LRRK2 inhibitors and compositions and uses thereof

Abstract

Disclosed herein are compounds that inhibit leucine-rich repeat kinase 2 (LRRK2), pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in a method of treating a disorder that derives in full or in part from LRRK2 kinase activity, such as neurodegenerative diseases, immune-mediated diseases, and forms of cancer.

Description

[0001] STDU2-44049.601

[0002] LRRK2 INHIBITORS AND COMPOSITIONS AND USES THEREOF

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 723,383, filed on November 21, 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0005] FIELD

[0006] Disclosed herein are compounds that inhibit leucine-rich repeat kinase 2 (LRRK.2), pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g.. in methods of treating disorders associated with LRRK2 such as neurodegenerative diseases, immune-mediated diseases, and forms of cancer.

[0007] BACKGROUND

[0008] Parkinson's disease ("PD") is the most common form of parkinsonism, a neurodegenerative movement disorder, and the second most common age-related neurodegenerative disease estimated to affect 1-2% of the population over age 65. PD patients experience a progressive loss of dopaminergic neurons leading to disease that is characterized by tremor, rigidity, postural instability, impaired speech, and bradykinesia. Nonmotor symptoms also manifest with PD and include sleep disorders, gastrointestinal dysfunction, depression, cognitive and emotional changes, and anosmia. It is a chronic, progressive disease with increasing disability and diminished quality of life. In addition to PD, parkinsonism is exhibited in a range of conditions such as progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, PD dementia, and dementia with Lewy bodies. Current therapeutic strategies for PD are primarily palliative and focus on reducing the severity of symptoms using supplemental dopaminergic medications. At present, there is no disease-modifying therapy that addresses the underlying neuropathological cause of the disease, thus constituting a significant unmet medical need.

[0009] It has long been known that family members of PD patients have an increased risk of developing the disease compared to the general population. Leucine-rich repeat kinase 2 ("LRRK2," also known as dardarin) is a 286 kDa multi-domain protein that has been linked to PD by genome-wide association studies (Mov. Disord. 2011, 26(6), 1042). LRRK2 expression in STDU2-44049.601 the brain is highest in areas impacted by PD (Eur. J. Neurosci. 2006, 23(3):659) and LRRK2 has been found to localize in Lewy Bodies, which are intracellular protein aggregates considered to be a hallmark of the disease. Patients with point mutations in LRRK2 present disease that is indistinguishable from idiopathic patients (Lancet Neurol. 2008, 7(7), 583).

[0010] Missense mutations in LRRK2 have been shown to enhance the kinase activity of the protein (Proc. Nat. Acad. Sci. USA 2005, 102(46), 16842) suggesting that hyperphosphorylation of LRRK2 substrates may play a role in disease progression. Recent findings in brain from idiopathic PD (iPD) patients suggest that genetic and sporadic forms of PD may be linked through increased LRRK2 kinase activity. Rab GTPases, which regulate vesicular trafficking, are endogenous LRRK2 substrates. A 4-fold increase in phosphorylated RablO levels has been observed in postmortem brain tissue from a cohort of iPD patients. This was correlated with a 6- fold increase in LRRK2 autophosphorylation of Seri 292; a similar effect occurs in a rotenone- induced rat model of PD (Sci. Transl. Med. 2018, 10, eaar5429). Increased RablO phosphorylation also occurs in human peripheral blood neutrophils (Biochem. J. 2018, 475. 23) and increased RablO phosphorylation was observed in patients with iPD in a Phase I clinical study of a LRRK2 type I kinase inhibitor (denalitherapeutics.gcs-web.com / node / 8141 / pdf). Together, these findings suggest a significant role for increased LRRK2 kinase activity in the etiology and pathogenesis of LRRK2 mutation-related PD and iPD. Thereby, inhibition of LRRK2 kinase activity has become a target for the treatment of PD (Nat. Med. 2010, 16(9), 998; J. Neurosci. Res. 2009, 87(6), 1283).

[0011] In addition to PD, LRRK2 has been linked to other diseases. Among these are cancer, leprosy, and Crohn's disease (Sci. Signal., 2012, 5(207), pe2). LRRK2 mutations are also associated with diverse pathologic changes in brain, including deposits of tau, also called “tauopathy”, especially the type characteristic of Alzheimer disease (AD) (Acta Neuropathol. Commun. 7:183 (2019)) but also a number other neurodegenerative diseases, as well as deposits of transactive response DNA binding protein of 43 kDa (TDP-43) (Mov. Disord. 2023 Aug; 38(8): 1541-1545) suggesting that LRRK2 inhibitors may be useful for the treatment of AD or other related disorders. LRRK2 is expressed in peripheral monocytes and macrophages and inflammation increases LRRK2 activity and expression suggesting a role for LRRK2 in regulating immune cell response (J. Neurosci. 2012, 32(05), 1602). LRRK2 inhibitors may therefore be useful for the treatment of a range of immune-mediated diseases. STDU2-44049.601

[0012] As there are presently limited therapeutic options for treating PD and other disorders associated with aberrant LRRK2 kinase activity, there remains a need for developing LRRK2 inhibitors.

[0013] SUMMARY

[0014] In one aspect, disclosed herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0015] X1, X2, and X3are each independently selected from CRXand N, wherein each Rxis independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0016] R1is selected from monocyclic aryl, monocyclic 5- or 6-membered heteroaryl, or monocyclic 5- or 6-membered heterocyclyl, each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0017] R2is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;

[0018] Z is -NHCO- or -CONH-;

[0019] R3is selected from monocyclic aryl, monocyclic 5- or 6-membered heteroaryl, and arylalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, Ci- C4 alkoxy, and C1-C4 haloalkoxy; and

[0020] R4is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0021] In some embodiments, X1is N or CH. In some embodiments, X1is N. In some embodiments, X1is CH. In some embodiments, X2is CH. In some embodiments, X3is CH. In some embodiments, X2and X3are each CH.

[0022] In some embodiments, the compound is a compound of formula (la): STDU2-44049.601 or a pharmaceutically acceptable salt thereof, wherein:

[0023] X1, X2, and X3are each independently selected from CRXand N, wherein each Rxis independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0024] R1is monocyclic aryl or monocyclic 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0025] R2is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;

[0026] Z is -NHCO- or -CONH-;

[0027] R3is monocyclic aryl or monocyclic 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy; and

[0028] R4is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0029] In some embodiments, X1is CH or N. In some embodiments, X2is CH. In some embodiments, X3is CH.

[0030] In some embodiments, R1is selected from phenyl, a 5- or 6-membered heteroaryl having one or two nitrogen atoms, and a 6-membered heterocyclyl having one or two nitrogen atoms, each of which is unsubstituted or substituted with one or two substituents independently selected from C1-C2 alkyl, halo, and C1-C2 alkoxy. In some embodiments, R1is selected from phenyl, pyridinyl, and piperidinyl, each of which is substituted with one substituent selected from methyl, methoxy, and halo.

[0031] In some embodiments, R1is phenyl substituted with one C1-C4 haloalkoxy substituent. In some embodiments, R1is phenyl substituted with three halo substituents.

[0032] In some embodiments, R1is a group selected from: STDU2-44049.601

[0033] In some embodiments, R1is a 6-membered heterocyclyl having one nitrogen atom and is substituted with one C1-C4 alkyl. In some embodiments, R1is

[0034] In some embodiments, R1is pyrazolyl that is substituted with one or two methyl substituents. In some embodiments,

[0035] In some embodiments, R1is a group selected from:

[0036] In some embodiments, R2is selected from hydrogen and methyl.

[0037] In some embodiments, R3is selected from phenyl, benzyl, and a 5-membered heteroaryl having one or two heteroatoms independently selected from N, O. and S, each of which is unsubstituted or substituted with one or two substituents independently selected from C1-C2 haloalkyl, halo, and C1-C2 alkyl. In some embodiments, R3is selected from phenyl, oxazolyl, and pyrazolyl, each of which is substituted with one substituent selected from C1-C2 haloalkyl.

[0038] In some embodiments, R3is a group selected from:

[0039] In some embodiments, R3is phenyl substituted with one or two substituents selected from halo, C1-C4 alkoxy, C1-C4 alkyl, and amino. In some embodiments, R3is selected from: STDU2-44049.601

[0040] In some embodiments, R3is benzyl that is substituted with one, two, or three halo

[0041] F substituents. In some embodiments, R3is ' z J F.

[0042] In some embodiments, R3is a group selected from:

[0043] In some embodiments, R4is C1-C3 alkyl. In some embodiments, R4is methyl.

[0044] In some embodiments, the compound is a compound of formula (lb): wherein:

[0045] R1is selected from phenyl, a 5- or 6-membered heteroaryl having one or two nitrogen atoms, and a 6-membered heterocyclyl having one or two nitrogen atoms each of which is unsubstituted or substituted with one, two, or three substituents independently selected from Ci- C2 alkyl, halo, C1-C2 alkoxy, and C1-C2 haloalkoxy;

[0046] X1is N or CH;

[0047] R2is selected from hydrogen and C1-C3 alkyl;

[0048] Z is -NHCO- or -CONH-: and

[0049] R3is selected from monocyclic aryl, monocyclic 5- or 6-membered heteroaryl, and arylalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, Ci- C4 alkoxy, and C1-C4 haloalkoxy.

[0050] In some embodiments, the compound is selected from: STDU2-44049.601 STDU2-44049.601

[0051] In another aspect, disclosed herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0052] In another aspect, disclosed herein is a method of inhibiting LRRK2 in a sample, comprising contacting the sample with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0053] In another aspect, disclosed herein is a method of treating Parkinson's disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune- mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the disorder is Parkinson's disease.

[0054] In another aspect, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for inhibiting LRRK2 in a sample.

[0055] In another aspect, disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for treatment of Parkinson's disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune-mediated disorder. In some embodiments, the disorder is Parkinson's disease. STDU2-44049.601

[0056] DETAILED DESCRIPTION

[0057] Provided herein are compounds that inhibit LRRK2, pharmaceutical compositions comprising the compounds, and methods of using the compounds, e.g., in methods of treating disorders associated with LRRK2 such as Parkinson’s disease, other neurodegenerative diseases, immune-mediated diseases, and cancer.

[0058] Definitions

[0059] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, synthetic chemistry, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0060] As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise.

[0061] As used herein, the term “and / or” includes any and all combinations of listed items, including any of the listed items individually. For example, “A, B, and / or C” encompasses A, B, C, AB, AC, BC, and ABC, each of which is to be considered separately described by the statement “A, B, and / or C.”

[0062] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9. and for the range 6.0-7.0, the number 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 contemplated.

[0063] 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, as well as specific functional moieties and reactivity, are described in Sorrell, Organic Chemistry, 2ndedition, University Science Books, STDU2-44049.601

[0064] Sausalito, 2006; Smith, March’s Advanced Organic Chemistry: Reactions, Mechanism, and Structure, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations. 3rdEdition, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0065] As used herein, the term “alkyl” refers to a radical of a straight or branched saturated hydrocarbon chain. The alkyl chain can include, e.g., from 1 to 24 carbon atoms (C1-C24 alkyl). 1 to 16 carbon atoms (C1-C16 alkyl), 1 to 14 carbon atoms (C1-C14 alkyl), 1 to 12 carbon atoms (Ci- C12 alkyl), 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 8 carbon atoms (Ci-Cs alkyl), 1 to 6 carbon atoms (Ci-Ce alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), 1 to 3 carbon atoms (C1-C3 alkyl), or 1 to 2 carbon atoms (C1-C2 alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl.

[0066] As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0067] As used herein, the term “amino” refers to a group -NRxRy, wherein Rxand Ryare selected from hydrogen and alkyl (e.g., C1-C4 alkyl). A group -NH(alkyl) may be referred to herein as “alkylamino” and a group -N(alkyl)2 may be referred to herein as “dialkylamino.”

[0068] As used herein, the term “aryl” refers to a radical of a monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 1471 electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms (“C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl,” i.e.. phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl,” e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl,” e.g., anthracenyl and phenanthrenyl).

[0069] As used herein, the term “cycloalkyl” refers to a radical of a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl STDU2-44049.601 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl.

[0070] As used herein, the term “cyano” refers to a -CN group.

[0071] As used herein, the term “halogen” or “halo” refers to F, Cl, Br, or I.

[0072] As used herein, the term “haloalkyl” refers to an alkyl group, as defined herein, in which at least one hydrogen atom (e.g., one, two, three, four, five, six, seven or eight hydrogen atoms) is replaced with a halogen. In some embodiments, each hydrogen atom of the alkyl group is replaced with a halogen (“perhaloalkyl”). Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and 3.3,3-trifluoropropyl.

[0073] As used herein, the term “haloalkoxy” refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of haloalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2- trifluoroethoxy.

[0074] As used herein, the term “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 n electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5- STDU2-44049.601 membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5 -membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl. benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0075] As used herein, the term “hydroxy” or “hydroxyl” refers to an -OH group.

[0076] When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable substituent group known to those of skill in the art (e.g., one or more of the groups recited below), provided that the designated atom’s normal valence is not exceeded. Substituent groups include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino. aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkenyl, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, phosphate, phosphonate, sulfonic acid, thiol, thione, or combinations thereof.

[0077] As used herein, in chemical structures the indication: represents a point of attachment of one moiety to another moiety (e.g., a substituent group to the rest of the compound).

[0078] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and STDU2-44049.601 substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0079] The terms “administer,” “administering,” or “administration,” as used herein refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound or a pharmaceutical composition.

[0080] As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.

[0081] An “effective amount” of a compound or composition refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of a compound or composition may reduce tumor burden or stop the growth or spread of a tumor.

[0082] A “therapeutically effective amount” of a compound or composition is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0083] A “subject” to which administration is contemplated includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and / or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or STDU2-44049.601 dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and / or turkeys).

[0084] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0085] Disclosed herein are compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0086] X1, X2, and X3are each independently selected from CRXand N, wherein each Rxis independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0087] R1is selected from monocyclic aryl, monocyclic 5- or 6-membered heteroaryl, or monocyclic 5- or 6-membered heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0088] R2is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;

[0089] Z is -NHCO- or -CONH-;

[0090] R3is selected from monocyclic aryl, monocyclic 5- or 6-membered heteroaryl, and arylalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently STDU2-44049.601 selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, Ci- C4 alkoxy, and C1-C4 haloalkoxy; and

[0091] R4is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0092] In some embodiments, X1is N or CH. In some embodiments, X1is N. In some embodiments, X1is CH. In some embodiments. X2is CH. In some embodiments, X3is CH. In some embodiments, X2and X3are each CH.

[0093] Also disclosed herein are compounds of formula (la): or a pharmaceutically acceptable salt thereof, wherein:

[0094] X1, X2, and X3are each independently selected from CRXand N, wherein each Rxis independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0095] R1is monocyclic aryl or monocyclic 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;

[0096] R2is selected from hydrogen. C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;

[0097] Z is -NHCO- or -CONH-;

[0098] R3is monocyclic aryl or monocyclic 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy; and

[0099] R4is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0100] In some embodiments, X1is N or CH. In some embodiments, X1is N. In some embodiments, X1is CH. In some embodiments. X2is CH. In some embodiments, X3is CH. In some embodiments, X2and X3are each CH. STDU2-44049.601

[0101] In some embodiments, R1is selected from phenyl, a 5- or 6-membered heteroaryl having one or two nitrogen atoms, and a 6-membered heterocyclyl having one or two nitrogen atoms each of which is unsubstituted or substituted with one, two, or three substituents independently selected from C1-C2 alkyl, halo, C1-C2 alkoxy, and C1-C2 haloalkoxy.

[0102] In some embodiments, R1is selected from phenyl and a 5- or 6-membered heteroaryl having one or two nitrogen atoms, each of which is unsubstituted or substituted with one, two, or three substituents independently selected from C1-C2 alkyl, halo, C1-C2 alkoxy, and C1-C2 haloalkoxy. In some embodiments, R1is selected from phenyl and a 6-membered heteroaryl having one or two nitrogen atoms, each of which is unsubstituted or substituted with one or two substituents independently selected from C1-C2 alkyl, halo, and C1-C2 alkoxy. In some embodiments, R1is phenyl substituted with one substituent selected from methyl, chloro, methoxy, and trifluoromethoxy. In some embodiments, R1is selected from phenyl and pyridinyl, each of which is substituted with one substituent selected from methyl, methoxy, and halo. In some embodiments, R1is phenyl substituted with one substituent selected from methyl, chloro, and methoxy. In some embodiments, R1is phenyl substituted with one C1-C4 haloalkoxy substituent. In some embodiments, R1is phenyl substituted with three halo substituents. In some embodiments, R1is phenyl substituted with three fluoro substituents. In some embodiments, R1is phenyl substituted with one trifluoromethoxy substituent. In some embodiments, R1is a group selected from:

[0103] In some embodiments, R1is a group selected from:

[0104] In some embodiments, R1is a 6-membered heterocyclyl having one nitrogen atom and is substituted with one C1-C4 alkyl. In some embodiments, R1is piperidinyl that is substituted with one C1-C4 alkyl substituent. In some embodiments, R1is piperidinyl that is substituted with one methyl substituent. In some embodiments, R1is: STDU2-44049.601

[0105] In some embodiments, R1is a 5-membered heteroaryl having two nitrogen atoms. In some embodiments, the 5-membered heteroaryl is substituted with one or two C1-C4 alkyl substituents. In some embodiments, the 5-membered heteroaryl is substituted with one or two methyl substituents. In some embodiments, R1is pyrazolyl. In some embodiments, R1is pyrazolyl that is substituted with one or two methyl substituents. In some embodiments, R1is:

[0106] In some embodiments, R1is a group selected from:

[0107] In some embodiments, R2is selected from hydrogen and methyl. In some embodiments, R2is hydrogen. In some embodiments, R2is methyl. In some embodiments, R2is ethyl.

[0108] In some embodiments, Z is -NHCO-. In some embodiments. Z is -CONH-.

[0109] In some embodiments, R3is selected from phenyl, benzyl, and a 5-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S, each of which is unsubstituted or substituted with one or two substituents independently selected from C1-C2 haloalkyl, halo, and C1-C2 alkyl.

[0110] In some embodiments, R3is selected from phenyl and a 5-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S, each of which is unsubstituted or substituted with one or two substituents independently selected from C1-C2 haloalkyl, halo, and C1-C2 alkyl. In some embodiments, R3is selected from phenyl, oxazolyl. and pyrazolyl, each of which is substituted with one substituent selected from C1-C2 haloalkyl (e.g., -CF3). In some embodiments, R3is a group selected from: STDU2-44049.601

[0111] In some embodiments, R3is phenyl substituted with one or two substituents selected from halo, C1-C4 alkoxy, C1-C4 alkyl, and amino. In some embodiments, R3is phenyl substituted with one chloro substituent. In some embodiments, R3is phenyl substituted with one methoxy substituent. In some embodiments, R3is phenyl substituted with one methyl substituent. In some embodiments, R3is phenyl substituted with one dimethylamino substituent. In some embodiments, R3is phenyl substituted with one dimethylamino substituent and one methyl substituent. In some embodiments. R3is phenyl substituted with one methyl substituent and one methoxy substituent. In some embodiments, R3is selected from:

[0112] In some embodiments, R3is arylalkyl that is substituted with one, two, or three halo substituents. In some embodiments, R3is benzyl that is substituted with two halo substituents. In some embodiments, R3is:

[0113] In some embodiments, R3is a group selected from:

[0114] In some embodiments, R4is C1-C3 alkyl. In some embodiments. R4is methyl.

[0115] In some embodiments, the compound is selected from: STDU2-44049.601 STDU2-44049.601

[0116] Certain compounds described herein may have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers, in mixtures and as pure or partially purified compounds, are included within the scope of this disclosure.

[0117] The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

[0118] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. STDU2-44049.601

[0119] Compounds may also possess tautomeric forms, and all tautomers also constitute embodiments of the disclosure.

[0120] The present disclosure also includes an isotopically-labeled compound, which is identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. Substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) arenC,13N.15O, and18F. Isotopically- labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent.

[0121] Compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure encompass both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. a. Methods of Synthesis

[0122] Compounds disclosed herein can be prepared by a variety of methods, including those illustrated in the Examples.

[0123] Compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or STDU2-44049.601 low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), by Fumiss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0124] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Reactions can be worked up in a conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

[0125] Standard experimentation, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the disclosure. Suitable protecting groups and the methods 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, in Greene's book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006).

[0126] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0127] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the procedures described herein using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation. STDU2-44049.601

[0128] The synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the disclosure or the claims. Alternatives, modifications, and equivalents of the synthetic methods and specific examples are contemplated. b. Pharmaceutically Acceptable Salts

[0129] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compound with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. Amino groups of the compounds may also be quatemized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0130] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine. N,N- STDU2-44049.601 dibenzylphenethylamine, 1 -ephenamine and N,N’ -dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0131] Pharmaceutical Compositions

[0132] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human).

[0133] The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semisolid 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, com 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, com oil and soybean oil; glycols; such as 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 also be present in the composition, according to the judgment of the formulator.

[0134] Thus, the compounds and their pharmaceutically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington’s Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0135] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g.. oral, rectal, nasal, sublingual, STDU2-44049.601 buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0136] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

[0137] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols 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% by weight of the composition.

[0138] 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, com oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10% by weight of the composition.

[0139] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50% by weight of the composition.

[0140] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10% by weight of the composition.

[0141] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1% by weight of the composition.

[0142] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%. STDU2-44049.601

[0143] Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s), when used, in a systemic or topical composition is typically about 0.001 to about 1% by weight of the composition.

[0144] 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% by weight of the composition.

[0145] 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% by weight of the composition.

[0146] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5% by weight of the composition.

[0147] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100% by weight of the composition.

[0148] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8% by weight of the composition.

[0149] Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the 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 the systemic or topical composition is typically about 0.1% to about 5% by weight of the composition.

[0150] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% by weight of an active compound and 50% to 99.99% by weight of one or more earners. Compositions for parenteral administration typically include 0.1% to 10% by weight of actives and 90% to 99.9% by weight of a carrier including a diluent and a solvent. STDU2-44049.601

[0151] 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, usually at least about 5% by weight, and more particularly from about 25% to about 50% by weight of actives. The oral dosage compositions include about 50% to about 95% by weight of carriers, and more particularly, from about 50% to about 75% by weight.

[0152] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0153] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0154] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this disclosure.

[0155] Solid compositions may be coated by conventional methods, typically with pH or timedependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes and shellac. STDU2-44049.601

[0156] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non- effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0157] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0158] The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I)), or a pharmaceutically acceptable salt thereof), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0159] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this disclosure 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 Ed., (1976).

[0160] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and STDU2-44049.601

[0161] E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0162] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0163] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl 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, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95% by weight of the composition.

[0164] 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 about 0% to about 95% by weight of the composition.

[0165] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

[0166] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants STDU2-44049.601 include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95% by weight of the composition.

[0167] The amount of thickener(s) in a topical composition is typically about 0% to about 95% by weight of the composition.

[0168] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95% by weight of the composition.

[0169] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1% by weight of the composition.

[0170] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

[0171] Methods of Use

[0172] The disclosed compounds and pharmaceutical compositions may be used in methods for treatment of disorders, including disorders associated with LRRK2. Such disorders include Parkinson’s disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune-mediated disorder. The disclosed compounds and pharmaceutical compositions may be used in methods for inhibiting the activity of LRRK2.

[0173] In the methods of treatment described herein, a compound or pharmaceutical composition may be administered to the subject by any convenient route of administration, whether systemically / peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; or by implant of a depot, for example, subcutaneously or intramuscularly. In STDU2-44049.601 some embodiments, the administration comprises oral administration. Additional modes of administration may include adding the compound and / or a composition comprising the compound to a food or beverage, including a water supply for an animal, to supply the compound as part of the animal’s diet.

[0174] It will be appreciated that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present disclosure. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and / or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.

[0175] Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be earned out with the dose level and pattern being selected by the treating physician. In general, a suitable dose of the compound is in the range of about 100 pg to about 250 mg per kilogram body weight of the subject per day.

[0176] The compound or composition may be administered once, on a continuous basis (e.g. by an intravenous drip), or on a periodic / intermittent basis, including about once per hour, about once per two hours, about once per four hours, about once per eight hours, about once per twelve hours, about once per day, about once per two days, about once per three days, about twice per week, about once per week, and about once per month. The composition may be administered until a desired reduction of symptoms is achieved. STDU2-44049.601

[0177] When used in methods of treatment disclosed herein, a compound or composition described herein may be used in combination with other known therapies. Administered “in combination,” as used herein, means that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, e.g., the two or more treatments are delivered after the subject has been diagnosed with the disorder and before the disorder has been cured or eliminated or treatment has ceased for other reasons. In some embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In some embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

[0178] Kits

[0179] For use in the therapeutic applications described herein, kits and articles of manufacture are also provided, which include a compound or pharmaceutical composition described herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical comosition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof ). In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic. STDU2-44049.601

[0180] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Patent Nos. 5,323.907, 5,052,558 and 5.033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, in some embodiments the container(s) includes a compound of formula (I, or a pharmaceutically acceptable salt thereof, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.

[0181] For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and / or devices) desirable from a commercial and user standpoint for use of a compound described herein. Nonlimiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and / or tube labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such STDU2-44049.601 notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0182] The following examples further illustrate aspects of the disclosure but, of course, should not be construed as in any way limiting its scope.

[0183] Examples

[0184] Abbreviations used in the Examples include the following: DIEA is diisopropylethylamine; DMF is dimethylformamide; DMSO is dimethylsulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; HATU is l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate; HPLC is high performance liquid chromatography; KOAc is potassium acetate; m-CPBA is 3 -chloroperbenzoic acid; MeOH is methanol; Mel is methyl iodide; MS-ESI is mass spectrometry - electrospray ionization; NMR is nuclear magnetic resonance; Pd(amphos)C12 is dichlorobis[di-tert-butyl(4- dimethylaminophenyl)phosphine]palladium(II); Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); TFA is trifluoroacetic acid; THF is tetrahydro furan; TMSCHN? is trimethylsilyldiazomethane; and XPhos is 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl.

[0185] Example 1

[0186] Compound Syntheses

[0187] Compound 1

[0188] A-(4-Methyl-3-(8-methyl-2-((6-methylpyridin-3-yl)amino)-7-oxo-7,8-dihydropyrido[2,3-

[0189] 6?]pyrimidin-6-yl)phenyl)-3-(trifluoromethyl)benzamide STDU2-44049.601

[0190] 6-Bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 6- bromo-2-(methylthio)pyrido[2,3-rZ]pyrimidin-7(8H)-one (1.7 g, 6.25 mmol) in DMF (30 mL) were added CS2CO3 (2.04 g, 6.25 mmol) and Mel (886.72 mg, 6.25 mmol) at 20 °C. The mixture was then stirred at 90 °C for 4 h. The reaction mixture was poured into water. A yellow solid formed that was filtered, washed with H2O (3x), and dried under vacuum to give the product (1.7 g) as a white solid that was used without further purification.1H NMR (400 MHz, DMSO-de) 8 8.87 (s, 1 H), 8.53 (s, 1 H), 3.66 (s, 3 H), 2.61 (s, 3 H). MS-ESI (m / z) calc’d for C9H9BrN3OS [M+H]+: 285.9 / 287.9. Found: 286.0 / 288.0.

[0191] 8-Methyl-6-(2-methyl-5-nitrophenyl )-2-( methylthio )pyrido[ 2,3 -d ]pyri midin- 7( 8H)-one. To a solution of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-flf]pyrimidin-7(8H)-one (720 mg, 2.52 mmol) in EtOH (15 mL) and H2O (15 mL) were added Pd(amphos)C12 (178.16 mg, 251.62 pmol), KOAc (740.83 mg, 7.55 mmol) and (2-methyl-5-nitrophenyl)boronic acid (910.62 mg, 5.03 mmol) at 20 °C. The mixture was then stirred at 80 °C for 12 h under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was diluted with MeOH to give a yellow solid that was filtered, washed with MeOH (2x), and dried under vacuum to give the product (500 mg) as a yellow solid that was used without further purification. MS-ESI (m / z) calc’d for C16H15N4O3S [M+H]+: 343.0. Found: 343.1.

[0192] 8-Methyl-6-(2-methyl-5-nitrophenyl)-2-( methylsulfonyl )pyrido[ 2, 3-d ]pyrimidin-7( 8H)- one. To a solution of 8-methyl-6-(2-methyl-5-nitrophenyl)-2-(methylthio)pyrido[2,3- ^pyrimidin-7(8H)-one (380 mg, 1.11 mmol) in CH2CI2 (10 mL) was added z -CPBA (718.24 mg, 3.33 mmol, 80% purity) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction was STDU2-44049.601 treated with a saturated aqueous NaHCCF solution to pH=8 and extracted with CH2CI2 (3x). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum to give the product (400 mg) as a yellow solid that was used without further purification. MS-ESI (m / z) calc’d for C16H15N4O5S [M+H]+: 375.0. Found: 375.1.

[0193] 8-Methyl-6-(2-methyl-5-nitrophenyl)-2-((6-methylpyridin-3-yl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one. To a solution of 8-methyl-6-(2-methyl-5-nitrophenyl)-2- (methylsulfonyl)pyrido[2,3-<flpyrimidin-7(8H)-one (400 mg, 1.07 mmol) in CH3CN (5 mL) were added CsF (162.30 mg, 1.07 mmol), 6-methylpyridin-3-amine (173.32 mg, 1.60 mmol) and DIEA (414.27 mg, 3.21 mmol) at 20 °C. The mixture was then stirred at 40 °C for 12 h. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a 0-12% CELCh / MeOH gradient eluent to give the product (60 mg, 7.5%) as a brown solid. MS-ESI (m / z) calc’d for C21H19N6O3 [M+H]+: 403.1. Found. 403.2.

[0194] 6-(5-Amino-2-methylphenyl)-8-methyl-2-((6-methylpyridin-3-yl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one. To a solution of 8-methyl-6-(2-methyl-5-nitrophenyl)-2-((6- methylpyridin-3-yl)amino)pyrido[2,3-i7]pyrimidin-7(8 / / )-one (40 mg, 99.40 pmol) in EtOH (4 mL) and H2O (1 mL) was added Fe (27.76 mg, 497.01 pmol) and NH4CI (26.59 mg, 497.01 pmol) at 20 °C. The mixture was stirred at 80 °C for 1 h. The mixture was filtered, and the filtrate was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to give the product (37 mg) as a brown solid that was used without further purification. MS-ESI (m / z) calc’d for C21H21N6O [M+H]+: 373.1. Found. 373.2. STDU2-44049.601

[0195] N-(4-Methyl-3-(8-methyl-2-((6-methylpyridin-3-yI)amino)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)phenyl)-3-(lrifluoromethyl)benz.amide. To a solution of 6-(5-amino-2- methylphenyl)-8-methyl-2-((6-methylpyridin-3-yl)amino)pyrido[2,3- ]pyrimidin-7(8H)-one (30 mg, 80.55 pmol) in DMF (4 mL) were added 3-(trifluoromethyl)benzoic acid (15.31 mg, 80.55 pmol), DIEA (52.05 mg, 402.77 pmol) and HATU (61.26 mg, 161.11 pmol) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18; 150 mm x 40 mm, 10 um; 45-75% CH3CN / H2O (10 mM NH4HCO3)) to afford the product (12.84 mg, 23.64%, 2 steps) as a pale-yellow solid. 'H NMR (400 MHz, DMSO-de) 8 10.46 (s, 1 H), 10.21 (br s, 1 H). 8.83-8.90 (m, 2 H). 8.24-8.32 (m, 2 H), 8.12 (dd, J=8.38, 2.63 Hz, 1 H), 7.96 (br d, J=7.88 Hz. 1 H), 7.84 (s, 1 H). 7.76-7.81 (m, 1 H). 7.66-7.72 (m, 2 H). 7.26 (t. J=8.32 Hz, 2 H), 3.67 (s, 3 H), 2.44 (s, 3 H), 2.15 (s, 3 H). MS-ESI (m / z) calc’d for C29H24F3N6O2 [M+H]+: 545.1. Found. 545.2.

[0196] Compound 2

[0197] N-(3-(7-((2-methoxyphenyl)amino)-l-methyl-2-oxo- 1 ,2-dihydro- 1 ,6-naphthyridin-3-yl)-4- methylpheny 1) -3 - (trifluor ome thy l)benzamide

[0198] 6-Chloro-4-(methylamino)nicotinaldehyde. A solution of 4,6-dichloropyridine-3- carbaldehyde (1 g, 5.68 mmol) in methanamine (2 M, 14.58 mL) at 20 °C. The mixture was stirred at 50 °C for 36 h. The mixture was diluted with CH2CI2 and 2M HC1, after stirring for 3 h, the mixture was extracted with CH2CI2 (3x). The combined organic phases were dried over STDU2-44049.601 anhydrous Na2SC>4, filtered, and the filtrate was concentrated to give the product (895 mg) as a yellow solid that was used without further purification. MS-ESI (m / z) calc’d for C7H8CIN2O [M+H]+: 171.0. Found: 171.1.

[0199] 2-(2-Methyl-5-nitrophenyl)acetic acid. Two solutions were prepared. Solution 1 consisted of o-tolylacetic acid (3.5 g, 23.31 mmol) in 98% H2SO4 (10.5 mL). Solution 2 consisted of 96% HNO3 in 98% H2SO4 (10.5 mL). Solution 1 was loaded into Pump 1 set at 4.163 mL / min. Solution 2 was loaded into Pump 2 set at 3.745 mL / min. Pumping was simultaneously initiated to the flow reactor (PFA coils reactor, 3.175 mm, 7.908 mL, 0 °C). Residence time was 1 min and the reaction mixture was collected into 100 mL of ice water. Upon completion the mixture was stirred at 20 °C for 10 min. A solid formed that was filtered, washed with H2O (2x), and dried under vacuum to give the product (4.55 g) as a white solid that was used without further purification.

[0200] Methyl 2-(2-methyl-5-nitrophenyl)acetate. To a solution of 2-(2-methyl-5-nitro- phenyl)acetic acid (4.2 g, 21.52 mmol) in MeOH (50 mL) was added SOCI2 (5.12 g, 43.04 mmol) at 0 °C. The mixture was stirred at 70 °C for 12 h. The mixture was concentrated to give a residue that was purified by silica gel chromatography using a 0-10% EtOAc / petroleum ether gradient eluent to give the product (2.91 g, 64.64%, 2 steps) as a white solid.

[0201] Methyl 2-(5-amino-2-methylphenyl)acetate. A mixture of methyl 2-(2-methyl-5-nitro- phenyl)acetate (2.91 g, 13.91 mmol) , 10% Pd / C (296.07 mg, 278.21 pmol) in EtOH (30 mL) was degassed and purged with H2 (3x), and then the mixture was stirred at 20 °C for 1 h under H2 atmosphere. (15 Psi). The mixture was filtered and concentrated to give a residue. The residue was purified by silica gel chromatography using a 0-14% EtOAc / petroleum ether gradient eluent STDU2-44049.601 to give the product (1.37 g, 54.96%) as a red oil. MS-ESI (m / z) calc’d for C10H14NO2 [M+H]+:

[0202] 180.0. Found. 180.5

[0203] 3-(5-Amino-2-methylphenyl)-7-chloro-l-methyl-3,4-dihydro-l,6-naphthyridin-2(lH)-one. To a solution of 6-chloro-4-(methylamino)pyridine-3-carbaldehyde (877 mg, 5.14 mmol) in DMF (20 mL) were added K2CO3 (2.13 g, 15.42 mmol) and methyl 2-(5-amino-2-methyl- phenyl)acetate (1.20 g, 6.68 mmol) at 20 °C. The mixture was then stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography using a 0-39% EtOAc / petroleum ether gradient eluent to give the product (966 mg, 62.69%) as a yellow solid. MS-ESI (m / z) calc’d for C16H15CIN3O [M+H]+: 300.1 / 302.1. Found. 300.3 / 302.3.

[0204] N-(3- 7-chloro-l-methyl-2-oxo-l,2,3,4-tetrahydro-l,6-naphthyridin-3-yl)-4- methylphenyl)-3-(trifluoromethyl)benzamide. To a solution of 3-(5-amino-2-methyl-phenyl)-7- chloro-1 -methyl- l,6-naphthyridin-2-one (966 mg, 3.22 mmol) in CH2Q2 (15 mL) were added DIEA (1.25 g, 9.67 mmol) and 3-(trifluoromethyl)benzoyl chloride (806.55 mg, 3.87 mmol) at 0 °C. The mixture was then stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography using a 0-18% EtOAc / petroleum ether gradient eluent to give the product (1.17 g, 76.94%) as a pale-yellow solid. MS-ESI (m / z) calc’d for C24H18CIF3N3O2 [M+H]+: 472.1 / 474.1. Found. 472.1 / 474.1. STDU2-44049.601

[0205] N-(3- 7-( 2-methoxyphenyl)ammo)-l-methyl-2-oxo-l,2-dihydro-l,6-naphthyridm-3-yl)-4- methylphenyl)-3-(trifluoromethyl)benzamide. A mixture of A-[3-(7-chloro- 1 -methyl-2-oxo-l ,6- naphthyridin-3-yl)-4-methyl-phenyl]-3-(trifluoromethyl)benzamide (150 mg, 317.89 pmol), 2- methoxyaniline (46.98 mg, 381.47 pmol), Pd2(dba)3(14.55 mg, 15.89 pmol), XPhos (30.31 mg, 63.58 pmol) and Cs2CO3(207.15 mg, 635.78 pmol) in dioxane (4 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 80 °C for 12 h under an N2atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 3 um; 35-65% CH3CN / H2O (0.1% TFA)) to afford the title compound (18 mg, 8.05%) as a pale yellow solid TFA salt.1H NMR (400 MHz, DMSO-d6) 5 10.45 (s, 1 H), 8.80 (br s, 1 H), 8.53 (s, 1 H), 8.23-8.32 (m, 2 H), 8.03 (br d, J=7.88 Hz, 1 H), 7.96 (d, J=7.88 Hz, 1 H), 7.75-7.84 (m, 2 H), 7.64-7.72 (m, 2 H), 7.26 (d, J=8.25 Hz, 1 H), 7.04-7.12 (m, 2 H), 6.90-6.99 (m, 2 H), 3.87 (s, 3 H), 3.54 (s. 3 H), 2.14 (s, 3 H). MS-ESI (m / z) calc’d for C3iH26F3N4O3[M+H]+: 559.2. Found. 559.3

[0206] Compound 3

[0207] 3-(7-((2-methoxyphenyl)amino)-l-methyl-2-oxo-1.2-dihydro-l,6-naphthyridin-3-yl)-4-methyl-

[0208] A-(3-(trifluoromethyl)phenyl)benzamide

[0209] Methyl 3-allyl-4-methylbenzoate. A mixture of methyl 3-bromo-4-methyl-benzoate (15 g, 65.48 mmol), allyl (tributyl) stannane (21.15 g. 63.87 mmol), LiCI (6.94 g, 163.71 mmol), Pd(PPh3)2Cl2(919.23 mg, 1.31 mmol) in DMF (210 mL) was degassed and purged with N2 (3x) STDU2-44049.601 at 20 °C, and then the mixture was stirred at 100 °C for 12 h under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using petroleum ether as eluent to give the product (11.5 g, 92.3%) as a colorless oil.

[0210] 2-(5-(Methoxycarbonyl)-2-methylphenyl)acetic acid. To a solution of methyl 3-allyl-4- methylbenzoate (4 g, 21 .03 mmol) in CCI4 (150 mL), CH3CN (150 mL) and H2O (200 mL) were added NalCM (22.37 g, 104.60 mmol) and RuCL^ffcO (711.85 mg, 3.16 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched by addition of saturated aqueous Na2SOs at 0 °C, and then diluted with H2O and extracted with CH2Q2 ( 3x ). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and the filtrate was concentrated under vacuum to give the title compound (680 mg) as a brown oil that was used without further purification.

[0211] Methyl 3-(2-methoxy-2-oxoethyl)-4-methylbenzoate. A mixture of 2-(5-methoxycarbonyl- 2-methylphenyl)acetic acid (680 mg, 3,27 mmol), TMSCHN2 (2 M, 10.20 mL) in MeOH (35 mL) was degassed and purged with N2 (3x) at 0 °C, and then the mixture was stirred at 20 °C for 0.5 h under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SC>4, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography using a 0-8% EtOAc / petroleum ether gradient eluent to give the product (240 mg, 33.1%, 2 steps) as a yellow oil. MS-ESI (m / z) calc’d for C12H15O4 [M+H]+: 223.1. Found. 223.4 STDU2-44049.601

[0212] Methyl 3-(7-chloro-l-methyl-2-oxo-l,2-dihydro-l,6-naphthyridm-3-yl)-4- methylbenzoate. To a solution of methyl 3-(2-methoxy-2-oxoethyl)-4-methylbenzoate (240 mg, 1.08 mmol) in DMF (7 mL) were added K.2CO3 (447.77 mg, 3.24 mmol) and 6-chloro-4- (methylamino)pyridine-3-carbaldehyde (184.23 mg, 1.08 mmol) at 20 °C. The mixture was stirred at 100 °C for 12 h. The reaction mixture was then diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous NazSO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography using a 0-21% EtOAc / petroleum ether gradient eluent to give the product (249 mg, 67.3%) as a pale-yellow solid. MS-ESI (m / z) calc’d for C18H16CIN2O3 [M+H]+: 343.1 / 345.1. Found. 343.1 / 345.1.

[0213] 3-(7-Chloro-l-methyl-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-4-methylbenzoic acid. To a solution of methyl 3-(7-chloro-l-methyl-2-oxo-l,6-naphthyridin-3-yl)-4-methylbenzoate (224 mg, 653.49 pmol) in FEO (2 mL) and THF (2 mL) was added NaOH (156.83 mg, 3.92 mmol) at 20 °C. The mixture was stirred at 60 °C for 12 h and then extracted with EtOAc (3x). The combined organic layers were discarded. The aqueous layer was diluted with IM HC1 to pH=l. A white solid formed that was filtered, washed with H2O (2x), and dried under vacuum to give the product (186 mg) as a white solid that was used without further purification. MS-ESI (m / z) calc’d for C17H14CIN2O3 [M+H]+: 329.1 / 331.1. Found: 329.1 / 331.1.

[0214] 3-(7-Chloro-l-methyl-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-4-inethyl-N-(3- (trifluoromethyl)phenyl)benzamide. To a solution of 3-(7-chloro-l-methyl-2-oxo-l,6- naphthyridin-3-yl)-4-methylbenzoic acid (183.63 mg, 558.58 pmol) in DMF (3 mL) were added 3 -(trifluoromethyl) aniline (100 mg, 620.64 pmol), HATU (353.98 mg, 930.96 pmol) and DIEA (240.64 mg, 1.86 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was then diluted with FEO and extracted with EtOAc (3x). The combined organic phases STDU2-44049.601 were dried over anhydrous Na2SC>4, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography using a 0-42% EtOAc / petroleum ether gradient eluent to give the product (168 mg, 54%, 2 steps) as a yellow solid. MS-ESI (m / z) calc’d for C24H18CIF3N3O2 [M+H]+: 472.1 / 474.1. Found. 472.2 / 474.2.

[0215] 3-( 7-( ( 2-Methoxyphenyl )amino )-l-melhyl-2-oxo-l,2-dihydro-l,6-naphlhyridin-3-yl)-4- methyl-N-(3-(trifluoromethyl)phenyl)benzamide. A mixture of 3-(7-chloro-l-methyl-2-oxo-l,6- naphthyridin-3-yl)-4-methyl V-[3-(trifluoromethyl)phenyl]benzamide (44 mg, 93.25 pmol), 2- methoxyaniline (17.23 mg, 139.87 pmol), Pd2(dba)3 (8.54 mg, 9.32 pmol), XPhos (8.89 mg, 18.65 pmol) and CS2CO3 (60.76 mg, 186.50 pmol) in dioxane (2 mb) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 80 °C for 12 h under an N2 atmosphere. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 35-65% CH3CN / H2O (0.1% TFA)) to afford the product (18.84 mg, 29.69%) as a yellow solid TFA salt. 'H NMR (400 MHz, CD3CN) 6 9.72 (br s, 1 H), 8.96 (s, 1 H), 8.35 (s, 1 H), 8.16 (s, 1 H), 7.85-7.94 (m, 2 H), 7.78 (d, 1=1.88 Hz, 1 H), 7.70 (s, 1 H), 7.62 (dd, 1=7.75, 1.38 Hz, 1 H), 7.55 (t, 1=8.00 Hz, 1 H), 7.43 (d, 1=7.88 Hz, 2 H), 7.27-7.36 (m, 1 H), 7.16 (dd, J=8.25. 1.00 Hz, 1 H), 7.07 (td, 1=7.63, 1.25 Hz, 1 H), 6.49 (s, 1 H), 3.88 (s, 3 H), 3.48 (s, 3 H), 2.27 (s, 3 H). MS-ESI (m / z) calc’d for C31H26F3N4O3 [M+H]+: 559.2. Found. 559.2

[0216] Compound 4

[0217] 4-Methyl-3-(l-methyl-2-oxo-7-(o-tolylamino)-l,2-dihydro-l,6-naphthyridin-3-yl)-A-(3-

[0218] (trifluoromethyl)phenyl)benzamide STDU2-44049.601

[0219] 4-Methyl-3-(l-methyl-2-oxo-7-(o-tolylamino)-l,2-dihydro-l,6-naphthyridin-3-yl)-N-(3- (trifluoromethyl)phenyl)benzamide. A mixture of 3-(7-chloro-l-methyl-2-oxo-l,6-naphthyridin- 3-yl)-4-methyl-A-[3-(trifluoromethyl)phenyl]benzamide (50 mg, 105.96 pmol), 2-methylaniline (17.03 mg, 158.95 pmol), Pd2(dba)3 (9.70 mg, 10.60 pmol), XPhos (10.10 mg, 21.19 pmol) and CS2CO3 (69.05 mg, 211 .93 pmol) in dioxane (2.5 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 80 °C for 12 h under an N2 atmosphere. The mixture was concentrated to give a residue that was purified by preparative HPLC (Phenomenex Luna Cl 8; 100 mm x 30 mm, 5 um; 35-65% CH3CN / H2O (0.1% TFA)) followed by a second purification by preparative HPLC (WePure Biotech XP tC18; 150 mm x 40 mm, 7 um; 50-90% CH3CN / H2O (10 mM NH4HCO3)) to afford the product (6.83 mg, 11.7%) as a pale-yellow solid. ’H NMR (400 MHz, CD3CN) 8 8.95 (s, 1 H), 8.41 (s, 1 H), 8.16 (s, 1 H), 7.83-7.94 (m, 2 H), 7.79 (d, J=2.00 Hz, 1 H), 7.69 (s, 1 H), 7.51-7.60 (m, 2 H), 7.38-7.45 (m, 2 H), 7.22-7.34 (m, 2 H), 7.11- 7.21 (m, 2 H), 6.41 (s, 1 H), 3.49 (s, 3 H), 2.28 (d, J=9.88 Hz, 6 H). MS-ESI (m / z) calc’d for C31H26F3N4O2 [M+H]+: 543.2. Found. 543.2

[0220] Compound 5

[0221] 3-(7-((2-Chlorophenyl)amino)- 1 -methyl-2-oxo- 1 ,2-dihydro- 1 ,6-naphthyridin-3-yl)-4-methyLA- (3 - (trifluor omethy l)pheny l)benzamide

[0222] 3-(7-((2-Chlorophenyl)amino)-l-methyl-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-4- methyl-N-(3-(trifluoromethyl)phenyl)benzamide. A mixture of 3-(7-chloro-l-methyl-2-oxo-l,6- STDU2-44049.601 naphthyridin-3-yl)-4-methyl- / V-[3-(trifluoromethyl)phenyl]benzamide (50 mg, 105.96 pmol), 2- chloroaniline (20.28 mg, 158.95 pmol), Pd2(dba)3(9.70 mg, 10.60 pmol), XPhos (10.10 mg, 21.19 pmol) and CS2CO3 (69.05 mg, 211.93 pmol) in dioxane (2.5 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 80 °C for 12 h under an N2 atmosphere. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 45-75% CH3CN / H2O (0.1% TFA)) followed by a second purification by preparative HPLC (WePure Biotech XP tC18 150 mm x 40 mm, 7 um; 55-95% CH3CN / H2O (10 mM NH4HCO3)) to afford the product (16.94 mg, 27.76%) as a white solid. 'H NMR (400 MHz, CD3CN) 6 8.96 (br s, 1 H), 8.48 (s, 1 H), 8.12-8.20 (m, 2 H), 7.84-7.94 (m, 2 H), 7.79 (d, J=2.00 Hz, 1 H), 7.73 (s, 1 H), 7.55 (t, J=8.00 Hz, 1 H), 7.38-7.50 (m, 4 H), 7.31-7.37 (m, 1 H), 7.08 (td, J=7.69, 1.50 Hz, 1 H), 6.76 (s, 1 H), 3.58 (s, 3 H), 2.27 (s, 3 H). MS-ESI (m / z) calc’d for C30H23CIF3N4O2 [M+H]+: 563.1 / 565.1. Found. 563.2 / 565.2.

[0223] Compound 6

[0224] 3-(2-((2-Methoxyphenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4- methyl- / V-(3-(trifluoromethyl)phenyl)benzamide

[0225] 6-Bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 6- bromo-2-methylsulfanyl-8H-pyrido[2,3-(7]pyrimidin-7-one (2 g, 7.35 mmol) in DMF (30 mL) were added CS2CO3 (2.39 g, 7.35 mmol) and Mel (1.04 g, 7.35 mmol) at 20 °C, and then the mixture was stirred at 90 °C for 4 h. The reaction mixture was poured into water and a yellow solid formed. The solid was filtered, washed with H2O (2x), and dried under vacuum to give the product (1.9 g) as a white solid that was used without further purification. MS-ESI (m / z) calc’d for C9H9BrN3OS [M+H]+: 285.9 / 287.9. Found: 286.0 / 287.9. STDU2-44049.601

[0226] Methyl 4-methyl-3-( 8-methyl-2-( methylthio )- 7-oxo-7, 8-dihydropyrido[ 2,3 -d ]pyrimidin-6- yl)benzoate. A mixture of 6-bromo-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 1.75 mmol), (5-methoxycarbonyl-2-methylphenyl)boronic acid (677.94 mg, 3.49 mmol), Pd(amphos)C12 (123.72 mg, 174.73 pmol), and KO Ac (514.47 mg, 5.24 mmol) in EtOH (10 mL) and H2O (1 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 80 °C for 12 h under an N2 atmosphere. The reaction mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was diluted with MeOH and a yellow solid formed that was filtered, washed with MeOH (2x), and dried under vacuum to give the product (350 mg) as a yellow solid that was used without further purification. MS-ESI (m / z) calc’d for CI8HI8N3O3S [M+H]+: 356.1. Found: 356.1.

[0227] Methyl 4-methyl-3-(8-methyl-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)benzoate . To a solution of methyl 4-methyl-3-(8-methyl-2-(methylthio)-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)benzoate (350 mg, 984.78 pmol) in CH2Q2 (10 mL) was added m-CPBA (479.83 mg, 2.36 mmol) at 20 °C and the mixture was stirred for 12 h. The reaction mixture was quenched by addition of saturated aqueous Na3S2O3at 0 °C, and then diluted with NaHCO3and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give the product (290 mg) as a yellow solid that was used without further purification. MS-ESI (m / z) calc’d for C18H18N3O5S [M+H]+: 388.0. Found: 388.1. STDU2-44049.601

[0228] Methyl 3-( 2-( (2-methoxyphenyl)amino)-8-methyl- 7-oxo-7,8-dihydropyrido[ 2,3- d]pyrimidin-6-yl)-4-methylbenzoate. To a solution of methyl 4-methyl-3-(8-methyl-2- (methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-^ / ]pyrimidin-6-yl)benzoate (200 mg, 516.25 pmol), 2-methoxyaniline (69.94 mg, 567.88 pmol) in butan-2-ol (4 mL) was added TFA (176.59 mg, 1.55 mmol) at 20 °C, and then the mixture was stirred at 90 °C for 12 h. The mixture was concentrated to give a residue. The residue was purified by silica gel chromatography using a 0- 10% EtOAc / petroleum ether gradient eluent to give the product (110 mg, 19.2%, 4 steps) as a white solid. MS-ESI (m / z) calc’d for C24H23N4O4 [M+H]+: 431.1. Found: 431.2.

[0229] 3-(2-((2-Methoxyphenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6- yl)-4-methylbenzoic acid. To a solution of methyl 3-(2-((2-methoxyphenyl)amino)-8-methyl-7- oxo-7, 8-dihydropyrido[2,3-<7]pyrimidin-6-yl)-4-methylbenzoate (90 mg, 209.08 pmol) in THF (2 mL), MeOH (0.2 mL), and H2O (0.2 mL) was added LiOH’I O (26.32 mg, 627.24 pmol) at 20 °C. The mixture was stirred at 20 °C for 12 h and then quenched by addition of IM HC1 to pH = 3. A white solid formed that was washed with H2O (2x), filtered, and dried under vacuum to give the product (50 mg) as a white solid that was used without further purification. MS-ESI (m / z) calc’d for C23H21N4O4 [M+H]+: 417.1. Found: 417.1.

[0230] 3-(2-( ( 2-Methoxyphenyl)amino )-8-methyl- 7 -oxo- 7, 8-dihydropyrido[ 2, 3-d ]pyrimidin-6- yl)-4-methyl-N-( 3-(trifluoromethyl)phenyl)benzamide . To a solution of 3-(2-((2- methoxyphenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-<7]pyrimidin-6-yl)-4- STDU2-44049.601 methylbenzoic acid (50 mg, 120.07 pmol) in DMF (2 mL) were added DIEA (46.55 mg, 360.21 pmol), 3-(trifluoromethyl)aniline (21.28 mg, 132.08 pmol), and HATU (54.78 mg, 144.08 pmol) at 20 °C. The mixture was stirred at 20 °C for 12 h and then concentrated to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna Cl 8; 100 mm x 30 mm, 5 um; 50- 80% CH3CN / H2O (0.1% TFA)) to give the product (24.93 mg, 17.7%, 2 steps) as a white solid TFA salt. 'H NMR (400 MHz, DMSO-d6) 8 10.49 (s. 1 H), 8.81 (s, 1 H). 8.75 (s, 1 H), 8.23 (s. 1 H), 8.08 (br d, 1=6.50 Hz, 2 H), 7.92-7.96 (m, 1 H), 7.84-7.91 (m, 2 H), 7.59 (t, 1=8.07 Hz, 1 H), 7.41-7.49 (m, 2 H), 7.08-7.16 (m, 2 H), 6.98-7.06 (m. 1 H), 3.87 (s, 3 H), 3.63 (s, 3 H), 2.25 (s, 3 H). MS-ESI (m / z) calc’d for C30H25F3N5O3 [M+H]+: 560.1. Found: 560.2.

[0231] Compound 7

[0232] 4-Methyl-3-(8-methyl-7-oxo-2-(o-tolylamino)-7,8-dihydropyrido[2,3-rf]pyrimidin-6-yl)-Ar-(3-

[0233] (trifluoromethyl)phenyl)benzamide

[0234] Methyl 4-methyl-3-(8-methyl-7-oxo-2-(o-tolylamino)-7,8-dihydropyrido[2,3-d]pyrimidin- 6-yl)benzoate. To a solution of methyl 4-methyl-3-(8-methyl-2-methylsulfonyl-7-oxo- pyrido[2,3-tZ]pyrimidin-6-yl)benzoate (300 mg, 774.38 pmol) and 2-methylaniline (91.27 mg, 851.81 pmol) in 2-butanol (5 mL) was added TFA (264.89 mg, 2.32 mmol) at 20 °C. The mixture was then stirred at 110 °C for 12 h and concentrated to give a residue. The residue was purified by silica gel chromatography using a 0-10% EtOAc / petroleum ether gradient eluent to give the product (160 mg, 49.9%) as a yellow solid. MS-ESI (m / z) calc’d for C24H23N4O3 [M+H]+: 415.1 Found: 415.2. STDU2-44049.601

[0235] 4-Methyl-3-( 8-methyl-7-oxo-2-( o-tolylamino )- 7, 8-dihydropyrido[ 2, 3-d ]pyrimidin-6- yl)benzoic acid. To a solution of methyl 4-methyl-3-(8-methyl-7-oxo-2-(o-tolylamino)-7,8- dihydropyrido[2,3-rZ]pyrimidin-6-yl)benzoate (40 mg, 96.51 pmol) in THF (1 mL), H2O (0.1 mL) and MeOH (0.1 mL) was added LiOH*H2O (12.15 mg, 289.54 pmol) at 20 °C, and then the mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by addition of IM HC1 to pH = 3. A white solid formed that was washed with H2O (2x), filtered, and dried to give the product (30 mg) as a white solid that was used without further purification. MS-ESI (m / z) calc’d for C23H21N4O3 [M+H]+: 401.1 Found: 401.2.

[0236] 4-Methyl-3 -( 8-methyl- 7 -oxo-2-( o-tolylamino )- 7,8-dihydropyridof 2, 3-d ]pyrimidin-6-yl)- N-(3-(trifluoromethyl)phenyl)benzamide. To a solution of 4-methyl-3-(8-methyl-7-oxo-2-(o- tolylamino)-7,8-dihydropyrido[2,3-rZ]pyrimidin-6-yl)benzoic acid (30 mg, 74.92 pmol) in DMF (1 mL) was added 3 -(trifluoromethyl) aniline (13.28 mg, 82.41 pmol), DIEA (29.05 mg, 224.76 pmol), HATU (34.18 mg, 89.90 pmol) at 20 °C, and then the mixture was stirred at 20 °C for 2 h. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 100 mm x 30 mm, 5 um; 45-85% CH3CN / H2O (0.1% TFA)) to give the product (7.8 mg, 12.2%, 2 steps) as a white solid TFA salt. 'H NMR (400 MHz, DMSO- d6) 8 10.49 (s, 1 H), 9.44 (s. 1 H), 8.75 (s, 1 H), 8.23 (s, 1 H), 8.07 (br d, J=8.00 Hz, 1 H). 7.93 (dd, J=7.94, 1.81 Hz, 1 H), 7.83-7.88 (m, 2 H), 7.52-7.63 (m, 2 H), 7.42-7.48 (m, 2 H), 7.20-7.30 (m, 2 H), 7.14 (d, .1=6.50 Hz, 1 H), 3.53 (br s, 3 H), 2.27 (s, 3 H), 2.24 (s, 3 H). MS-ESI (m / z) calc’d for C30H25F3N5O2 [M+H]+: 544.1 Found: 544.2.

[0237] Compound 8 STDU2-44049.601

[0238] 3-(2-((2-Chlorophenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4- methyl-A-(3-(trifluoromethyl)phenyl)benzamide

[0239] Methyl 3-(2-( (2-chlorophenyl )amino )-8-methyl-7-oxo-7,8-dihydropyrido[ 2,3- d]pyrimidin-6-yl)-4-methylbenzoate. To a solution of methyl 4-methyl-3-(8-methyl-2- methylsulfonyl-7-oxo-pyrido[2,3-<7]pyrimidin-6-yl)benzoate (350 mg, 903.44 pmol) and 2- chloroaniline (126.78 mg, 993.78 pmol) in dioxane (5 mL) was added TFA (309.03 mg, 2.71 mmol) at 20 °C. The mixture was then stirred at 120 °C for 12 h and concentrated to give a residue. The residue was purified by silica gel chromatography using a 0-10% EtOAc / petroleum ether gradient eluent to give the product (180 mg, 45.8%) as a yellow solid. MS-ESI (m / z) calc’d for C23H20CIN4O3 [M+H]+: 435.1 Found: 435.1.

[0240] 3-(2-((2-ChlorophenyI)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)~ 4-methylbenzoic acid. To a solution of methyl 3-(2-((2-chlorophenyl)amino)-8-methyl-7-oxo- 7,8-dihydropyrido[2,3-<7]pyrimidin-6-yl)-4-methylbenzoate (80 mg, 183.96 pmol) in THF (1 mL), H2O (0.1 mL) and MeOH (0.1 mL) was added LiOFFEEO (23.16 mg, 551.88 pmol) at 20 °C, and the mixture was stirred at 20 °C for 4 h. The reaction mixture was quenched by addition of IM HC1 to pH = 3. A white solid formed that was washed with H2O (2x), filtered, and dried to give the product (50 mg) as a white solid that was used without further purification. MS-ESI (m / z) calc’d for C22H18CIN4O3 [M+H]+: 421.1 Found: 421.1. STDU2-44049.601

[0241] 3-(2-((2-ChlorophenyI)amino)-8-methyl-7-oxo-7, 8-dihydropyrido[2,3-d]pyrimidin-6-yl)- 4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide. To a solution of 3-(2-((2- chlorophenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-6 / ]pyrimidin-6-yl)-4-methylbenzoic acid (50 mg, 118.81 pmol) in DMF (1 mL) were added 3-(trifluoromethyl)aniline (21.06 mg, 130.69 pmol), DIEA (46.06 mg, 356.42 pmol) and HATU (54.21 mg. 142.57 pmol) at 20 °C. The mixture was then stirred at 20 °C for 12 h. The mixture was concentrated to give a residue that was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 60- 85% CH3CN / H2O (0.1% TFA)) to give the product (22.66 mg, 18.16%, 2 steps) as a white solid TFA salt. 'H NMR (400 MHz, DMSO-d6) 8 10.50 (s, 1 H), 9.56 (s, 1 H), 8.80 (s, 1 H), 8.23 (s, 1 H), 8.07 (br d, J=8.50 Hz. 1 H). 7.93 (dd, J=7.88, 1.75 Hz, 1 H), 7.89 (s, 1 H), 7.85 (d. J=1.50 Hz, 1 H), 7.81 (d, J=7.75 Hz, 1 H), 7.53-7.63 (m, 2 H), 7.36-7.48 (m, 3 H), 7.22-7.28 (m, 1 H), 3.55 (s, 3 H), 2.24 (s, 3 H). MS-ESI (m / z) calc’d for C29H22CIF3N5O2 [M+H]+: 564.1 Found: 564.2.

[0242] Compound 9

[0243] 3-(2-((2-Methoxyphenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-rZ]pyrimidin-6-yl)-4- methyl- / V-(5-(trifluoromethyl)oxazol-2-yl)benzamide

[0244] 3-(2-( (2-Methoxyphenyl )amino )-8-methyl-7-oxo- 7, 8-dihydropyrido[ 2,3 -d ]pyrimidin-6- yl)-4-methyl-N-(5-(trifluoromethyl)oxazol-2-yl)benzamide. To a solution of 3-[2-(2- methoxyanilino)-8-methyl-7-oxo-pyrido[2,3-<f|pyrimidin-6-yl]-4-methyl-benzoic acid (40 mg, STDU2-44049.601

[0245] 96.05 pmol) and 5-(trifluoromethyl)oxazol-2-amine (21.91 mg, 144.08 pmol) in pyridine (1 mL) was added POCh (29.46 mg, 192.11 pmol) at 0 °C. The mixture was then stirred at 20 °C for 12 hrs. The reaction mixture was quenched with saturated aqueous NaHCCh (10 ml) at 0 °C, and then diluted with H2O (10 ml) and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous NazSC , filtered, and the filtrate was concentrated. The mixture was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 35-65% CH3CN / H2O (0.1% TFA)) to give the product (4.89 mg, 7.54%) as a yellow solid, TFA salt. 'H NMR (400 MHz, DMSO-d6) 5 11.99 (s, 1 H), 8.80 (s, 1 H), 8.71-8.79 (m, 2 H), 8.00-8.12 (m, 1 H), 7.93 (dd, J=8.00, 1.88 Hz, 1 H), 7.81-7.90 (m, 2 H), 7.46 (d, 1=8.13 Hz, 1 H), 7.06-7.17 (m, 2 H), 6.98-7.05 (m, 1 H), 3.87 (s, 3 H), 3.62 (s, 3 H), 2.25 (s, 3 H). MS-ESI (m / z) cak’d for C27H22F3N6O4 [M+H]+: 551.1. Found. 551.3.

[0246] Compound 10

[0247] 3-(2-((2-Methoxyphenyl)amino)-7-oxo-7,8-dihydropyrido[2,3- ]pyrimidin-6-yl)-4-methyl- / V-(3-

[0248] (trifluoromethyl)phenyl)benzamide

[0249] Methyl 4-methyl-3-(2 -( methylthio )-7-oxo- 7, 8-dihydropyrido[ 2, 3 -d ]pyrimidin-6- yl)benzoate. A mixture of 6-bromo-2-methylsulfanyl-8H-pyrido[2,3-<7]pyrimidin-7-one (850 mg, 3.12 mmol), (5-methoxycarbonyl-2-methyl-phenyl)boronic acid (727.14 mg, 3.75 mmol), Pd(amphos)C12 (221.17 mg, 312.36 pmol), and KOAc (919.67 mg, 9.37 mmol) in EtOH (21 mL) and H2O (7 mL) was degassed and purged with N2 (3x) at 20 °C. The mixture was then stirred at 80 °C for 12 hrs under an N2 atmosphere. The mixture was concentrated to give a residue which was treated with EtOAc (3 mL) and H2O (2 mL). A white solid formed that was filtered and washed with EtOAc and dried under vacuum to give the product (923 mg, 86.26%) as a paleyellow solid that was used without further purification. 'H NMR (400 MHz, DMSO-de) 8 12.28- STDU2-44049.601

[0250] 13.02 (m, 1 H), 8.86 (s, 1 H), 7.85-7.95 (m, 2 H), 7.79 (d, J=1.63 Hz, 1 H), 7.44 (d, J=8.00 Hz, 1

[0251] H), 3.84 (s, 3 H), 2.58 (s, 3 H), 2.24 (s, 3 H). MS-ESI (m / z) calc’d for C17H16N3O3S [M+H]+: 342.0 Found. 342.1.

[0252] Methyl 4-methyl-3-(2 -( methylsulfonyl )- 7 -oxo -7, 8-dihydropyrido[ 2,3 -d ]pyrimidin-6- yljbenzoate. To a solution of methyl 4-methyl-3-(2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)benzoate (300 mg, 878.78 pmol) in MeOH (7 mL) and THF (7 mL) was added oxone (1.35 g, 2.20 mmol) in H2O (7 mL) at 0 °C. The mixture was then stirred at 20 °C for 12 hrs. The reaction mixture was diluted with NaHCO? to pH=7. The aqueous layers were extracted with CH2CI2 (3x). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography using a 0-37% EtOAc / petroleum ether gradient eluant to give the product (200 mg, 61.0%) as a yellow solid. MS-ESI (m / z) calc’d for C17H16N3O5S [M+H]+: 374.0 Found. 374.2.

[0253] Methyl 3-(2-(( 2-methoxyphenyl )amlno)-7-oxo-7, 8-dihydropyrido[ 2,3 -d ]pyrimidin-6-yl )- 4-methylbenzoate. To a solution of methyl 4-methyl-3-(2-(methylsulfonyl)-7-oxo-7,8- dihydropyrido[2,3-<flpyrimidin-6-yl)benzoate (170 mg, 455.30 pmol) and 2-methoxyaniline (67.28 mg, 546.36 pmol) in dioxane (3 mL) was added TFA (51.91 mg, 455.30 pmol) at 20 °C. The mixture was stirred at 120 °C for 12 hrs and then concentrated to give a residue. The residue was purified by silica gel chromatography using a 0-80% EtOAc / petroleum ether gradient eluant to give the product (170 mg, 89.7%) as a yellow solid. MS-ESI (m / z) calc’d for C23H21N4O4 [M+H]+: 417.1 Found. 417.2. STDU2-44049.601

[0254] 3-(2-(( 2-Methoxyphenyl)amino )- 7-oxo-7, 8-dihydropyrido[ 2, 3 -d ]pyrimidin-6-yl )-4- methylbenzoic acid. To a solution of methyl 3-(2-((2-methoxyphenyl)amino)-7-oxo-7,8- dihydropyrido[2,3-r / ]pyrimidin-6-yl)-4-methylbenzoate (100 mg, 240.14 pmol) in THF (1 mL), MeOH (0.1 mL) and H2O (0.1 mL) was added LiOH^ELO (30.23 mg, 720.41 pmol) at 20 °C. The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was quenched by addition IM HC1 to pH = 5. A white solid formed that was filtered and washed with H2O (2x) and dried to give the product (50 mg) as a yellow solid that was used without further purification. MS-ESI (m / z) calc’d for C22H19N4O4 [M+H]+: 403.1 Found. 403.1.

[0255] 3 -(2 -((2 -Methoxyphenyl )amino)-7-oxo-7, 8-dihydropyrido[ 2,3 -d ]pyrimidin-6-yl )-4- methyl-N-(3-(trifluoromethyl)phenyl)benzamide. To a solution of 3-(2-((2- methoxyphenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-r / ]pyrimidin-6-yl)-4-methylbenzoic acid (50 mg, 124.25 pmol) and 3-(trifluoromethyl)aniline (20.02 mg, 124.25 pmol) in DMF (1 mL) were added DIEA (48.18 mg, 372.76 pmol) and HATU (70.87 mg, 186.38 pmol) at 20 °C and the mixture was stirred for 12 hrs. The reaction mixture was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 40-70% CH3CN / H2O (0.1% TFA)) to give the product (8.00 mg, 5.05%, 2 steps) as a yellow solid, TFA salt. 'H NMR (400 MHz, DMSO-dfi) 5 12.34 (s, 1 H), 10.49 (s, 1 H), 8.77 (s, 1 H), 8.48 (s, 1 H), 8.21-8.30 (m, 2 H), 8.08 (d, J=9.13 Hz, 1 H), 7.93 (dd, J=8.00, 1.88 Hz, 1 H), 7.85-7.90 (m, 2 H), 7.60 (t, J=8.07 Hz. 1 H), 7.45 (br d, J=7.88 Hz, 2 H), 7.07-7.12 (m, 2 H), 6.98 (s, 1 H), 3.87 (s, 3 H), 2.27 (s, 3 H). MS-ESI (m / z) calc’d for C29H23F3N5O3 [M+H]+: 546.1 Found. 546.2. STDU2-44049.601

[0256] Compound 11

[0257] 3-(2-((2-Methoxyphenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-<f|pyrimidin-6-yl)-4- methyl-A-(l -(trifluoromethyl)- l / / -pyrazol-3-yl)benzamide

[0258] 3-( 2-(( 2-Methoxyphenyl )amino )-8-melhyl-7-oxo- 7, 8-dihydropyrido[ 2, 3-d ]pyrimidin-6- yl)-4-methyl-N-(l-( trifluoromethyl)-] H-pyrazol-3-yl)benzamide. To a solution of 3-(2-((2- methoxyphenyl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4- methylbenzoic acid (50 mg, 120.07 pmol) and l-(trifluoromethyl)pyrazol-3-amine (36.28 mg, 240.14 pmol) in Py (2 mL) was added POCh (36.82 mg, 240.14 pmol) at 0 °C. The mixture was then stirred at 20 °C for 12 hrs. The reaction mixture was quenched by addition of saturated aqueous NaHCCh (10 mL) at 0 °C. and then diluted with H2O (10 ml) and extracted with EtOAc (3x). The combined organic phases were dried over anhydrous NaiSCU, filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18; 100 mm x 30 mm, 5 um; 40-75% CH3CN / H2O (0.1% TFA)) to afford the product (5.3 mg, 6.6%) as a yellow solid, TFA salt. 'H NMR (400 MHz, DMSO-d6) 5 11.37 (s, 1 H), 8.80 (s, 1 H), 8.76 (s, 1 H), 8.43 (d, J=2.88 Hz, 1 H), 8.08 (br d, J=8.38 Hz. 1 H), 7.92-8.00 (m, 2 H), 7.89 (s, 1 H), 7.42 (d, J=8.00 Hz, 1 H), 7.08-7.18 (m, 2 H), 6.98 - 7.07 (m, 2 H), 3.87 (s, 3 H), 3.62 (s, 3 H), 2.23 (s, 3 H). MS-ESI (m / z) calc’d for C27H23F3N7O3 [M+H]+: 550.1. Found. 550.3.

[0259] Compounds 12-17

[0260] Compounds 12-17 were synthesized in a similar manner to compounds 1-11. using appropriate starting materials. STDU2-44049.601

[0261] Compound 12

[0262] 3-(2-((l,3-dimethyl-lH-pyrazol-5-yl)amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimldin-6-yl)-4-melhyl-N-(3-(lrifluoromelhyl)phenyl)benzamide.rH NMR (400 MHz, DMSO-de) d 10.50 (s, 1 H), 9.97 (br s, 1 H), 8.82 (s, 1 H), 8.23 (s, 1 H), 8.08 (br d, J=8.38 Hz, 1 H), 7.94 (dd, J=7.94, 1.81 Hz, 1 H), 7.91 (s, 1 H), 7.86 (d, J=1.75 Hz, 1 H), 7.59 (t, 1=8.00 Hz, 1 H), 7.41-7.49 (m, 2 H), 6.17 (br s, 1 H), 3.65 (s, 3 H). 3.60 (s, 3 H), 2.24 (s, 3 H), 2.15 (s, 3 H). MS-ESI (m / z) calc’d for C28H25F3N7O2 [M+H]+: 548.2. Found. 548.2.

[0263] Compound 13

[0264] N-(3-(2-(( 1 ,3-dimethyl-lH-pyrazol-5-yl )ammo )-8-methyl- 7 -oxo- 7, 8-dihydropyridol2,3- d]pyrimidin-6-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide. 'H NMR (400 MHz, DMSO- de) d 10.46 (s, 1 H) 9.94 (br s, 1 H) 8.82 (s, 1 H) 8.30 (s, 1 H) 8.24-8.28 (m, 1 H) 7.96 (br d, J=7.88 Hz, 1 H) 7.83 (s, 1 H) 7.75-7.82 (m, 1 H) 7.64-7.72 (m, 2 H) 7.27 (d, J=8.38 Hz, 1 H) 6.17 (s, 1 H) 3.65 (s, 3 H) 3.59 (s, 3 H) 2.14 (d, J=4.50 Hz, 6 H). MS-ESI (m / z) calc’d for C28H25F3N7O2 [M+H]+: 548.2. Found. 548.2.

[0265] Compound 14

[0266] N-(4-chlorophenyl)-3-(2-((2-methoxyphenyI)amino)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylbenzamide. 'H NMR (400 MHz, DMSO-de) d STDU2-44049.601

[0267] 10.32 (s, 1 H), 8.78 (br d, J=18.14 Hz, 2 H), 8.08 (br d, 1=7.75 Hz, 1 H), 7.87-7.97 (m, 2 H), 7.76-7.87 (m, 3 H), 7.33-7.53 (m, 3 H), 7.07-7.18 (m, 2 H), 6.96-7.05 (m, 1 H), 3.87 (s, 3 H), 3.62 (s, 3 H). 2.24 (s, 3 H). MS-ESI (m / z) calc’d for C29H26CIN5O3 [M+H]+: 526.4. Found. 526.2.

[0268] Compound 15

[0269] N-(4-methoxyphenyl )-3-(2-( (2-methoxyphenyl)amino )-8-methyl-7-oxo-7, 8- dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylbenzamide. 'H NMR (400 MHz, DMSO-de) d 10.08 (s, 1 H), 8.60-8.84 (m, 2 H), 8.09 (br d, J=7.25 Hz, 1 H), 7.84-7.94 (m, 2 H), 7.82 (d, 1=1.38 Hz, 1 H), 7.66 (br d, 1=9.01 Hz, 2 H), 7.42 (d, J=8.00 Hz, 1 H), 7.07-7.16 (m, 2 H), 6.97- 7.05 (m, 1 H), 6.92 (br d, J=9.01 Hz. 2 H). 3.87 (s, 3 H), 3.74 (s. 3 H), 3.62 (s, 3 H). 2.23 (s, 3 H). MS-ESI (m / z) calc’d for C30H28N5O4 [M+H]+: 522.4. Found. 522.2.

[0270] Compound 16

[0271] 3-(2 -(( 2-methoxyphenyl)amino )-8-methyl- 7-oxo-7, 8-dihydropyrido[ 2,3 -d ]pyrimidin-6- yl)-4-methyl-N-(p-tolyl)benzamide. 'H NMR (400 MHz, DMSO-de) d 10.12 (s, 1 H), 8.80 (s, 1 H), 8.76 (s, 1 H), 8.08 (br d, 1=7.88 Hz, 1 H), 7.86-7.93 (m, 2 H), 7.82 (d, 1=1.63 Hz, 1 H), 7.64 (d, 1=8.38 Hz, 2 H), 7.42 (d, 1=8.00 Hz, 1 H), 7.08-7.17 (m, 4 H), 6.97-7.05 (m, 1 H), 3.87 (s. 3 H), 3.62 (s, 3 H), 2.27 (s, 3 H), 2.23 (s, 3 H). MS-ESI (m / z) calc’d for C30H26N5O3 [M+H]+: 506.4. Found. 506.2. STDU2-44049.601

[0272] Compound 17

[0273] 3-(8-ethyl-2-((2-methoxyphenyl)amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)- 4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide.rH NMR (400 MHz, DMSO-de) d 10.49 (s, 1 H), 8.81 (s, 1 H), 8.75 (s, 1 H), 8.23 (s, 1 H), 8.07 (br t, 1=6.57 Hz, 2 H), 7.93 (dd, J=7.88, 1.88 Hz, 1 H), 7.85-7.91 (m, 2 H), 7.59 (t, 1=7.94 Hz, 1 H), 7.42-7.48 (m, 2 H), 7.08-7.16 (m, 2 H), 6.98-7.05 (m, 1 H), 4.34 (q, 1=6.84 Hz, 2 H), 3.87 (s, 3 H), 2.24 (s, 3 H), 1.25 (t, 1=6.94 Hz, 3 H). MS-ESI (m / z) calc’d for C31H27F3N5O3 [M+H]+: 574.2. Found. 574.4.

[0274] Compound 18

[0275] N-( 4-methoxy-3 -methylphenyl )-3-( 2-(( 2-methoxyphenyl )amino )-8-methyl-7 -oxo- 7, 8- dihydropyrido[2,3-d]pyrimldin-6-yl)-4-methylbenzamide. 'H NMR (400 MHz, DMSO-de) d 9.99 (s, 1 H), 8.80 (s, 1 H), 8.73 (s, 1 H), 8.10 (br d, J=7.75 Hz, 1 H), 7.85-7.93 (m, 2 H), 7.83 (d, J=1.63 Hz, 1 H), 7.50-7.58 (m, 2 H), 7.41 (d, J=8.00 Hz, 1 H), 7.08-7.16 (m, 2 H), 6.98-7.05 (m, 1 H), 6.90 (d, 1=8.76 Hz, 1 H), 3.87 (s, 3 H), 3.76 (s, 3 H), 3.63 (s, 3 H), 2.23 (s, 3 H), 2.14 (s, 3 H). MS-ESI (m / z) calc’d for C31H30N5O4 [M+H]+: 536.2. Found. 536.2.

[0276] Compound 19 STDU2-44049.601

[0277] N-(4-(dimethyIamino)phenyl)-3-(2-((2-methoxyphenyl)amino)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylbenzamide. 'H NMR (400 MHz, DMSO-de) d 10.11 (br s. 1 H), 8.80 (s, 1 H), 8.74 (s. 1 H), 8.09 (br d, .1=7.75 Hz, 1 H), 7.86-7.93 (m, 2 H), 7.82 (d, 1=1.38 Hz, 1 H), 7.70 (br d, J=7.38 Hz, 2 H), 7.42 (d, J=8.00 Hz, 1 H), 6.96-7.18 (m, 5 H), 3.87 (s, 3 H), 3.63 (s, 3 H), 2.98 (br s, 6 H), 2.24 (s, 3 H). MS-ESI (m / z) calc’d for C31H31N6O3 [M+H]+: 535.3. Found. 535.2.

[0278] Compound 20

[0279] N-( 4-( dimethylamino )-3-methylphenyl)-3-( 2 -((2 -methoxyphenyl )amino )-8-methyl-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylbenzamide.!H NMR (400 MHz, CDCI3) d 8.59 (s. 1 H). 8.40-8.51 (m. 2 H). 8.35 (s, 1 H), 7.79 (br t, J=6.69 Hz, 2 H). 7.70 (s, 1 H), 7.56 (s. 1 H), 7.51 (s, 1 H), 7.35 (t, J=7.57 Hz, 2 H), 7.04-7.14 (m, 2 H), 6.96 (d, J=7.63 Hz, 1 H), 3.94 (s. 3 H), 3.79 (s, 3 H), 3.22 (s, 6 H), 2.54 (s, 3 H), 2.28 (s, 3 H). MS-ESI (m / z) calc’d for C32H33N6O3 [M+H]+: 549.3. Found. 549.2.

[0280] Compound 21

[0281] N-(3,5-difluorobenzyl)-3-(2-((2-methoxyphenyl)amino)-8-methyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylbenzamide. 'H NMR (400 MHz, DMSO-de) d 9.07 (t, J=6.00 Hz, 1 H), 8.79 (s, 1 H). 8.73 (s, 1 H), 8.08 (d. 1=7.50 Hz, 1 H), 7.81-7.88 (m, 2 H), 7.76 (d, 1=1.75 Hz, 1 H), 7.39 (d, 1=8.13 Hz, 1 H), 7.06-7.17 (m, 3 H), 6.97-7.05 (m, 3 H), 4.48 (d, 1=5.88 Hz, 2 H), 3.87 (s, 3 H), 3.61 (s, 3 H), 2.21 (s, 3 H). MS-ESI (m / z) calc’d for C30H26F2N5O3 [M+H]+: 542.2. Found. 542.2. STDU2-44049.601

[0282] Compound 22

[0283] 4-methyl-3-(8-methyl-7-oxo-2-((2,4,6-trifluorophenyl)amino)-7,8-dihydropyrido[2,3- d]pyrimidin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzamide. 'H NMR (400 MHz, DMSO-de) d 10.48 (s, 1 H) 9.63 (br s, 1 H) 8.77 (br s, 1 H) 8.22 (s, 1 H) 8.07 (br d, 1=8.38 Hz, 1 H) 7.93 (dd, J=7.94, 1.81 Hz, 1 H) 7.88 (s, 1 H) 7.83-7.86 (m, 1 H) 7.52-7.65 (m, 1 H) 7.42-7.48 (m, 2 H) 7.34 (br t, J=8.57 Hz, 2 H) 3.51 (br s, 3 H) 2.23 (s, 3 H). MS-ESI (m / z) calc’d for C29H20F6N5O2 [M+H]+: 584.2. Found. 584.1.

[0284] Compound 23

[0285] 4-methyl-3-( 8-methyl- 7-oxo-2-( (2-( trifluoromethoxy )phenyl )amino )-7, 8- dihydropyrido[2,3-d]pyrimidin-6-yl)-N-(3-( trifluoromethyl)phenyl)henzamide. 'H NMR (400 MHz, DMSO-de) d 10.49 (s, 1 H), 9.73 (s, 1 H), 8.81 (s, 1 H), 8.23 (s, 1 H), 8.07 (br d, J=8.13 Hz, 1 H), 7.93 (br d. 1=2.13 Hz, 2 H), 7.82-7.90 (m, 2 H), 7.59 (t, J=8.00 Hz. 1 H), 7.39-7.48 (m. 4 H), 7.27-7.34 (m, 1 H), 3.57 (s, 3 H), 2.24 (s, 3 H). MS-ESI (m / z) calc’d for C30H22F6N5O3 [M+H]+: 614.2. Found. 614.2. STDU2-44049.601

[0286] Compound 24

[0287] 4-methyl-3-(8-methyl-2-(( 1 -methylpiperidin-4-yl)amino)-7-oxo-7 ',8-dihydropyrido[2,3- d]pyrimidin-6-yl)-N-(3-(lrijluoromelhyl)phenyl)benzamide. 'H NMR (400 MHz, DMSO-de) d 10.50 (s, 1 H), 9.24-9.46 (m, 1 H), 8.65-8.75 (m, 1 H), 8.24 (s, 1 H), 8.09 (br d, J=8.63 Hz, 1 H), 7.94 (dd, J=7.94, 1.69 Hz, 1 H), 7.78-7.89 (m, 2 H), 7.61 (t, J=8.00 Hz, 1 H), 7.46 (d, J=8.00 Hz, 2 H), 4.24-4.34 (m, 1 H), 3.59-3.68 (m, 3 H), 3.35-3.54 (m, 2 H), 3.10-3.33 (m, 2 H), 2.76-2.85 (m, 3 H), 2.24 (s, 3 H), 2.01-2.21 (m, 2 H), 1.64-1.90 (m, 2 H). MS-ESI (m / z) calc’d for C29H30F3N6O2 [M+H]+: 551.2. Found. 551.3.

[0288] Example 2 Kinase Activity Assay

[0289] ERRK2 kinase activity was measured using a EanthaScreen™ Kinase Activity Assay from ThermoFisher Scientific. Recombinant wild type or G2019S-ERRK2 protein (Fife Technologies, PR8604B or PV4881, respectively), was incubated with a fluorescein-labeled peptide substrate called ERRKtide that is based upon ezrin / radixin / moesin (ERM) (Fife Technologies, PV4901) in the presence of ATP and serially diluted compound. After an incubation period of 1 hr, the phosphotransferase activity was stopped and a terbium-labelled anti-pERM antibody (Fife Technologies, PV4899) was added to detect the phosphorylation of ERRKtide by measuring the time resolved-Forster resonant energy transfer (TR-FRET) signal from the terbium label on the antibody to the fluorescein tag on ERRKtide, expressed as the 520 nm / 495 nm emission ratio. Compound-dependent inhibition of the TR-FRET signal was used to generate a concentration-response curve for IC50 determination.

[0290] The assay was carried out under the following protocol conditions: 1 mM compound in DMSO was serially diluted 1:3, 11 points in DMSO with a Biomek FX and 0.1 pF of the diluted compound was subsequently stamped into the assay plate (384-well format Eumitrac 200, Greiner, 781075) with an Echo Eabcyte such that the final compound concentration in the assay was 10 pM to 169 pM. Subsequently, 5 pF of 2x kinase solution (2.9 nM final concentration) STDU2-44049.601 was added to the assay plate in assay buffer composed of 50 mM Tris pH 8.5 (Sigma, T6791), 5 mM MgCh (Fluka, 63020), 1 mM EGTA (Sigma, E3889), 0.01% BRIJ-35 (Sigma, PI 254) and 2 mM DTT. The reaction was started by addition of 2x ATP / LRRKtide solution in assay buffer such that the final concentration was 400 nM LRRKtide and 25 pM ATP. After 60 min incubation at room temperature, the reaction was stopped by addition of 10 pL of 2x stop solution containing a final concentation of 2 nM anti-pERM antibody and 10 mM EDTA. After a 30 min incubation at RT, the TR-FRET signal was measured on a Wallac 2104 EnVision® multilabel reader at an excitation wavelength of 340 nm and reading emission at 520 nm and 495 nm. The ratio of the 520 nm and 495 nm emission was used to analyze the data. The Results of the LRRK2 kinase activity assay are shown below:

Claims

STDU2-44049.601CLAIMSor a pharmaceutically acceptable salt thereof, wherein:X1, X2, and X3are each independently selected from CRXand N, wherein each Rxis independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;R1is selected from monocyclic aryl, monocyclic 5- or 6-membered heteroaryl, or monocyclic 5- or 6-membered heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;R2is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;Z is -NHCO- or -CONH-;R3is selected from monocyclic aryl, monocyclic 5- or 6-membered heteroaryl, and arylalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, Ci- C4 alkoxy, and C1-C4 haloalkoxy; andR4is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy.In some embodiments, X1is N or CH. In some embodiments, X1is N. In some embodiments, X1is CH. In some embodiments, X2is CH. In some embodiments, X3is CH. In some embodiments, X2and X3are each CH.

2. The compound of formula (I), wherein the compound is a compound of formula (la):STDU2-44049.601da) or a pharmaceutically acceptable salt thereof, wherein:X1, X2, and X3are each independently selected from CRXand N, wherein each Rxis independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;R1is monocyclic aryl or monocyclic 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy;R2is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and C1-C4 haloalkyl;Z is -NHCO- or -CONH-;R3is monocyclic aryl or monocyclic 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy; andR4is selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, C1-C4 alkoxy, and C1-C4 haloalkoxy.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein X1is CH or N.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X2is CH.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein X3is CH.STDU2-44049.6016. The compound of any one of claims 1 -5, or a pharmaceutically acceptable salt thereof, wherein R1is selected from phenyl, a 5- or 6-membered heteroaryl having one or two nitrogen atoms, and a 6-membered heterocyclyl having one or two nitrogen atoms, each of which is unsubstituted or substituted with one or two substituents independently selected from C1-C2 alkyl, halo, and C1-C2 alkoxy.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1is selected from phenyl, pyridinyl, and piperidinyl, each of which is substituted with one substituent selected from methyl, methoxy, and halo.

8. The compound of any one of claims 1 and 3-5, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with one C1-C4 haloalkoxy substituent.

9. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl substituted with three halo substituents.

10. The compound of any one of claims 6-10, or a pharmaceutically acceptable salt thereof, wherein R1is a group selected from:

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is a 6-membered heterocyclyl having one nitrogen atom and is substituted with one C1-C4 alkyl.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R1is13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is pyrazolyl that is substituted with one or two methyl substituents.STDU2-44049.60114. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R1is15. The compound of any one of claims 1 and 3-5, or a pharmaceutically acceptable salt thereof, wherein R1is a group selected from:

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen and methyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R3is selected from phenyl, benzyl, and a 5-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S, each of which is unsubstituted or substituted with one or two substituents independently selected from C1-C2 haloalkyl, halo, and C1-C2 alkyl.

18. The compound of claim 17. wherein R3is selected from phenyl, oxazolyl, and pyrazolyl, each of which is substituted with one substituent selected from C1-C2 haloalkyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R3is a group selected from:STDU2-44049.60120. The compound of any one of claims 1 -15, or a pharmaceutically acceptable salt thereof, wherein R3is phenyl substituted with one or two substituents selected from halo, C1-C4 alkoxy, C1-C4 alkyl, and amino.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R3is selected from:

22. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R3is benzyl that is substituted with one, two, or three halo substituents.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R3is24. The compound of any one of claims 1-23, wherein R3is a group selected from:

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof. wherein R4is C1-C3 alkyl.

26. The compound of claim 25. or a pharmaceutically acceptable salt thereof, wherein R4is methyl.STDU2-44049.60127. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (lb):wherein:R1is selected from phenyl, a 5- or 6-membered heteroaryl having one or two nitrogen atoms, and a 6-membered heterocyclyl having one or two nitrogen atoms each of which is unsubstituted or substituted with one, two, or three substituents independently selected from Ci- C2 alkyl, halo, C1-C2 alkoxy, and C1-C2 haloalkoxy;X1is N or CH;R2is selected from hydrogen and C1-C3 alkyl;Z is -NHCO- or -CONH-; andR3is selected from monocyclic aryl, monocyclic 5- or 6-membered heteroaryl, and arylalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, halo, hydroxy, amino, cyano, Ci- C4 alkoxy, and C1-C4 haloalkoxy.

28. The compound of claim 1, wherein the compound is selected from:STDU2-44049.601STDU2-44049.601 and pharmaceutically acceptable salts thereof.

29. A pharmaceutical composition comprising a compound of any one of claims 1-28. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30. A method of inhibiting LRRK2 in a sample, comprising contacting the sample with an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof.

31. A method of treating Parkinson's disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein the disorder is Parkinson's disease.

33. A compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, for inhibiting LRRK2 in a sample.

34. A compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, for treatment of Parkinson's disease, cancer, leprosy, Crohn's disease, Alzheimer’s disease, other neurodegenerative diseases, or an immune-mediated disorder.

35. The compound for use of claim 34, wherein the disorder is Parkinson's disease.

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