IP Library › Patent Application 18485224

Patent Application

App. No. 18/485,224

INHIBITORS OF SOLUTE CARRIER FAMILY 6A MEMBER 19 (SLC6A19) AND METHODS OF USE THEREOF

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Patent No.: US None
App. No.: 18/485,224

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Abstract

Provided herein are compounds of formula (II): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m, n, R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , and X are as defined elsewhere herein. Also provided herein are methods of preparing compounds of formula (II). Also provided herein are methods of inhibiting SLC6A19 and methods of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

Claims (271)

1 . A compound of formula (I-H):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

m is an integer from 1 to 4;

n is an integer from 0 to 4;

X is —O—, —S—, —C(R 12a )(R 12b )—, —N(H)—, or —N(C 1-6 alkyl)-;

R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(O)C 1-6 alkyl, C 3-10 cycloalkyl, —N(R 4 ) 2 , 5-20 membered heteroaryl, —C 1-6 alkyl(5-20 membered heteroaryl), or 4-10 membered heterocyclyl, wherein each R 3 is optionally substituted with one or more R a , and wherein when R 3 is 6-10 membered heteroaryl, the 6-10 membered heteroaryl is unsubstituted;

each R 4 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, —C 1-6 alkyl(5-20 membered heteroaryl), or C 3-10 cycloalkyl, or

both R 4 are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R a ;

R 5 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, or 5-20 membered heteroaryl, wherein

the C 1-6 alkyl, C 1-6 alkoxy, or C 3-10 cycloalkyl of R 5 and R 7 are each independently optionally substituted with one or more halo or CN;

R 6 and R 9 are each independently H or halo;

R 11a and R 11b are each independently at each occurrence, H or C 1-6 alkyl, or

one of R 11a and R 11b is H or C 1-6 alkyl, and the other of R 11a and R 11b is taken together with one of R 12a or R 12b to form a C 3-10 cycloalkyl;

R 12a and R 12b are each independently, H or C 1-6 alkyl, or

one of R 12a and R 12b is H or C 1-6 alkyl, and the other of R 12a and R 12b is taken together with one of R 11a or R 11b to form a C 3-10 cycloalkyl;

each R a is independently D, —OH, oxo, —CN, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, wherein

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl of R a is optionally substituted with one or more R b ;

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy

Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently —C—, —CH—, —CH 2 —, —N—, —NH—, —S—, or —O—;

s is an integer from 0-6;

t is 1 or 2; and

represents a single or double bond.

2 - 9 . (canceled)

10 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1 and n is 1.

11 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein m is 1 and n is 0.

12 - 13 . (canceled)

14 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is methyl, ethyl, or isopropyl.

15 . (canceled)

16 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is selected from the group consisting of

17 - 18 . (canceled)

19 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is selected from the group consisting of

20 - 24 . (canceled)

25 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is selected from the group consisting of

26 . (canceled)

27 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is selected from the group consisting of

28 . (canceled)

29 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is

30 - 51 . (canceled)

52 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is —O—.

53 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is —S—.

54 - 55 . (canceled)

56 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is —CH 2 —, or —CH(C 1-6 alkyl)-.

57 . (canceled)

58 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is —NH—.

59 . The compound of claim 1 , wherein, n is 1, one of R 12a and R 12b is H, or C 1-6 alkyl, and the other of R 12a and R 12b is taken together with R 11a or R 11b to form a C 3-10 cycloalkyl.

60 - 62 . (canceled)

63 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of formula:

64 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound, is selected from the group consisting of

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

65 . A process for preparing a compound of formula (I′):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

m is an integer from 1 to 4;

n is an integer from 0 to 4;

X is —O—, —S—, —C(R 12a )(R 12b )—, —N(H)—, or —N(C 1-6 alkyl)-;

R 1 is —NH—, —O—, or —S—;

R 2 is H;

R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, —N(R 4 ) 2 , or 4-10 membered heterocyclyl, wherein each R 3 is optionally substituted with one or more R a ;

each R 4 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl, or

both R 4 are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R a ;

R 5 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 haloalkyl, wherein

the C 1-6 alkyl of R 5 and R 7 are each independently optionally substituted with one or more halo or CN;

R 6 and R 9 are each independently H or halo;

R 8 is —C(O)N(R 4 ) 2 , C 3-10 cycloalkyl, C 6-20 aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R 8 is optionally substituted with one or more R a ;

R 10 is H;

R 11a and R 11b are each independently at each occurrence, H or C 1-6 alkyl, or

one of R 11a and R 11b is H or C 1-6 alkyl, and the other of R 11a and R 11b is taken together with one of R 12a or R 12b to form a C 3-10 cycloalkyl;

R 12a and R 12b are each independently, H or C 1-6 alkyl, or

one of R 12a and R 12b is H or C 1-6 alkyl, and the other of R 12a and R 12b is taken together with one of R 11a or R 11b to form a C 3-10 cycloalkyl;

each R a is independently —OH, oxo, —CN, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, wherein

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy,

wherein the process comprises:

(a) reacting a compound of formula (I′-1):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

Q 1 is halo, boronic acid, or boronic ester;

PG is absent, or a protecting group;

m is an integer from 1 to 4;

R 1 is —N—, —NH—, —O—, or —S—;

R 2 is H;

R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, —N(R 4 ) 2 , or 4-10 membered heterocyclyl, wherein each R 3 is optionally substituted with one or more R a ;

each R 4 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl, or

both R 4 are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R a ;

R 5 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 haloalkyl, wherein

the C 1-6 alkyl of R 5 and R 7 are each independently optionally substituted with one or more halo or CN;

R 6 and R 9 are each independently H, or halo;

R 10 is H; and

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy;

with a compound of formula (I′-2):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

Y 1 is H, hydrazone, boronic acid, boronic ester, or halo;

n is an integer from 0 to 4;

X is —O—, —S—, —C(R 12a )(R 12b )—, —N(H)—, or —N(C 1-6 alkyl)-;

R 8 is —C(O)N(R 4 ) 2 , C 3-10 cycloalkyl, C 6-20 aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R 8 is optionally substituted with one or more R a ;

R 11a and R 11b are each independently at each occurrence, H, or C 1-6 alkyl, or taken together with one of R 12a or R 12b to form a C 3-10 cycloalkyl;

R 12a and R 12b are each independently, H, or C 1-6 alkyl, or

one of R 12a and R 12b is H, or C 1-6 alkyl, and the other of R 12a and R 12b is taken together with R 11a or R 11b to form a C 3-10 cycloalkyl; and

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy;

in the presence of one or more coupling reagent, to provide a compound of formula (I′-3):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

PG is absent or a protecting group;

m is an integer from 1 to 4;

n is an integer from 0 to 4;

X is —O—, —S—, —C(R 12a )(R 12b )—, —N(H)—, or —N(C 1-6 alkyl)-;

R 1 is —N—NH—, —O—, or —S—;

R 2 is H;

R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, —N(R 4 ) 2 , or 4-10 membered heterocyclyl, wherein each R 3 is optionally substituted with one or more R a ;

each R 4 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl, or

both R 4 are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R a ;

R 5 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 haloalkyl, wherein

the C 1-6 alkyl of R 5 and R 7 are each independently optionally substituted with one or more halo or CN;

R 6 and R 9 are each independently H, or halo;

R 8 is —C(O)N(R 4 ) 2 , C 3-10 cycloalkyl, C 6-20 aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R 8 is optionally substituted with one or more R a ;

R 10 is H;

R 11a and R 11b are each independently at each occurrence, H, or C 1-6 alkyl, or taken together with one of R 12a or R 12b to form a C 3-10 cycloalkyl;

R 12a and R 12b are each independently, H, or C 1-6 alkyl, or one of R 12a and R 12b is H, or C 1-6 alkyl, and the other of R 12a and R 12b is taken together with R 11a or R 11b to form a C 3-10 cycloalkyl;

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy;

followed by,

(b) optionally contacting the compound of formula (I′-3) with a deprotecting agent;

to provide a compound of formula (I′).

66 - 68 . (canceled)

69 . A process for preparing a compound of formula (I′):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

m is an integer from 1 to 4;

n is an integer from 0 to 4;

X is —O—, —S—, —C(R 12a )(R 12b )—, —N(H)—, or —N(C 1-6 alkyl)-;

R 1 is —NH—, —O—, or —S—;

R 2 is H;

R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, —N(R 4 ) 2 , or 4-10 membered heterocyclyl, wherein each R 3 is optionally substituted with one or more R a ;

each R 4 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl, or

both R 4 are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R a ;

R 5 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 haloalkyl, wherein

the C 1-6 alkyl of R 5 and R 7 are each independently optionally substituted with one or more halo or CN;

R 6 and R 9 are each independently H or halo;

R 8 is —C(O)N(R 4 ) 2 , C 3-10 cycloalkyl, C 6-20 aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R 8 is optionally substituted with one or more R a ;

R 10 is H;

R 11a and R 11b are each independently at each occurrence, H or C 1-6 alkyl, or

one of R 11a and R 11b is H or C 1-6 alkyl, and the other of R 11a and R 11b is taken together with one of R 12a or R 12b to form a C 3-10 cycloalkyl;

R 12a and R 12b are each independently, H or C 1-6 alkyl, or

one of R 12a and R 12b is H or C 1-6 alkyl, and the other of R 12a and R 12b is taken together with one of R 11a or R 11b to form a C 3-10 cycloalkyl;

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy,

wherein the process comprises:

(a) reacting a compound of formula (IV′-1):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

PG is absent or a protecting group;

Q 2 is H, or (═O);

m is an integer from 1 to 4;

X is —O—, —S—, —C(R 12a )(R 12b )—, —N(H)—, or —N(C 1-6 alkyl)-;

R 1 is —N—, —NH—, —O—, or —S—;

R 2 is H;

R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, —N(R 4 ) 2 , or 4-10 membered heterocyclyl, wherein each R 3 is optionally substituted with one or more R a ;

each R 4 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl, or

both R 4 are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R a ;

R 5 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 haloalkyl, wherein

the C 1-6 alkyl of R 5 and R 7 are each independently optionally substituted with one or more halo or CN;

R 6 and R 9 are each independently H, or halo;

R 10 is H;

R 12a and R 12b are each independently, H, or C 1-6 alkyl; and

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy;

with a compound of formula (II′-2):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

Y 2 is OH, (═O), halo, triphenylphosphonium salt, or sulfonic ester;

n is an integer from 0 to 4; R 8 is —C(O)N(R 4 ) 2 , C 3-10 cycloalkyl, C 6-20 aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R 8 is optionally substituted with one or more R a ;

R 11a and R 11b are each independently at each occurrence, H, or C 1-6 alkyl; and

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy;

in the presence of one or more coupling reagents, to provide a compound of formula (I′-3):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

PG is absent or a protecting group;

m is an integer from 1 to 4;

n is an integer from 0 to 4;

X is —O—, —S—, —C(R 12a )(R 12b )—, —N(H)—, or —N(C 1-6 alkyl)-;

R 1 is —N—NH—, —O—, or —S—;

R 2 is H;

R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, —N(R 4 ) 2 , or 4-10 membered heterocyclyl, wherein each R 3 is optionally substituted with one or more R a ;

each R 4 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl, or

both R 4 are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R a ;

R 5 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 haloalkyl, wherein

the C 1-6 alkyl of R 5 and R 7 are each independently optionally substituted with one or more halo or CN;

R 6 and R 9 are each independently H, or halo;

R 8 is —C(O)N(R 4 ) 2 , C 3-10 cycloalkyl, C 6-20 aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R 8 is optionally substituted with one or more R a ;

R 10 is H;

R 11a and R 11b are each independently at each occurrence, H, or C 1-6 alkyl, or taken together with one of R 12a or R 12b to form a C 3-10 cycloalkyl;

R 12a and R 12b are each independently, H, or C 1-6 alkyl, or

one of R 12a and R 12b is H, or C 1-6 alkyl, and the other of R 12a and R 12b is taken together with R 11a or R 11b to form a C 3-10 cycloalkyl;

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy;

followed by,

(b) optionally contacting the compound of formula (I′-3) with a deprotecting agent;

to provide a compound of formula (I′).

70 - 74 . (canceled)

75 . A process for preparing a compound of formula (I′):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

m is an integer from 1 to 4;

n is an integer from 0 to 4;

X is —O—, —S—, —C(R 12a )(R 12b )—, —N(H)—, or —N(C 1-6 alkyl)-;

R 1 is —NH—, —O—, or —S—;

R 2 is H;

R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, —N(R 4 ) 2 , or 4-10 membered heterocyclyl, wherein each R 3 is optionally substituted with one or more R a ;

each R 4 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl, or

both R 4 are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R a ;

R 5 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 haloalkyl, wherein

the C 1-6 alkyl of R 5 and R 7 are each independently optionally substituted with one or more halo or CN;

R 6 and R 9 are each independently H or halo;

R 8 is —C(O)N(R 4 ) 2 , C 3-10 cycloalkyl, C 6-20 aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R 8 is optionally substituted with one or more R a ;

R 10 is H;

R 11a and R 11b are each independently at each occurrence, H or C 1-6 alkyl, or

one of R 11a and R 11b is H or C 1-6 alkyl, and the other of R 11a and R 11b is taken together with one of R 12a or R 12b to form a C 3-10 cycloalkyl;

R 12a and R 12b are each independently, H or C 1-6 alkyl, or

one of R 12a and R 12b is H or C 1-6 alkyl, and the other of R 12a and R 12b is taken together with one of R 11a or R 11b to form a C 3-10 cycloalkyl;

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy,

wherein the process comprises:

reacting a compound of formula (III′-1):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

Q 3 is H;

m is an integer from 1 to 4;

n is an integer from 0 to 4;

X is —O—, —S—, —C(R 12a )(R 12b )—, —N(H)—, or —N(C 1-6 alkyl)-;

R 1 is —NH—, —O—, or —S—;

R 2 is H;

each R 4 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl, or

both R 4 are taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl optionally substituted with one or more R a ;

R 5 and R 7 are each independently H, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 haloalkyl, wherein

the C 1-6 alkyl of R 5 and R 7 are each independently optionally substituted with one or more halo or CN;

R 6 and R 9 are each independently H, or halo;

R 8 is —C(O)N(R 4 ) 2 , C 3-10 cycloalkyl, C 6-20 aryl, 3-10 membered heterocyclyl, or 5-20 membered heteroaryl, wherein each R 8 is optionally substituted with one or more R a ;

R 10 is H;

R 11a and R 11b are each independently at each occurrence, H, or C 1-6 alkyl, or taken together with one of R 12a or R 12b to form a C 3-10 cycloalkyl;

R 12a and R 12b are each independently, H, or C 1-6 alkyl, or

one of R 12a and R 12b is H, or C 1-6 alkyl, and the other of R 12a and R 12b is taken together with R 11a or R 11b to form a C 3-10 cycloalkyl; and

the C 1-6 alkyl, C 1-6 alkoxy, 4-10 membered heterocyclyl, C 3-10 cycloalkyl, or —O—C 3-10 cycloalkyl, of R a is optionally substituted with one or more R b ; and

each R b is independently D, —OH, halo, C 1-6 alkyl, or C 1-6 alkoxy;

with a compound of formula (III′-2):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

Y 3 is —C(O)OH, or —C(O)-halo;

R 3 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, —N(R 4 ) 2 , or 4-10 membered heterocyclyl, wherein each R 3 is optionally substituted with one or more R a ; and

each R a is, independently at each occurrence, —OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-10 cycloalkyl;

in the presence of one or more coupling reagent, to provide a compound of formula (I′).

76 . (canceled)

77 . A pharmaceutical composition comprising (i) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

78 . A method of modulating SLC6A19 in a cell, comprising exposing the cell to a an effective amount of

a) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or

b) a pharmaceutical composition comprising (i) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

79 . A method of inhibiting SLC6A19 in a cell, comprising exposing the cell to an effective amount of

a) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or

80 . A method of reducing systemic phenylalanine, tyrosine, glutamine, or glycine levels in an individual in need thereof, comprising administering to the individual an effective amount of

a) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or

81 . A method of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual,

a) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or

82 - 87 . (canceled)

88 . A kit, comprising:

(i) a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients and

(ii) instructions for use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

89 - 100 . (canceled)

Assignments (2)

SECURITY INTEREST Recorded Feb 4, 2026

From: MAZE THERAPEUTICS, INC.

To: HERCULES CAPITAL, INC., AS AGENT

Reel/Frame 073691/0579 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 7, 2024

From: PITZEN, JENNIFER; DE LA HIGUERA MACIAS, MAXIMILIANO; COOPER, NICOLE; SINZ, CHRISTOPHER JOSEPH; LEE, PATRICK SANG TAE; WAHLERS, JESSICA; FASTMAN, NATHAN; TZITZILONIS, CHRISTOS; MORGANS, DAVID JOHN, JR.; LIU, YUXI; MELLEM, KEVIN; SCHAMMEL, ALEXANDER WAYNE; ZIEBENHAUS, CHRIS; REID, ADAM NEIL; KARMEL, CALEB HENRY

To: MAZE THERAPEUTICS, INC.

Reel/Frame 069190/0802 →