# US 11,028,080 B2 · Substituted pyrimidines as LRKK2 inhibitors

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- Number: US 11,028,080 B2
- Document ID: US11028080B2
- Status: Granted
- Kind: B2
- Application number: 16/083,438
- Filed: 2017-03-10
- Published: 2019-03-21
- Granted: 2021-06-08
- Earliest claimed: 2016-03-11
- Assignees: Denali Therapeutics Inc.
- Applicants: Denali Therapeutics Inc.
- Inventors: Anthony A. Estrada; Jianwen A. Feng; Joseph P. Lyssikatos; Zachary K. Sweeney; Javier de Vicente Fidalgo
- Web page: https://patentgrep.com/patent/US11028080B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 498/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present disclosure relates generally to compounds of formula (I) or a pharmaceutically acceptable salt, prodrug, deuterated analog, tautomer, stereoisomer, or mixture of stereoisomers thereof and their use as LRRK2 inhibitors.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof,
wherein:
m is 1 or 2;
ring A is isothiazolyl or thiazolyl;
R1 is halo, cyano, C1-6 alkyl, or C1-6 haloalkyl;
R2 is N(R5)(R6), C1-6 alkoxy, or cycloalkyl;
each R3 is independently H, halo, cyano, C1-6 alkyl, C6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, amidoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C(O)R7, amido, N(R16)2, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkytheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, halo, cyano, hydrazino, azido, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, alkenyl, alkynyl, imino, hydrazone, amidino, oxime, C(O)H, amido, imido, carboxy, C(O)Oalkyl, amino, guanidino, NHC(O)Oalkyl, hydroxy, alkoxy, haloalkoxy, OC(O)NH2, thiol, thiocyanate, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido, sulfinic acid, sulfonic acid, cycloalkyl, heterocyclyl, aryl, heteroaryl, and Si(RY)3;
R5 is H, C1-6 alkyl, C1-6 haloalkyl, or cycloalkyl;
R6 is H, C1-6 alkyl, C1-6 haloalkyl, or cycloalkyl;
each R7 is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or heterocyclyl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C1-6 alkoxy, and C1-6 alkylsulfonyl;
each R16 is independently H or C1-6 alkyl, wherein each C1-6 alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C1-6 alkoxy, and C1-6 alkylsulfonyl; and
each RY is independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
with the proviso that if R5 or R6 is cycloalkyl, then ring A is not isothiazolyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is of formula (I′):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof,
wherein:
(i) R8 is H or C1-3 alkyl;
R9 is H or C1-2 alkyl;
R10 is H, cyano, C(O)NR12R13, heteroaryl, or alkylheteroaryl; or
R8 and R9, together with the carbon to which they are attached, form a C3-6 cycloalkyl; or
R9 and R10, together with the carbon to which they are attached, form a heterocyclyl, wherein the heterocyclyl is substituted with oxo and further optionally and independently substituted with one, two, three, or four substituents independently selected from the group consisting of halo and C1-6 alkyl;
R12 is H, C1-6 alkyl, heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
R13 is H, C1-6 alkyl, heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
R12 and R13, together with the nitrogen to which they are attached, form a 3- to 6-membered heterocyclyl; or
(ii) R9 and R10, together with the carbon to which they are attached, form a C(O); and
R10 is C1-6 alkyl, C1-6 haloalkyl, amino, C1-6 alkylamino, or heterocyclyl, wherein the heterocyclyl is optionally and independently substituted with one or more independently selected halo substituents; and
p is 1.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein ring A is thiazolyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein the compound is of formula (I′a):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof,
wherein:
(i) R8 is H or C1-3 alkyl;
R9 is H or C1-2 alkyl;
R10 is H, cyano, C(O)NR12R13, heteroaryl, or alkylheteroaryl; or
R8 and R9, together with the carbon to which they are attached, form a C3-6 cycloalkyl; or
R9 and R10, together with the carbon to which they are attached, form a heterocyclyl, wherein the heterocyclyl is substituted with oxo and further optionally and independently substituted with one, two, three, or four substituents independently selected from the group consisting of halo and C1-6 alkyl;
R12 is H, C1-6 alkyl, heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and
R13 is H, C1-6 alkyl, heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
R12 and R13, together with the nitrogen to which they are attached, form a 3- to 6-membered heterocyclyl; or
(ii) R9 and R10, together with the carbon to which they are attached, form a C(O); and
R10 is C1-6 alkyl, C1-6 haloalkyl, amino, C1-6 alkylamino, or heterocyclyl, wherein the heterocyclyl is optionally and independently substituted with one or more independently selected halo substituents.

### Claim 5 (depends on 4)

The compound of claim 4, wherein the compound is of formula (I′aa):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof,
wherein:
R10 is H, cyano, C(O)NR12R13, heteroaryl, or alkylheteroaryl.

### Claim 6 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R10 is cyano, C(O)NR12R13, heteroaryl, or alkylheteroaryl.

### Claim 7 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R10 is cyano, C(O)NH2, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, or 2-methyl-2H-tetrazol-5-yl.

### Claim 8 (depends on 4)

The compound of claim 4, wherein the compound is of formula (I′ab):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof,
wherein:
R10 is H, cyano, C(O)NR12R13, heteroaryl, or alkylheteroaryl.

### Claim 9 (depends on 8)

The compound of claim 8, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R10 is H, cyano, or heteroaryl.

### Claim 10 (depends on 8)

The compound of claim 8, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R10 is H, cyano, or 1H-1,2,4-triazol-3-yl.

### Claim 11 (depends on 4)

The compound of claim 4, wherein the compound is of formula (I′ac):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof,
wherein:
R10 is C1-6 alkyl, C1-6 haloalkyl, amino, C1-6 alkylamino, or heterocyclyl, wherein the heterocyclyl is optionally and independently substituted with one or more independently selected halo substituents.

### Claim 12 (depends on 11)

The compound of claim 11, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R10 is methylamino, morpholin-4-yl, 3,3-difluoropyrrolidin-1-yl, or 8-oxa-3-azabicyclo[3.2.1]octan-3-yl.

### Claim 13 (depends on 4)

The compound of claim 4, wherein the compound is of formula (I′ad):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof,
wherein:
R10 is H, cyano, C(O)NR12R13, heteroaryl, or alkylheteroaryl.

### Claim 14 (depends on 13)

The compound of claim 13, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R10 is cyano or 1H-1,2,4-triazol-1-yl.

### Claim 15 (depends on 2)

The compound of claim 2, wherein the compound is of formula (I′ae):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof.

### Claim 16 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein:
R12 is H; and
R13 is H.

### Claim 17 (depends on 2)

The compound of claim 2, wherein the compound is of formula (I′ag):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof,
wherein:
q is 0, 1, 2, or 3;
Z is —NR15— or —O—;
R14 is halo or C1-6 alkyl; and
R15 is H or C1-6 alkyl.

### Claim 18 (depends on 17)

The compound of claim 17, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein:
q is 1 or 2; and
each R14 is independently CD3.

### Claim 19 (depends on 17)

The compound of claim 17, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R3 is halo.

### Claim 20 (depends on 1)

The compound of claim 1, wherein the compound is of formula (I′d):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof.

### Claim 21 (depends on 3)

The compound of claim 3, wherein the compound is of formula (II):
or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof,
wherein:
Cy is cycloalkyl, optionally and independently substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, halo, cyano, hydrazino, azido, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, alkenyl, alkynyl, imino, hydrazone, amidino, oxime, C(O)H, amido, imido, carboxy, C(O)Oalkyl, amino, guanidino, NHC(O)Oalkyl, hydroxy, alkoxy, haloalkoxy, OC(O)NH2, thiol, thiocyanate, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido, sulfinic acid, sulfonic acid, cycloalkyl, heterocyclyl, aryl, heteroaryl, and Si(RY)3;
Y is H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, amidoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C(O)R7, amido, N(R16)2, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, halo, cyano, hydrazino, azido, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, alkenyl, alkynyl, imino, hydrazone, amidino, oxime, C(O)H, amido, imido, carboxy, C(O)Oalkyl, amino, guanidino, NHC(O)Oalkyl, hydroxy, alkoxy, haloalkoxy, OC(O)NH2, thiol, thiocyanate, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido, sulfinic acid, sulfonic acid, cycloalkyl, heterocyclyl, aryl, heteroaryl, and Si(RY)3;
R7 is C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or heterocyclyl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C1-6 alkoxy, and C1-6 alkylsulfonyl; and
each R16 is independently H or C1-6 alkyl, wherein each C1-6 alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C1-6 alkoxy, and C1-6 alkylsulfonyl.

### Claim 22 (depends on 21)

The compound of claim 21, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein Cy is cycloalkyl, optionally and independently substituted with one or two substituents independently selected from the group consisting of halo, hydroxy, and heteroaryl.

### Claim 23 (depends on 21)

The compound of claim 21, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein:
Y is cyano, C1-6 alkyl, amidoalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C(O)R7, C(O)NHC1-6 alkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, or heterocyclyl, wherein the heterocyclyl is optionally and independently substituted with oxo and one or two independently selected C1-6 alkyl substituents; and
R7 is heterocyclyl, optionally and independently substituted with one, two, or three independently selected halo substituents.

### Claim 24 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R1 is halo or C1-6 alkyl.

### Claim 25 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R1 is halo or C1-6 haloalkyl.

### Claim 26 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R1 is C1-6 fluoroalkyl.

### Claim 27 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R1 is CF3.

### Claim 28 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R2 is NHCH3, NHCH2CH3, NH(CF2CH3), or NHcyclopropyl.

### Claim 29 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein R2 is NHCH2CH3.

### Claim 30 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein each R3 is independently halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, amidoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C(O)R7, amido, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, or aryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, and aryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, halo, cyano, hydrazino, azido, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, alkenyl, alkynyl, imino, hydrazone, amidino, oxime, C(O)H, amido, imido, carboxy, C(O)Oalkyl, amino, guanidino, NHC(O)Oalkyl, hydroxy, alkoxy, haloalkoxy, OC(O)NH2, thiol, thiocyanate, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido, sulfinic acid, sulfonic acid, cycloalkyl, heterocyclyl, aryl, heteroaryl, and Si(RY)3.

### Claim 31 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein each R3 is independently H, halo, C1-6 alkyl, or cycloalkyl.

### Claim 32 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein at least one R3 is not H.

### Claim 33 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein at least one R3 is H.

### Claim 34 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein at least one R3 is optionally substituted cycloalkyl.

### Claim 35 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein at least one R3 is cyclopropyl or cyclobutyl, wherein each cyclopropyl and cyclobutyl is optionally and independently substituted with one or two substituents independently selected from the group consisting of halo, hydroxy, alkoxy, and heteroaryl.

### Claim 36 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein:
m is 2;
ring A is thiazolyl; and
each R3 is independently halo, C1-6 alkyl, C1-6 haloalkyl, cycloalkyl, or heterocyclyl, wherein each C1-6 alkyl, cycloalkyl, and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of oxo, halo, C1-6 alkyl, C1-6 haloalkyl, cycloalkyl, and heterocyclyl;
wherein one, two, three, four, five, or six hydrogens of each C1-6 alkyl is optionally and independently replaced by deuterium.

### Claim 37 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, wherein:
R1 is halo or C1-6 haloalkyl;
R2 is N(R5)(R6), C1-6alkoxy, or cycloalkyl;
each R3 is independently H, halo, cyano, C1-6 alkyl, C1-6 cyanoalkyl, C(O)R7, C(O)NH(C1-6 alkyl), heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, or heterocyclyl, wherein each heterocyclyl is substituted with oxo and one or two independently selected C1-6 alkyl substituents;
R5 is H, C1-6 alkyl, or cycloalkyl, wherein the C1-6 alkyl is optionally and independently substituted with one, two, or three independently selected halo substituents;
R6 is H, C1-6 alkyl, or cycloalkyl, wherein the C1-6 alkyl is optionally and independently substituted with one, two, or three independently selected halo substituents; and
each R7 is independently heterocyclyl, each optionally and independently substituted with one, two, or three independently selected halo substituents.

### Claim 38 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim 39 (depends on 1)

A method for enhancing cognitive memory in a subject, comprising administering to the subject in need thereof an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof.

### Claim 40 (depends on 1)

A method for enhancing memory in a subject, comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim 41 (depends on 1)

A method for modulating leucine-rich repeat kinase 2 activity in a subject, comprising administering to the subject in need thereof an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof.

### Claim 42 (depends on 41)

The method of claim 41, wherein the subject has cancer.

### Claim 43 (depends on 42)

The method of claim 42, wherein the cancer is acute myelogenous leukemia, blood cancer, breast cancer, lung cancer, kidney cancer, prostate cancer, papillary cancer, or multiple myeloma.

### Claim 44 (depends on 41)

The method of claim 41, wherein the subject has an inflammatory disease.

### Claim 45 (depends on 44)

The method of claim 44, wherein the inflammatory disease is amyotrophic lateral sclerosis, ankylosing spondylitis, Crohn's disease, inflammatory bowel disease, leprosy, rheumatoid arthritis, or ulcerative colitis.

### Claim 46 (depends on 41)

The method of claim 41, wherein the subject has a neurodegenerative disease.

### Claim 47 (depends on 46)

The method of claim 46, wherein the neurodegenerative disease is a central nervous system disorder.

### Claim 48 (depends on 47)

The method of claim 47, wherein the central nervous system disorder is Alzheimer's disease or levodopa-induced dyskinesia.

### Claim 49 (depends on 46)

The method of claim 46, wherein the neurodegenerative disease is dementia or Parkinson's disease.

### Claim 50 (depends on 1)

A method for modulating leucine-rich repeat kinase 2 activity in a subject, comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim 51 (depends on 1)

A process for preparing the compound of formula (I) of claim 1:
wherein:
m is 1 or 2;
ring A is isothiazolyl or thiazolyl;
R1 is halo, cyano, C1-6 alkyl, or C1-6 haloalkyl;
R2 is N(R5)(R6), C1-6 alkoxy, or cycloalkyl;
each R3 is independently H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, amidoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C(O)R7, amido, N(R16)2, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, halo, cyano, hydrazino, azido, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, alkenyl, alkynyl, imino, hydrazone, amidino, oxime, C(O)H, amido, imido, carboxy, C(O)Oalkyl, amino, guanidino, NHC(O)Oalkyl, hydroxy, alkoxy, haloalkoxy, OC(O)NH2, thiol, thiocyanate, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido, sulfinic acid, sulfonic acid, cycloalkyl, heterocyclyl, aryl, heteroaryl, and Si(RY)3;
R5 is H, C1-6alkyl, C1-6 haloalkyl, or cycloalkyl;
R6 is H, C1-6 alkyl C1-6 haloalkyl, or cycloalkyl;
each R7 is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or heterocyclyl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C1-6 alkoxy, and C1-6 alkylsulfonyl;
each R16 is independently H or C1-6 alkyl, wherein each C1-6 alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C1-6 alkoxy, and C1-6 alkylsulfonyl; and
each RY is independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
with the proviso that if R5 or R6 is cycloalkyl, then ring A is not isothiazolyl;
wherein the process comprises:
coupling a compound of formula (Y):
wherein:
R1 is halo, cyano, C1-6 alkyl, or C1-6 haloalkyl;
R2 is N(R5)(R6), C1-6 alkoxy, or cycloalkyl;
R5 is H, C1-6 alkyl, C1-6 haloalkyl, or cycloalkyl;
R6 is H, C1-6 alkyl, C1-6 haloalkyl, or cycloalkyl; and
X is selected from the group consisting of:
halo
with a compound of formula (Z):
wherein:
m is 1 or 2;
ring A is isothiazolyl or thiazolyl;
each R3 is independently H, halo, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, amidoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C(O)R7, amido, N(R16)2, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylheterocyclylalkyl, arylalkyl, heteroarylalkyl, alkylheteroarylalkyl, cycloalkyl, cyanocycloalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of oxo, thioxo, halo, cyano, hydrazino, azido, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, alkenyl, alkynyl, imino, hydrazone, amidino, oxime, C(O)H, amido, imido, carboxy, C(O)Oalkyl, amino, guanidino, NHC(O)Oalkyl, hydroxy, alkoxy, haloalkoxy, OC(O)NH2, thiol, thiocyanate, alkylthio, alkylsulfinyl, alkylsulfonyl, sulfonamido, sulfinic acid, sulfonic acid, cycloalkyl, heterocyclyl, aryl, heteroaryl, and Si(RY)3;
each R7 is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or heterocyclyl, wherein each C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C1-6 alkoxy, and C1-6 alkylsulfonyl;
each R16 is independently H or C1-6 alkyl, wherein each C1-6 alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C1-6 alkoxy, and C1-6 alkylsulfonyl; and
each RY is independently H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
with the proviso that if R5 or R6 is cycloalkyl, then ring A is not isothiazolyl;
in the presence of trifluoroacetic acid, toluenesulfonic acid, or triethylamine, to provide the compound of formula (I) above.

### Claim 52

A compound, or a pharmaceutically acceptable salt, deuterated isotope, or stereoisomer thereof, selected from the group consisting of:

### Claim 53

A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: