US2022119371A1PendingUtilityA1
Compound, compositions, and methods
Est. expiryNov 20, 2035(~9.3 yrs left)· nominal 20-yr term from priority
Inventors:Anthony A. EstradaJianwen A. FengJoseph P. LyssikatosZachary K. SweeneyJavier De Vicente Fidalgo
C07D 403/12A61P 25/28C07D 471/04C07D 487/04C07D 403/14A61P 29/00C07D 413/14C07D 417/14A61P 35/00A61P 25/16
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Claims
Abstract
Compounds having activity as LRRK2 inhibitors are disclosed. The compounds are of formula (I) including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
Claims
exact text as granted — not AI-modified1 . A compound having the following formula (I):
or a pharmaceutically acceptable salt, stereoisomer, or a mixture of stereoisomers, tautomer or prodrug thereof, wherein:
Z is N or CH;
R 1 is halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkyloxy, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkyloxycarbonyl, aminocarbonyl, or heterocyclylcarbonyl, wherein each is optionally substituted; and R 5 is H; or
R 1 and R 5 together with the atom to which they are attached form a 5-membered ring having the structure:
Y is N or CR 6 ;
R 6 is H, halo, cyano, C 1 -C 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, —S(O) w (C 1 -C 6 alkyl), cycloalkyl, heterocyclyl, heteroaryl, aryl, acyl, or amido, wherein each is optionally substituted;
R 10 is H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl;
R 2 is C 1 -C 6 alkyl, cycloalkyl, cycloalkylalkyl, C 1 -C 6 alkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino, C 1 -C 6 alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, or heterocyclylalkylamino, wherein each is optionally substituted;
R 3a and R 3b are each independently H, halo, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, aminocarbonyl, heterocyclylcarbonyl, or -L 2 -R 8 , wherein each is optionally substituted;
or R 4 and either R 3a or R 3b when attached to an adjacent carbon, together with the atoms bound thereto join to form a heterocyclyl or heteroaryl, wherein each heterocyclyl or heteroaryl is optionally substituted;
or R 3a and R 3b when attached to an adjacent carbon, together with the atoms bound thereto join to form a cycloalkyl, heterocyclyl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted;
R 4 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 haloalkoxyalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkoxycarbonylalkyl, aminocarbonyl, heterocyclylcarbonyl, or -L 1 -R 7 , wherein each is optionally substituted;
L 1 is —S(O) p —, —S(O) p N(R 9 )—, —(CH 2 ) m —, —C(O)—, —C(O)O—, or —C(O)N(R 9 )—;
each L 2 is independently —O—, —S(O) m —, —(CH 2 ) m —, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R 9 )—, —N(R 9 )C(O)—, —N(R 9 )C(O)—, —OC(O)N(R 9 )—, —N(R 9 )C(O)N(R 9 )—, —S(O) p N(R 9 )—, —N(R 9 )S(O) p N(R 9 )— or —N(R 9 )S(O) p —;
R 7 is C 1 -C 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, wherein each is optionally substituted;
each R 8 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, wherein each is optionally substituted;
each R 9 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
each p is independently 1 or 2;
each w is independently 0, 1 or 2; and
each m is independently 0, 1, 2 or 3;
provided that:
a) when R 5 is H, then Z is N, and R 2 is C-heterocyclyl, which is optionally substituted; and
b) when R 1 and R 5 together with the atom to which they are attached form the 5-membered ring, then either:
i) R 2 is C 1 -C 6 alkoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino, C 1 -C 6 alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, or heterocyclylalkylamino; Z is N; R 5 is H; Y is N or CR 6 ; and R 6 is halo, C 1 -C 6 haloalkyl or cycloalkyl; or
ii) R 2 is C 1 -C 6 alkyl, cycloalkyl or cycloalkylalkyl, wherein each is optionally substituted.
2 . A compound of formula (A-Ic):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer, or prodrug thereof, wherein:
R 11 is chloro or —CF 3 ;
R 12 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 haloalkoxyalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylsulfonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylalkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkoxycarbonylalkyl, aminocarbonyl or heterocyclylcarbonyl, wherein each C 1 -C 6 alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl is optionally substituted; and
one of R 13a and R 13b is H, and the other of R 13a and R 13b is H, halo, or methyl.
3 . The compound of claim 2 , wherein R 12 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylsulfonyl, cycloalkyl, heterocyclyl, heteroaryl wherein each cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted.
4 . The compound of claim 2 wherein one of R 13a or R 13b is H, and the other of R 3a or R 3b is methyl.
5 . A compound of formula (B-I):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer or prodrug thereof, wherein:
Y is N or CR 21 ;
R 21 is halo, C 1 -C 6 haloalkyl or cycloalkyl;
R 22 is C 1 -C 6 alkoxy; cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heterocyclylalkyloxy, amino, C 1 -C 6 alkylamino, cycloalkylamino, cycloalkylalkylamino, heterocyclylamino, or heterocyclylalkylamino;
R 23a and R 23b are each independently H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, aminocarbonyl or heterocyclylcarbonyl; and
R 24 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylylalkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkoxycarbonylalkyl, aminocarbonyl or heterocyclylcarbonyl.
6 . The compound of claim 5 , wherein Y is N.
7 . The compound of claim 5 , wherein Y is CR 21 .
8 . The compound of claim 7 , wherein R 21 is chloro.
9 . The compound of claim 7 , wherein R 21 is C 1 -C 6 haloalkyl or cycloalkyl.
10 . The compound of claim 5 , wherein R 22 is C 1 -C 6 alkoxy or C 1 -C 6 alkylamino.
11 . The compound of claim 10 , wherein R 22 is C 1 -C 6 alkoxy.
12 . The compound of claim 10 , wherein R 22 is C 1 -C 6 alkylamino.
13 . The compound of any one claim 5 , wherein one of R 23a or R 2b is H, and the other of R 23a or R 23b is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 aminoalkyl, cycloalkyl, cycloalkylalkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkyloxycarbonyl, aminocarbonyl or heterocyclylcarbonyl.
14 . The compound of claim 5 , wherein R 24 is C 1 -C 6 alkyl.
15 . The compound of claim 5 , wherein R 24 is C 1 -C 6 cyanoalkyl.
16 . A compound having the following formula (C-I):
or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, tautomer or prodrug thereof, wherein:
Y is N or CR 36 ;
Z is N or CH;
R 31 is C 1 -C 6 alkyl, cycloalkyl or cycloalkylalkyl, each of which is optionally substituted;
R 32 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or -L 3 -R 37 , wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted;
R 33 and R 34 are each independently H, halo, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or -L 4 -R 38 , wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; or
or R 33 and R 34 together with the atom to which they are attached form a cycloalkyl, heterocyclyl or heteroaryl, wherein each cycloalkyl, heterocyclyl and heteroaryl is optionally substituted;
or R 32 and R 33 together with the atom to which they are attached form a heterocyclyl or heteroaryl, wherein each heterocyclyl and heteroaryl is optionally substituted;
R 35 is H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl;
R 36 is H, halo, cyano, C 1 -C 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, —S(O) w (C 1 -C 6 alkyl), cycloalkyl, heterocyclyl, heteroaryl, aryl, acyl, or amido, wherein each alkyl, alkoxyl, haloalkyl, alkoxyalkyl, -cycloalkyl, heterocyclyl, heteroaryl, aryl, acyl, or amido are independently optionally substituted;
L 3 is —S(O) p —, —S(O) p N(R 39 )—, —(CH 2 ) m —, —C(O)—, —C(O)O—, or —C(O)N(R 39 )—;
each L 4 is independently —O—, —S(O) w —, —(CH 2 ) m —, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R 39 )—, —N(R 39 )C(O)—, —N(R 9 )C(O)—, —OC(O)N(R 39 )—, —N(R 39 )C(O)N(R 39 )—, —S(O) p N(R 39 )—, —N(R 39 )S(O) p N(R 39 )— or —N(R 39 )S(O) p —;
R 37 is C 1 -C 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl is optionally substituted;
each R 38 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, wherein each C 1 -C 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl is optionally substituted;
each R 39 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
each p is independently 1 or 2;
each w is independently 0, 1 or 2; and
each m is independently 0, 1, 2 or 3.
17 . The compound of claim 16 , wherein R 31 is cycloalkyl.
18 . The compound of claim 16 , wherein R 32 is C 1 -C 6 alkyl, or cycloalkyl, wherein each C 1 -C 6 alkyl and cycloalkyl is optionally substituted.
19 . The compound of claim 16 , wherein R 32 and R 33 are each independently C 1 -C 6 alkyl.
20 . The compound of claim 16 , wherein R 32 and R 33 together with the atom to which they are attached form a heterocyclyl or heteroaryl, wherein each heterocyclyl and heteroaryl is optionally substituted.
21 . The compound of claim 16 , wherein R 34 is H.
22 . The compound of claim 16 , wherein R 33 and R 34 together with the atom to which they are attached form a cycloalkyl, heterocyclyl or heteroaryl, wherein each cycloalkyl, heterocyclyl and heteroaryl is optionally substituted.
23 . The compound of claim 16 , wherein R 35 is H or methyl.
24 . The compound of claim 16 , wherein Y is N.
25 . The compound of claim 16 , wherein Y is CR 26 .
26 . The compound of claim 25 , wherein R 36 is C 1 -C 6 haloalkyl, cycloalkyl, halo or cyano.
27 . The compound of claim 16 , wherein Z is N.
28 . The compound of claim 16 , wherein Z is CH.
29 . The compound of claim 16 , wherein R 35 is H; one of R 33 and R 34 is H and the other is halo, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or -L 4 -R 38 , wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted.
30 - 39 . (canceled)
40 . A compound of Table A-1 or Table A-1A or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, prodrug, or tautomer thereof.
41 . A compound of Table B-1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, prodrug, or tautomer thereof.
42 . A compound selected from Table C-1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, prodrug, or tautomer thereof.
43 . (canceled)
44 . A pharmaceutical composition comprising the compound as in claim 1 , or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
45 . A method for treating a disease or condition mediated, at least in part, by LRRK2, the method comprising administering an effective amount of the pharmaceutical composition of claim 1 to a subject in need thereof.
46 . The method of claim 45 , wherein the disease or condition is a neurodegenerative disease.
47 . The method of claim 46 , wherein the neurodegenerative disease is Parkinson's disease or dementia.
48 . The method of claim 45 , wherein the disease or condition is a central nervous system (CNS) disorder.
49 . The method of claim 48 , wherein the CNS disorder is Alzheimer's disease or L-Dopa induced dyskinesia.
50 . The method of claim 45 , wherein the disease or condition is a cancer.
51 . The method of claim 50 , wherein the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia or multiple myeloma.
52 . The method of claim 45 , wherein the disease or condition is an inflammatory disease.
53 . The method of claim 52 , wherein the inflammatory disease is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis or ankylosing spondylitis.
54 . A method for enhancing cognitive memory, the method comprising administering an effective amount of the pharmaceutical composition of claim 44 to a subject in need thereof.
55 . A compound of claim 1 for use in therapy.
56 . A compound of claim 1 for use in the treatment of a neurodegenerative disease, cancer, or an inflammatory disease.
57 . A compound of claim 1 for use in the treatment of Alzheimer's disease, L-Dopa induced dyskinesia, Parkinson's disease, dementia, ALS, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
58 . Use of a compound of claim 1 for the manufacture of a medicament for treating a neurodegenerative disease, cancer, or an inflammatory disease.
59 . Use of a compound of claim 1 for the manufacture of a medicament for treating Alzheimer's disease, L-Dopa induced dyskinesia, Parkinson's disease, dementia, amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myelogenous leukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
60 . A method of preparing a compound of formula (I) of claim 1 , comprising coupling a compound of formula (b):
wherein X is halogen, with a compound of formula (c):
under conditions to provide the compound of formula (I).Join the waitlist — get patent alerts
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