering the disclosed compositions. The modes of administration can include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions (e.g., oil-in-water emulsions), liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. To prepare a pharmaceutical composition for oral administration, the agent can be mixed with the commonly known and used adjuvants and excipients, such as gum arabic, talc, starch, sugars (e.g., mannitol, methylcellulose, lactose), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, preservatives, flavorings (e.g., ether oil), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g., Gelucire™). In the pharmaceutical composition, the agent can also be dispersed in microparticles (e.g., nanoparticulate compositions).

[0278] For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as water, buffer, oil, with or without a solubilizing agent, surfactant, dispersant or emulsifier. As oils, for example but not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil can be used. More generally, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily or other type of solution or suspension, and can even be administered in the form of liposomes or nanosuspensions.

[0279] As used herein, the term "parenteral" refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

[0280] 5. Kit In an aspect, the disclosure provides a kit comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, and instructions for use thereof.

[0281] In some embodiments, the at least one disclosed compound and the at least one agent are co-formulated. In some embodiments, the at least one disclosed compound and the at least one agent are co-packaged. The kit can also comprise compounds and / or products co-packaged, co-formulated and / or co-delivered with other components. For example, a pharmaceutical manufacturer, a pharmaceutical distributor, a physician, a compounding shop or a pharmacist can provide a kit comprising a disclosed compound and / or product for delivery to a patient and another component.

[0282] The kit can include information, instructions, or both, that the kit is to be used to provide treatment for a medical condition in a mammal, particularly a human. The information and instructions can be in the form of text, pictures, or both, or the like. Additionally or alternatively, the kit can contain a compound, a composition, or both; and information, instructions, or both, regarding the method of use of the compound or composition, preferably with a benefit of treating or preventing a medical condition in a mammal, e.g., a human.

[0283] 6. Examples All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer. 1 H chemical shifts are reported as delta values in ppm downfield from TMS with deuterated solvent as internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, integration. Reverse phase LCMS analysis was performed using the following parameters using an Agilent 1200 system consisting of a binary pump with degasser, high performance autosampler, thermostatted column compartment, C18 column, diode array detector (DAD) and Agilent 6150 MSD. The gradient conditions were 5% to 95% acetonitrile over 1.4 minutes with the aqueous phase being 0.1% TFA in water. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 µm, 1.0 x 50 mm) at 0.5 mL / min with the column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 nm to 300 nm and the signals used were 220 nm and 254 nm (both with a bandwidth of 4 nm). The MS detector was configured with an electrospray ionisation source and low resolution mass spectra were obtained by scanning from 140 to 700 AMU (step size of 0.2 AMU at 0.13 weeks / second, peak width of 0.008 minutes). The dry gas flow was set to 13 litres per minute at 300 °C and the nebuliser pressure was set to 30 psi. The capillary needle voltage was set to 3000 V and the fragmentation voltage was set to 100 V. Data collection was performed using Agilent Chemstation and Analytical Studio Reviewer software.

[0284] Abbreviations: AcOH is acetic acid; aq is aqueous solution; BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc is tert-butyloxycarbonyl; BrettPhos-Pd-G3 is [(2-Dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS No. 1470372-59-8); tBuOH is tert-butanol; B2Pin2 is bis(pinacolato)diboron; Celite® is diatomaceous earth; DCE is 1,2-dichloroethane; DCM is dichloromethane; DIAD is diisopropyl azodicarboxylate; DIPEA is N,N - diisopropylethylamine; DMAP is 4-dimethylaminopyridine; DMF is N , N - dimethylformamide; DMSO is dimethyl sulfoxide; eq, eq., or equiv is equivalent; Et20 is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; Et3N is triethylamine; HATU is 2-(7-aza-1 H - benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HOBt is hydroxybenzotriazole; h or h. is hour(s); hex is hexane; IPA is isopropyl alcohol; LCMS is liquid chromatography mass spectrometry; LiAlD4 is lithium aluminum deuteride; LiAlH(OtBu)3 is lithium tri-t-butoxyaluminum hydride; LiHMDS is lithium bis(trimethylsilyl)amide; m-CPBA is meta-chloroperoxybenzoic acid; MeCN is acetonitrile; MeMgBr is methylmagnesium bromide; MeOH is methanol; MeOD is deuterated methanol; min or min. is minute(s); MTBE is methyl tert-butyl ether; NaBH(OAc)3 is sodium triacetoxyborohydride (i.e., STAB); NMP is N-methyl-2-pyrrolidone; Pd(OAc)2 is palladium(II) acetate; Pd(dppf)Cl2 is [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PPh3 is triphenylphosphine; RP-HPLC is reverse phase-high performance liquid chromatography; RuPhos-Pd-G3 is (2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’- biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate (CAS number 1445085-77-7); rt, RT, or r.t. is room temperature; sat. is saturated; SFC is supercritical fluid chromatography; soln. is solution; TESCl is triethylsilyl chloride; TFA is trifluoroacetic acid; THF is tetrahydrofuran; tosyl is tosyl;

[0285] b. Preparation of intermediates Intermediate Example 1. 6-Bromo-5-methyl-1-(1-methyl-1 H -pyrazol-4-yl)-1 H -indazole The title compound was synthesized similarly to previously described in WO 2020 / 092136. To a solution of 6-bromo-5-methyl-1 H -indazole (500 mg, 2.37 mmol, 1 eq), 1-methyl-4-iodopyrazole (739 mg, 3.55 mmol, 1.5 eq) in DMSO (5 mL) was added rel , trans )- N , N'-Dimethylcyclohexane-1,2-diamine (0.19 mL, 1.18 mmol, 0.5 eq), CuI (90 mg, 0.47 mmol, 0.2 eq), and K3PO4 (1530 mg, 7.11 mmol, 3 eq). The resulting mixture was stirred at 90 °C under N2 for 5 h, cooled to rt, and diluted with H2O (5 mL). The organics were then extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give a crude residue. The crude residue was purified by rapid silica chromatography (0-100% EtOAc, in hexane) to provide the title compound (637 mg, 92%). LCMS ES-MS [M+H] + = 291 and 293.

[0286] Intermediate example 2. (3a) R ,6a S )-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,4,6a-tetrahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-Formic acid ( rac )- tert-butyl ester Step A. (3a) R ,6a R )-5-(((trifluoromethyl)sulfonyl)oxy)-3,3a,4,6a-tetrahydrocyclopentadienyl[ c ]Pyrrole-2(1 H )-Formic acid ( rac )- tert-butyl Ester. At -78°C under N2, towards (3a) R ,6a S )-5-oxohexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-Formic acid tert-butyl LiHMDS (1.0 M, in THF, 4.9 mL, 4.9 mmol, 1.1 eq) was added dropwise to a solution of ester (1000 mg, 4.4 mmol, 1 eq) in 12 mL of THF. The reaction mixture was then stirred at -78 °C for 20 min, after which LiHMDS was added dropwise. N- phenyl trifluoromethanesulfonimide (1665 mg, 4.7 mmol, 1.05 eq) in THF (12 mL). The reaction mixture was then gradually warmed to 0 °C and stirred at 0 °C for 3 h. Upon completion, the reaction mixture was quenched with saturated aqueous NH4Cl (10 mL). The resulting mixture was then extracted with DCM (3 x 100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified using flash silica chromatography (0-100% EtOAc in hexanes) to provide the title compound (613.2 mg, 38%). LCMS ES-MS [M+2H-tBu] + = 302.

[0287] Step B. (3a R ,6a S )-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,4,6a- tetrahydrocyclopenta[ c ]pyrrol-2(1 H )-carboxylic acid ( rac - tert-butyl ester. To a mixture of (3a R ,6a R )-5-(((trifluoromethyl)sulfonyl)oxy)-3,3a,4,6a- tetrahydrocyclopenta[ c ]pyrrol-2(1 H )-carboxylic acid ( rac - tert-butyl ester (613.2 mg, 1.72 mmol, 1 eq), bis(pinacolato)diboron (523 mg, 2.06 mmol, 1.2 eq), KOAc (539 mg, 5.49 mmol, 3.2 eq), and Pd(dppf)Cl2-DCM (140 mg, 0.17 mmol, 0.1 eq) was added 1,4-dioxane (10 mL). The resulting mixture was purged with N2and stirred at 90 °C overnight. The reaction was then filtered through a pad of Celite® and concentrated to provide a crude mixture of the title compound which was used without purification in the next step (575 mg, assumed theoretical yield). LCMS ES-MS [M+2H-tBu] + = 280.

[0288] Intermediate Example 3. 5-methyl-1-(1-methyl-1 H - pyrazol-4-yl)-6-((3a R ,5 s ,6a S)-Octahhydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole and 5-methyl-1-(1-methyl-1 H -pyrazole-4-yl)-6-((3a) R 5 r ,6a S )-Octahhydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole Step A. (3a) R ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -indazole-6-yl)-3,3a,4,6a-tetrahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-Formic acid ( rac )- tert-butyl Ester. To (3a) R ,6a S )-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,3a,4,6a-tetrahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-Formic acid ( rac )- tert-butyl The ester (575 mg, 1.72 mmol, 1 eq) was added to a solution of 6-bromo-5-methyl-1-(1-methylpyrazol-4-yl)indazole (506 mg, 1.74 mmol, 1 eq), Pd(dppf)Cl2-DCM (142 mg, 0.17 mmol, 0.1 eq), K2CO3 (731 mg, 5.22 mmol, 3 eq), and H2O (1.5 mL) in 1,4-dioxane (7.5 mL). The resulting mixture was then stirred overnight at 100 °C, cooled to rt, diluted with EtOAc (10 mL), filtered through a Celite® pad, washed with EtOAc, and concentrated under reduced pressure. The crude residue was purified by rapid silica chromatography (0-100% EtOAc, in hexane) to provide the title compound (441.2 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.82 (s,1H), 7.74 (s, 1H), 7.52 (s, 1H), 7.28 (s, 1H), 5.65 (s, 1H), 3.99 (s, 3H), 3.72 (m, 1H), 3.61 – 3.43 (m, 3H), 3.18 (m, 1H), 2.99 (m, 2H), 2.51 (d, J =14.0 Hz, 1H), 2.41 (s, 3H), 1.46 (s, 9H); LCMS ES-MS [M+H] + = 420.

[0289] Step B. rac )-6-((3a R ,6a S )-1,2,3,3a,4,6a-hexahydrocyclopentadiene[ c ]pyrrolo-5-yl)-5-methyl-1-(1-methyl-1 H -pyrazole-4-yl)-1 H -Indazole. (3a) R ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -indazole-6-yl)-3,3a,4,6a-tetrahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-Formic acid ( rac )- tert-butyl The ester (506.4 mg, 1.21 mmol, 1 eq) was dissolved in DCM (4 mL), followed by the addition of TFA (2.3 mL, 30.2 mmol, 25 eq). The reaction was stirred at rt for 6 h, diluted with H2O (3 mL) and DCM (20 mL), and neutralized with K2CO3. The organics were then extracted with a 3:1 CHCl3:IPA mixture (3 x 20 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was used for the next step without further purification (385.5 mg, assuming theoretical yield). 1 H NMR (400 MHz, MeOD) δ8.07 (s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.61 (s, 1H), 7.45 (s, 1H), 5.70(q,J = 2.1 Hz, 1H), 3.99 (s, 3H), 3.80 (tp, J = 7.7, 2.4 Hz, 1H), 3.52 (dd, J =11.5, 8.1 Hz, 1H), 3.44 (dd, J = 11.8, 7.7 Hz, 1H), 3.37 – 3.32 (m, 1H), 3.29 –3.13 (m, 3H), 2.70 – 2.63 (m, 1H), 2.45 (s, 3H);LCMS ES-MS [M+H] + = 320.

[0290] Step C. 5-Methyl-l-(l-methyl-l H - pyrazol-4-yl)-6-((3a R ,5 s ,6a S )- octahydrocyclopenta[ c ]pyrrol-5-yl)-l H - indazole and 5-methyl-l-(l-methyl-l H - pyrazol-4-yl)-6-((3a R ,5 r ,6a S )- octahydrocyclopenta[ c ]pyrrol-5-yl)-l H - indazole. To a solution of 5-methyl-l-(l-methyl-l rac )-6-((3a R ,6a S )- 1,2,3,3a,4,6a-hexahydrocyclopenta[ c ]pyrrol-5-yl)-5-methyl-l-(l-methyl-l H - pyrazol-4-yl)-l H - indazole (375.1 mg, 1.17 mmol, 1 eq) in EtOH (20 mL) and 1,4-dioxane (3 mL) was added 10% Pd / C (125 mg, 0.12 mmol, 0.1 eq) and 20% Pd(OH)2 / C (82.5 mg, 0.12 mmol, 0.1 eq). The reaction was charged with H2(50 psi) and stirred in a Parr shaker at 50 °C for 2 days. The reaction mixture was then filtered and concentrated under reduced pressure to provide the title compound (377 mg, 99%). The crude product was used for the next step without further purification. LCMS ES-MS [M+H]+ = 322; [M+H] + = 322.

[0291] d. Preparation of representative compounds Example 1. 4-((3a) R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide and 4-((3a) R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide (compounds 7 and 8) To 5-methyl-1-(1-methyl-1 H -pyrazole-4-yl)-6-((3a) R 5 s ,6a S )-Octahhydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole and 5-methyl-1-(1-methyl-1 H -pyrazole-4-yl)-6-((3a) R 5 r ,6a S )-Octahhydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole (total 20 mg, 0.06 mmol, 1 eq) was added to a solution of THF (0.5 mL). N , N -Diisopropylethylamine (16 µL, 0.09 mmol, 1.5 eq), followed by the addition of tetrahydro-4 H1,1-dioxide of thiaran-4-one (18.4 mg, 0.12 mmol, 2 eq). The reaction mixture was stirred at 50 °C for 10 min. Then NaBH(OAc)3 (40 mg, 0.19 mmol, 3 eq) was added and the reaction was stirred at 50 °C for 6 h. The reaction mixture was then quenched with MeOH (1 mL) and concentrated under reduced pressure. The crude residue was purified by reversed-phase HPLC (8%-95% CH3CN in H2O containing 0.05% NH4OH) to give the title compound: 4-((3a R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H 1,1-Thiaran dioxide (4.8 mg, 17%) LC-MS / ES-MS [M+H] + = 454 and 4-((3a) R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H 1,1-Thiaran dioxide (13.8 mg, 48%). LCMS ES-MS [M+H] + = 454.

[0292] Example 2. ( rac )-3-((3a R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide and ( rac )-3-((3a R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H- pyrazol-4-yl)-1 H - indazol-6-yl)hexahydrocyclopenta[ c ]pyrrol-2(1 H )-yl)tetrahydro-2 H - thiopyran 1,1-dioxide (Compound 15 and Compound 20) To a solution of 5-methyl-1-(1-methyl-1 H - pyrazol-4-yl)-6-((3a R ,5 s ,6a S )- octahydrocyclopenta[ c ]pyrrol-5-yl)-1 H - indazol and 5-methyl-1-(1-methyl-1 H - pyrazol-4-yl)-6-((3a R ,5 r ,6a S )- octahydrocyclopenta[ c ]pyrrol-5-yl)-1 H - indazol (50 mg, 0.156 mmol, 1 eq) in MeOH (1.37 mL) and acetic acid (137 µL) was added dihydro-2 H - thiopyran-3(4 H )-one 1,1-dioxide (69 mg, 0.47 mmol, 3 eq) followed by 2-methylpyridine borane complex (85.4 mg, 0.80 mmol, 5.1 eq). The reaction mixture was purged with N2and gradually heated to 60 °C until complete consumption of starting material (about 16 h). Upon completion, the crude residue was purified using reverse phase HPLC (5%-80% CH3CN in H2O with 0.05% NH4OH) to give the title compound: ( rac )-3-((3a R ,5 s ,6a S )-5-(5-methyl-1-(1-methyl-1 H - pyrazol-4-yl)-1 H - indazol-6-yl)hexahydrocyclopenta[ c ]pyrrol-2(1 H )-yl)tetrahydro-2 H - thiopyran 1,1-dioxide (10.2 mg, 14 %). 1 H NMR (400 MHz, MeOD) δ 8.07 (s,1H), 8.02 (d, J= 0.8 Hz, 1H), 7.82 (d, J = 0.5 Hz, 1H), 7.56 (s, 1H), 7.42 (s,1H), 3.99 (s, 3H), 3.59 – 3.48 (m, 1H), 3.36 (m, 1H), 3.14 – 2.98 (m, 5H),2.89 – 2.77 (m, 3H), 2.48 (s, 3H), 2.27 (ddd, J = 23.1, 9.2, 6.2 Hz, 2H), 2.22– 2.10 (m, 2H), 2.00 – 1.79 (m, 5H), 1.56 – 1.44 (m, 1H); LCMS ES-MS [M+H] + =454 and ( rac )-3-((3a R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H 1,1-Thiaran dioxide (29.8 mg, 42%) LCMS ES-MS [M+H] + = 454.

[0293] Example 3. (4-Methyl-1,2,3-thiadiazol-5-yl)((3a) R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-yl) methyl ketone and (4-methyl-1,2,3-thiadiazol-5-yl)((3a) R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-yl)methyl ketone (compounds 9 and 10) To 5-methyl-1-(1-methyl-1 H -pyrazole-4-yl)-6-((3a) R 5 s ,6a S )-Octahhydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole and 5-methyl-1-(1-methyl-1 H -pyrazole-4-yl)-6-((3a) R 5 r ,6a S )-Octahhydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole (total 20 mg, 0.06 mmol, 1 eq) was added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18 mg, 0.09 mmol, 1.5 eq), 4-methyl-1,2,3-thiadiazole-5-carboxylic acid (13.5 mg, 0.09 mmol, 1.5 eq), DMAP (3.8 mg, 0.03 mmol, 0.5 eq), and HOBt (4.2 mg, 0.03 mmol, 0.5 eq) in DMF (1 mL). The reaction mixture was then stirred at rt for 1.5 h. After completion, the reaction mixture was quenched with MeOH (1 mL) and concentrated. The crude residue was purified by reversed-phase HPLC (8%-95% CH3CN in H2O containing 0.05% NH4OH) to give the title compound: (4-methyl-1,2,3-thiadiazole-5-yl)((3a R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-methyl ketone (1.5 mg, 5%). LCMS ES-MS [M+H] + = 448 and (4-methyl-1,2,3-thiadiazol-5-yl)((3a) R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H)-yl) methanone (7.3 mg, 26%). LCMS ES-MS [M+H] + = 448.

[0294] The compounds shown in Table 1 can be prepared similarly to the above compounds using appropriate starting materials.

[0295] Table 1 Commercial starting materials

[0296] Biological activity Biochemical LRRK2 LanthaScreen assay.

[0297] In vitro LRRK2 wild-type (WT) and G2019S (GS) mutant enzyme activity was assessed for their ability to phosphorylate a peptide substrate using the LanthaScreen™ (Thermo Fisher) time-resolved fluorescence energy transfer (TR-FRET) kinase assay format. The kinase reaction consisted of purified human LRRK2 WT or GS enzyme, a fluorescein-labeled peptide substrate (LRRKtide), and ATP. Subsequently, the resulting phosphorylated LRRKtide was recognized by a terbium-labeled antibody that specifically binds only to the phosphorylated form of LRRKtide. This association results in an increase in the TR-FRET emission ratio of 520 nm / 495 nm. Specifically, when phosphorylated LRRKtide binds to the terbium (donor)-labeled antibody, the FRET signal measured with a 495 nm filter specific for terbium induces the fluorescein (acceptor) of the phosphorylated LRRKtide. This then results in a FRET emission signal measured with a 520 nm filter specific for fluorescein. Thus, an increase in the FRET ratio (520 / 495) is directly proportional to the activation of LRRK2 kinase activity.

[0298] The newly synthesized LRRK2 inhibitors were evaluated for their ability to block phosphorylation of a LRRK kinase substrate polypeptide substrate by both WT and GS mutant enzymes. The level of phosphorylation inhibition is directly proportional to the decrease in the FRET ratio. The 384-well assay format accommodates a total of 16 inhibitors in replicates in a single plate, and inhibitor activity is measured in both WT and GS mutant. Each assay plate also includes 3 reference controls; (1) a complete kinase activity control well containing 1% DMSO vehicle, (2) a maximum kinase inhibition control well containing 1 µM MLi-2, a known LRRK2 inhibitor, and (3) an enzyme-free control well as a measure of background levels, which should match the maximum enzyme inhibition level of the 1 µM MLi-2 control.

[0299] Inhibitors (1 mM stock solution in DMSO) were serially diluted 1 :4 into 11-point concentration response curves in DMSO using a Bravo liquid handler (Agilent). Using an Echo 650 acoustic liquid handler (Beckman Coulter), 100 nl of each solution was transferred into 384-well Lumitrac 200 assay plates (Greiner, #781075) to a 100 X transfer into a 10 µL kinase reaction volume per well. Thus, the final concentration range for the 11-point dose response curves of the inhibitors was 10 µM to 0.01 nM. For the complete enzyme control well and enzyme-free control well, 100 nL DMSO was added. For the maximum enzyme inhibition well, 100 nL of 0.1 mM MLi-2 was added.

[0300] Next, LRRK2 enzyme, substrate, and ATP were diluted 2X in IX kinase buffer (50 mM Tris, pH 8.5, 5 mM MgCl2, 1 mM EGTA, 0.01% BRIJ-35, 2 mM DTT). First, purified human LRRK2 enzyme was diluted to 6 nM (2X) in a 5 µL per well volume. After adding WT protein (Thermo Scientific, cat# PR8604B) and GS mutant protein (Thermo Scientific, cat# PR8764C) to separate assay plates containing inhibitors / DMSO, the plates were spun down at 100xg for 1 min, then placed on a shaker at 50 rpm to gently rock to incubate the enzyme with inhibitors / DMSO at 25 °C for 15 min. Kinase buffer (5 µL / well) was added to enzyme-free control wells alone. Second, LRRK kinase substrate peptide substrate (Thermo Scientific #PV4901) and ATP (Thermo Scientific #PV3227) were diluted to 2X (0.4 µM and 50 µM, respectively) in a 5 µL per well volume. After the 15 min enzyme incubation, 5 µL of LRRK kinase substrate peptide and ATP mix was added to the entire plate. The plates were spun down at 100xg for 1 min and covered with black caps to protect from light. The kinase reaction was allowed to proceed at 25 °C for 120 min with gentle rocking at 50 rpm.

[0301] A 2X TR-FRET detection / stop solution was prepared by adding 0.5 nM terbium-pLRRK kinase substrate peptide antibody (Thermo Scientific, #PV4899) and 20 mM EDTA (Thermo Scientific, #15575-020) to TR-FRET dilution buffer (Thermo Scientific, #PV3574). The kinase reaction was stopped immediately by adding 10 µL of 2X TR-FRET detection solution to the entire plate. The plates were spun down at 100xg for 1 min and covered with black caps to protect from light. The TR-FRET detection reaction was allowed to proceed at 25 °C for 30 min with gentle rocking at 50 rpm.

[0302] The TR-FRET signal was measured using an EnVision plate reader (Perkin Elmer) in two channels at 495 and 520 nm. The fluorescence ratio (520 / 495) with the full enzyme activity control with DMSO was converted to 100% enzyme activity and the maximum enzyme inhibition with 1 µM MLi-2 was converted to 0% activity. All ratio data were then normalized to % enzyme activity. Curve fitting and potency (IC 50). Selectivity of inhibitors is expressed as the WT / G2019S ratio, by dividing the IC 50 of G2019S 50 .

[0303] Cellular phospho-LRRK2 S935 HTRF assay.

[0304] Cellular LRRK2 kinase activity readout of WT and G2019S mutant is measured by measuring the level of phosphorylation at serine 935 of LRRK2. The cellular LRRK2 kinase activity of LRRK2 inhibitors is assessed in HEK293 cells stably expressing human LRRK2 WT or G2019S mutant using the homogeneous time-resolved fluorescence technique (HTRF). This method takes advantage of two antibodies, an europium-cryptate (donor) antibody and a d2-cryptate (acceptor) antibody, which specifically bind to the sum of phospho S935 of LRRK2, respectively. When the two fluorophores are in close proximity, i.e. upon kinase activation, a time-resolved fluorescence energy transfer (TR-FRET) occurs, in which the light source excites the europium donor, which in turn excites the d2 acceptor at 615 nm. This results in an emission at 665 nm, leading to an increase in the FRET ratio (665 / 615). Thus, the FRET ratio (665 / 615) is directly proportional to the LRRK2 kinase activity.

[0305] Human LRRK2 WT- or G2019S-HEK293 cells are cultured in DMEM medium containing 10% fetal bovine serum, 2 mM GlutaMax, 100 units / mL of antibiotic / antimycotic, and 0.4 mg / mL G418 in a 37 °C humidified incubator in the presence of 5% CO2. All cell culture reagents are purchased from Life Technologies and the phospho-LRRK2 S935 assay reagents are purchased from Perkin Elmer (#6FLRKPEH). Briefly, cells (5,000 cells / 20 μL / well) are prepared in plating medium (growth medium without G418) the day before the assay. Cells are plated onto white solid flat bottom 384-well cell plates (Greiner Bio-One, #78108) coated with poly-d-lysine (50 μg / mL) and incubated overnight at 37 °C in the presence of 5% CO2. Our 384-well assay plates can accommodate a total of 16 inhibitors as replicates in a single plate. Inhibitor activity is measured for WT and GS mutants in separate cell plates.

[0306] The next day, inhibitors (2 mM stock) were serially diluted 1 :3 into DMSO into an 11-point concentration response curve using a Bravo liquid handler (Agilent). Using an Echo acoustic liquid handler (Beckman Coulter), 600 nL of each solution was transferred into a 384-well compound plate. For full enzyme control and maximum enzyme inhibition wells, 600 nL of DMSO and 0.2 mM MLi-2 were transferred, respectively. A final 2X compound plate was prepared by adding 60 µL of plating media to each well. After the compound plate was gently shaken on a shaker for 1 min, 20 µL of each solution was added directly into the entire cell plate using the 384-tip of the Bravo liquid handler. The final concentration range for the 11-point dose response curve of inhibitors was 10 µM to 0.17 nM. Compounds were incubated for 2 hr in a 37 °C humidified incubator.

[0307] During the compound incubation period, 4X lysis buffer and 100X blocking buffer were diluted 1X with H2O. After 2 hr of incubation, treatment media was removed using an ELx405 microplate washer (Agilent) and 16 µL of lysis / blocking buffer was immediately added to each well of the entire plate. The plate was sealed with a plate sealer and placed on a shaker at 200 rpm for 30 min at room temperature.

[0308] During the lysis step, 1X antibody working solutions were prepared by diluting 40X Eu-cryptate antibody and d2-antibody in detection buffer. After the cell plate was spun at 100xg for 1 min, 4 µL of antibody solution was added to each well of the entire plate. The plate was sealed with a plate sealer and placed on a shaker at 200 rpm for 4 hr at room temperature.

[0309] TR-FRET signal was measured using an EnVision plate reader (PerkinElmer) in two channels at 615 and 665 nm. The fluorescence ratio (665 / 615) for the full enzyme activity control with DMSO was converted to 100% enzyme activity and the maximum enzyme inhibition with 1 µM MLi-2 was converted to 0% activity. All ratio data were then normalized to % enzyme activity. Curve fitting and potency (IC 50 ) of inhibitors were determined using GraphPad Prism (La Jolla, CA) by a four-parameter logistic equation. Selectivity of inhibitors is expressed as a WT / G2019S ratio by dividing the IC 50 of WT by the IC 50 of G2019S.

[0310] Table 2. LRRK2 Biochemical Activity Assay Numbering LRRK2 G2019S IC 50 (nM) LRRK2 WT IC 50 (nM) 1 142.1 113 2 5604 2293 3 160 716 4 30 526 5 19.3 287 6 2185 1861 7 3.5 79 8 1254 813 9 54.9 156 10 672 643 11 90 247 12 940 642 13 16 61 14 961 885 15 1 15 16 10 28 17 203 281 18 166 1528 19 1502 1224 20 1662 1940

[0311] Table 3. pS935 LRRK2 cellular activity assay Numbering LRRK2 G2019S IC 50 (nM) LRRK2 WT IC 50 (nM) 1 3626 7584 2 Inert Inert 3 2982 >10000 4 2963 >10000 5 876 >10000 6 >10000 Inert 7 122 7332 8 >10000 Inert 9 4893 8434 10 9136 Inert 11 2313 4339 12 8721 Inert 13 482 8732 14 5527 >10000 15 8.1 1490 16 108 1640 17 2202 >10000 18 4107 Inert 19 Inert Inert 20 >10000 Inert

[0312] It is to be understood that the foregoing detailed description and the accompanying examples are merely illustrative and that other embodiments will be apparent to those skilled in the art in view of this disclosure. The scope of the present application should not be limited by the above description and examples. Rather, the scope of the present application is limited only by the claims and their equivalents.

[0313] Various modifications and changes in the disclosed embodiments will occur to those skilled in the art. Such modifications and changes will be seen as falling within the scope of the present application, including but not limited to those related to the chemical structures, substituents, derivatives, intermediates, synthesis, compositions, formulations, or methods of use.

Claims

1. A compound having formula (I): Or its pharmaceutically acceptable salt, wherein: " "Represents a single or double bond; R 1 yes R 1a It is G 1 –L 1 –G 1 –C 2-4 Alkylene – OR A –C 2-4 Alkylene–NR A R B C 1-6 Alkyl, C 1-6 Fluoroalkyl or H; R A It is G 1 –L 1 –G 1 C 1-6 Alkyl, C 1-6 fluoroalkyl, C 3-6 cycloalkyl or –C 1-3 Alkylene-C 3-6 cycloalkyl; R B It is H, C 1-6 Alkyl, C 1-6 fluoroalkyl, C 3-6 cycloalkyl or –C 1-3 Alkylene-C 3-6 cycloalkyl; R 1b It is halogen, C 1-4 Alkyl, C 1-2 Fluoroalkyl, CN, C 3-4 cycloalkyl, –OC 1-3 Alkyl, –OC 1-2 Fluoroalkyl or H; R 1c It is H, halogen, C 1-4 Alkyl, C 1-2 Fluoroalkyl, CN, phenyl, C 3-4 cycloalkyl, –OR 1d or –N(R) 1d )2; R 1d Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively selected. 1d Together with these two Rs 1d The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; L 1 It is C 1-5 Alkylene or C 2-5 alkenyl; G 1 It is a 5- or 6-membered aromatic or partially unsaturated heterocycle containing a first nitrogen atom and optionally 1-2 other heteroatoms, which are independently nitrogen, oxygen, or sulfur, attached to an unsaturated carbon atom in the heterocycle, or G. 1 It is phenyl, G 1 The first substituent may be optionally substituted by a group consisting of: halogen, C 1-4 Alkyl, cyano, C 1-2 fluoroalkyl, oxo, –OR 10 –N(R) 10 )2、–C 1-3 Alkylene – OR 10 C 3-5 cycloalkyl and –C 1-3 alkylene–C 3-5 Cycloalkyl, and optionally further substituted by 1-2 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl, cyano and C 1-2 fluoroalkyl; R 10 Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively selected. 10 Together with these two Rs 10 The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; R 2 It is G 2 –L 2 –G 2 –L 3 –C 1-6 Alkyl, –C 2-6 alkylene–R 2a C 1-6 Alkyl, C 1-6 Fluoroalkyl or H; L 2 It is C 1-3 alkylene or L 3 ; L 3 It is C(O), SO2, S(O)(NH), C(O)NH or C(O)O; G 2 It is a 4- to 12-membered heterocyclic group, C 3-12 Carbocyclic, 5- to 12-membered heteroaryl or 6- to 12-membered aryl, wherein G 2 The first substituent may be optionally substituted by a group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-2 fluoroalkyl, G 2a Oxygenation, –OR 13 –N(R) 13 )2、–C 1-3 Alkylene – OR 13 –C 1-3 Alkylene–N(R) 13 )2、–C(O)N(R 13 )2、–C(O)OR 13 –SO2R 13 and S(O)(NH)R 13 Optionally further substituted with oxygen, and optionally further substituted with 1-3 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl and C 1-2 fluoroalkyl; G 2a It is C 3-4 cycloalkyl; R 13 Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively selected. 13 Together with these two Rs 13 The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; R 2a is –OR 14 , –N(R 14 )2, –SO2R 14 , S(O)(NH)R 14 , –NR 14 C(O)N(R 14 )2 or –NR 14 C(O)OR 14 ; R 14 Each time it appears, it is independently H or C. 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl or –C 1-3 Alkylene-C 3-4 cycloalkyl, wherein the two Rs may be alternatively selected. 14 Together with these two Rs 14 The attached nitrogen forms a 4- to 6-membered heterocycle, which is optionally substituted by 1-4 substituents independently selected from the group consisting of halogens and C. 1-4 alkyl; R 3 Each time it appears, it is independently either fluorine or carbon. 1-4 Alkyl; and n is 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a It is G 1 And G 1 It is a 5- to 6-membered aromatic heterocycle that is optionally substituted.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein G 1 The ring system of the optionally substituted 5- to 6-membered aromatic heterocycle contains 1-2 nitrogen atoms.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein G 1 The first substituent may be optionally substituted by a group consisting of: halogen, C 1-4 Alkyl, cyano, C 1-2 fluoroalkyl, –OR 10 C 3-5 cycloalkyl and –C 1-3 alkylene–C 3-5 Cycloalkyl, and further optionally substituted by 1-2 substituents independently selected from the group consisting of: halogens and C 1-4 alkyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1a It is G 1 And G 1 It is a 5- to 6-membered partially unsaturated heterocycle that is optionally substituted.

6. The compound of claim 1 or 5 or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- or 6-membered partially unsaturated heterocycle is 1,2-dihydropyridin-4-yl.

7. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein G 1 yes .

8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R 1b Is it halogen or C? 1-4 alkyl.

9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R 1c It's H.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R 2 It is G 2 .

11. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R 2 Yes –L 2 –G 2 .

12. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9 or 11, wherein L 2 It is C 1-3 Alkylene.

13. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9 or 11, wherein L 2 It is L 3 And L 3 It is C(O).

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 4- to 12-membered heterocyclic group that is optionally substituted.

15. The compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 4- to 12-membered heterocyclic group is a 4- to 8-membered heterocyclic group or an 8- to 10-membered fused bicyclic heterocyclic group, which contains 1-2 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur.

16. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein G 2 C is arbitrarily replaced 3-12 Carbon cyclic group.

17. The compound of any one of claims 1-13 or 16, or a pharmaceutically acceptable salt thereof, wherein G 2 The C that can be arbitrarily replaced at this location 3-12 The ring system of the carbon cyclic group is C 3-6 Cycloalkyl.

18. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 5 to 12 heteroaryl group that is optionally substituted.

19. The compound of any one of claims 1-13 or 18, or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 5 to 12-membered heteroaryl group is a 5 to 6-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur.

20. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 6 to 12 aryl group that is optionally substituted.

21. The compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof, wherein G 2 yes 。 22. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein n is 0.

23. The compound of any one of claims 1-22 or a pharmaceutically acceptable salt thereof, wherein R 1 yes .

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (II-C): 。 25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (III-C): 。 26. The compound of claim 1, wherein the compound is selected from the group consisting of: 6-((3a R ,6a S )-1,2,3,3a,4,6a-hexahydrocyclopentadiene[ c ]pyrrolo-5-yl)-5-methyl-1-(1-methyl-1 H -pyrazole-4-yl)-1 H -Indazole; (3a R ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -indazole-6-yl)-3,3a,4,6a-tetrahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-Formic acid tert-butyl ester; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R ,6a S )-2-(tetrahydro-2 H -pyran-4-yl)-1,2,3,3a,4,6a-hexahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 4-((3a R ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)-3,3a,4,6a-tetrahydrocyclopentadien[c]pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 s ,6a S )-2-(tetrahydro-2 H -pyran-4-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 r ,6a S )-2-(tetrahydro-2 H -pyran-4-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 4-((3a R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide; 4-((3a R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide; (4-Methyl-1,2,3-thiadiazol-5-yl)((3a) R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-methyl ketone; (4-Methyl-1,2,3-thiadiazol-5-yl)((3a) R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-methyl ketone; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 s ,6a S )-2-(tetrahydro-2 H -pyran-3-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 r ,6a S )-2-(tetrahydro-2 H -pyran-3-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 s ,6a S )-2-(tetrahydrofuran-3-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 r ,6a S )-2-(tetrahydrofuran-3-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 3-((3a R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 s ,6a S )-2-(oxacyclobut-3-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 5-Methyl-1-(1-methyl-1) H -pyrazole-4-yl)-6-((3a) R 5 r ,6a S )-2-(oxacyclobut-3-yl)octahydrocyclopentadiene[ c ]pyrrole-5-yl)-1 H -Indazole; 3-((3a R 5 s ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-yl)piperidine-1-carboxylic acid methyl ester; 3-((3a R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-yl)piperidine-1-carboxylic acid methyl ester; 3-((3a R 5 r ,6a S )-5-(5-methyl-1-(1-methyl-1) H -pyrazole-4-yl)-1 H -Indazole-6-yl)hexahydrocyclopentadiene[ c ]Pyrrole-2(1 H )-B-tetrahydro-2 H -Thiaran 1,1-dioxide; Or its pharmaceutically acceptable salt.

27. A pharmaceutical composition comprising the compound of any one of claims 1-26 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

28. A method of treating a disease or condition, the method comprising administering to a subject in need a therapeutically effective amount of a compound of any one of claims 1-26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 27, wherein the disease or condition is a CNS disease or disorder, an immune disease or condition, cancer, or leprosy.

29. The method of claim 28, wherein the disease or condition is a CNS disease or disorder, and the CNS disease or disorder is selected from the group consisting of: familial / hereditary and / or sporadic Parkinson's disease, tau proteinosis, Alzheimer's disease, neuroinflammation, HIV-induced dementia, ALS, ischemic stroke, traumatic brain injury, and spinal cord injury.

30. The method of claim 28, wherein the disease or condition is an immune disease or condition, and the immune disease or condition is selected from the group consisting of: lymphoma, leukemia, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous dermatitis, type I diabetes, Sjögren's syndrome, Delvke's disease, inflammatory myopathy, ankylosing spondylitis, and Crohn's disease.

31. The method of claim 28, wherein the disease or condition is cancer, and the cancer is selected from the group consisting of: kidney cancer, breast cancer, lung cancer, prostate cancer, acute myeloid leukemia (AML), papillary renal cell carcinoma, thyroid cancer, and low-grade glioma.

32. The method of claim 28, wherein the disease or condition is leprosy.

33. A method for inhibiting LRRK2 in a subject, the method comprising administering to the subject an amount of a compound as described in any one of claims 1-26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 27, that effectively inhibits LRRK2.

34. The method of claim 33, wherein LRRK2 is a G2019S mutant of LRRK2.

35. The method of any one of claims 28-34, wherein the subject expresses an LRRK G2019S mutation.

36. The method of any one of claims 28-35, wherein LRRK2 is amplified or overexpressed in the subject.

37. The compound of any one of claims 1-26 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27, for use in treating a disease or condition selected from the group consisting of: CNS diseases or disorders, immune diseases or conditions, cancer, and leprosy.

38. Use of any compound of claims 1-26 or a pharmaceutically acceptable salt thereof, or of any pharmaceutical composition of claim 27, in the manufacture of a medicament for treating a disease or condition selected from the group consisting of: CNS diseases or disorders, immune diseases or conditions, cancer, and leprosy.

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