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

1 . A compound of formula (I):

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

R 1 is H, halo, or C 1-6 alkyl,

R 2 is H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a , and

R 3 is H or halo,

wherein at least one of R 1 and R 2 is other than H, or R 3 is F;

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ;

R 5 is H or halo;

R a is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R a is optionally substituted with one or more D or halo;

R b is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R b is optionally substituted with one or more D or halo;

either:

(i) one of X and Y is —O—, —N(R w )—, or —C(R x )(R y )—, and

the other of X and Y is C 1-6 alkylene optionally substituted with one or more D, or halo;

or

(ii) X is absent and Y is C 1-6 cycloalkyl;

R w is H or C 1-6 alkyl; and

R x and R y are independently H, D, halo, or C 1-6 alkyl.

2 . The compound of claim 1 , wherein the compound is a compound of formula (I):

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

R 1 is H, halo, or C 1-6 alkyl, and

R 2 is H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a ,

wherein at least one of R 1 and R 2 is other than H;

R 3 is H or halo;

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ;

R 5 is H or halo; R a is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R a is optionally substituted with one or more D or halo;

R b is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R b is optionally substituted with one or more D or halo;

one of X and Y is —O—, —N(R w )—, or —C(R x )(R y )—, and

the other of X and Y is C 1-6 alkylene optionally substituted with one or more D, or halo;

R w is H or C 1-6 alkyl; and

R x and R y are independently H, D, halo, or C 1-6 alkyl.

3 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 1 is H, halo, or C 1-3 alkyl, and

R 2 is H, halo, —CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 3-4 cycloalkyl, wherein the C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 3-4 cycloalkyl of R 2 are each independently optionally substituted with one or more R a ,

wherein at least one of R 1 and R 2 is other than H;

R a is, independently at each occurrence, halo or C 1-3 alkyl, wherein the C 1-3 alkyl of R a is optionally substituted with one or more D or halo;

R b is, independently at each occurrence, halo or C 1-3 alkyl, wherein the C 1-3 alkyl of R b is optionally substituted with one or more D or halo;

one of X and Y is —O—, —N(R w )—, or —C(R x )(R y )—, and

the other of X and Y is C 1-3 alkylene optionally substituted with one or more D, or halo;

R w is H or C 1-3 alkyl; and

R x and R y are independently H, D, halo, or C 1-3 alkyl.

4 . The compound of any one of claims 1-3 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 1 is H, halo, or C 1-3 alkyl, and

R 2 is H, halo, —CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl of R 2 are each independently optionally substituted with one or more R a ,

wherein at least one of R 1 and R 2 is other than H;

R a is, independently at each occurrence, C 1-3 alkyl;

R b is, independently at each occurrence, halo or C 1-3 alkyl, wherein the C 1-3 alkyl of R b is optionally substituted with one or more D;

one of X and Y is —O—, —N(R w )—, or —C(R x )(R y )—, and

the other of X and Y is C 1-3 alkylene optionally substituted with one or more D;

R w is H; and

R x and R y are independently H.

5 . The compound of any one of claims 1-4 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 3 is F;

one of X and Y is —O—, —N(R w )—, or —C(R x )(R y )—, and

the other of X and Y is C 1-6 alkylene optionally substituted with one or more D, or halo.

6 . The compound of claim any one of claims 1-5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

X is —O—, —N(R w )—, or —C(R x )(R y )—; and

Y is C 1-3 alkylene optionally substituted with one or more D, or halo.

7 . The compound of any one of claims 1-5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

X is —O—, —N(R w )—, or —C(R x )(R y )—;

Y is C 1-3 alkylene, optionally substituted with one or more D;

R w is H; and

R x and R y are independently H.

8 . The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is absent and Y is C 1-6 cycloalkyl.

9 . The compound of any one of claims 1-7 , wherein the compound is of formula (I-A1):

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

X is —O—, —N(R w )—, or —C(R x )(R y )—; and

R 6a and R 6b are each independently H, D, or halo.

10 . The compound of claim 9 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein,

R 1 is H, halo, or C 1-3 alkyl, and

R 2 is H, halo, —CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 3-4 cycloalkyl, wherein the C 3-4 cycloalkyl of R 2 is optionally substituted with one or more R a , wherein at least one of R 1 and R 2 is other than H;

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ;

R 6a and R 6b are each independently H, or D;

R a is, independently at each occurrence, C 1-6 alkyl;

R b is, independently at each occurrence, halo or C 1-3 alkyl, wherein the C 1-3 alkyl of R b is optionally substituted with one or more D;

X is —O—, —N(R w )—, or —C(R x )(R y )—;

R w is H; and

R x and R y are independently H.

11 . The compound of any one of claims 1-5 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

Y is —O—, —N(R w )—, or —C(R x )(R y )—; and

X is C 1-3 alkylene optionally substituted with one or more D, or halo.

12 . The compound of any one of claims 1-5, or 11 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

Y is —O—, —N(R w )—, or —C(R x )(R y )—;

X is C 1-3 alkylene;

R w is H; and

R x and R y are independently H.

13 . The compound of any one of claims 1-5, 11, or 12 , wherein the compound is of formula (I-B1):

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

Y is —O—, —N(R w )—, or —C(R x )(R y )—; and

R 6a and R 6b are each independently H, D, or halo.

14 . The compound of claim 13 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:

R 1 is H, halo, or C 1-3 alkyl, and

R 2 is halo;

R 3 is H;

R 4 is a 5-6 membered heteroaryl optionally substituted with one or more R b ;

R 5 is H;

R 6a and R 6b are each independently H;

R b is, independently at each occurrence, C 1-3 alkyl;

Y is —O—, —N(R w )—, or —C(R x )(R y )—;

R w is H; and

R x and R y are independently H.

15 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

R 1 is H; and

R 2 is halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a .

16 . The compound of any one of claims 1-13, or 15 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

R 1 is H; and

R 2 is halo, —CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 3-4 cycloalkyl, wherein C 3-4 cycloalkyl of R 2 is optionally substituted with one or more CH 3 .

17 . The compound of claim 1 or claim 2 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

R 1 is halo, or C 1-6 alkyl; and

R 2 is H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a .

18 . The compound of any one of claims 1-13, or 17 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

R 1 is halo, or C 1-3 alkyl; and

R 2 is H, halo, C 1-3 alkyl.

19 . The compound of any one of claims 1-18 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

R 3 is H.

20 . The compound of any one of claims 1-13, or 15-18 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

R 3 is halo.

21 . The compound of any one of claims 1-13, or 15-20 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ; and

R b is, independently at each occurrence, halo or C 1-3 alkyl, wherein the C 1-3 alkyl of R b is optionally substituted with one or more D.

22 . The compound of any one of claims 1-13, or 15-21 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 is selected from the group consisting of

23 . 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 Compounds 1-81 of Table 1.

24 . A process for preparing a compound of formula (I), as defined in any one of claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the process comprises:

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 —OH, or —NH(R w );

PG is H, or a protecting group;

R 1 is H, halo, or C 1-6 alkyl,

R 2 is H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a , and

R 3 is H or halo,

wherein at least one of R 1 and R 2 is other than H, or R 3 is F;

R 5 is H or halo;

R a is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R a is optionally substituted with one or more D or halo;

R w is H or C 1-6 alkyl; and

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 halo, or a sulfonic ester;

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ;

R b is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R b is optionally substituted with one or more D or halo;

Y is C 1-6 alkylene optionally substituted with one or more D, or halo;

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 H, or a protecting group;

R 1 is H, halo, or C 1-6 alkyl,

R 2 is H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a , and

R 3 is H or halo,

wherein at least one of R 1 and R 2 is other than H, or R 3 is F;

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ;

R 5 is H or halo;

R a is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R a is optionally substituted with one or more D or halo;

R b is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R b is optionally substituted with one or more D or halo;

Q 2 is —O—, —N(R w )—;

Y is C 1-6 alkylene optionally substituted with one or more D, or halo; and

R w is H or C 1-6 alkyl.

25 . The process of claim 24 , wherein the one or more coupling reagents comprises a base.

26 . The process of claim 24 or 25 , wherein the process further comprises contacting the compound of formula (I-3) with a deprotecting agent to provide a compound of formula (I).

27 . A process for preparing a compound of formula (I), as defined in any one of claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the process comprises:

reacting a compound of formula (II-1):

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

Q 3 is —CHO, —CDO, or —C(O)(C 1-6 alkyl);

PG is H, or a protecting group;

R 1 is H, halo, or C 1-6 alkyl,

R 2 is H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a , and

R 3 is H or halo,

wherein at least one of R 1 and R 2 is other than H, or R 3 is F;

R 5 is H or halo; and

R a is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R a is optionally substituted with one or more D or halo;

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 a phosphonium salt;

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ;

R b is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R b is optionally substituted with one or more D or halo;

Y is C 1-6 alkylene optionally substituted with one or more D, or halo;

to provide a compound of formula (II-3):

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

PG is H, or a protecting group;

R 1 is H, halo, or C 1-6 alkyl, and

R 2 is H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a , and

R 3 is H or halo,

wherein at least one of R 1 and R 2 is other than H, or R 3 is F;

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ;

R 5 is H or halo;

R a is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R a is optionally substituted with one or more D or halo;

R b is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of Rh is optionally substituted with one or more D or halo;

X is —C(R t )—;

Y′ is absent or C 1-5 alkylene optionally substituted with one or more D, or halo; and

R t is H, D, or C 1-6 alkyl.

28 . The process of claim 27 , wherein the reaction further comprises a hydrogenation step.

29 . The process of claim 27 or claim 28 , wherein the process further comprises contacting the compound of formula (II-3) with a deprotecting agent to provide a compound of formula (I).

30 . A process for preparing a compound of formula (I), as defined in any one of claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the process comprises:

reacting a compound of formula (II-1):

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

Q 3 is —CHO, —CDO, or —C(O)(C 1-6 alkyl);

PG is H, or a protecting group;

R 1 is H, halo, or C 1-6 alkyl, and

R 2 is H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a ,

wherein at least one of R 1 and R 2 is other than H;

R 3 is H or halo;

R 5 is H or halo; and

R a is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R a is optionally substituted with one or more D or halo; and

R t is C 1-6 alkyl;

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 —N(R w )—;

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ;

R b is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R b is optionally substituted with one or more D or halo; and

R w is H or C 1-6 alkyl;

with a reducing agent to provide a compound of formula (III-3):

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

PG is H, or a protecting group;

R 1 is H, halo, or C 1-6 alkyl, and

R 2 is H, halo, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl of R 2 are each independently optionally substituted with one or more R a ,

wherein at least one of R 1 and R 2 is other than H;

R 3 is H or halo;

R 4 is a 5-10 membered heteroaryl optionally substituted with one or more R b ;

R 5 is H or halo;

R a is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R a is optionally substituted with one or more D or halo;

R b is, independently at each occurrence, halo or C 1-6 alkyl, wherein the C 1-6 alkyl of R b is optionally substituted with one or more D or halo;

Y 3 is —N(R w )—; and

R t is H, D, or C 1-6 alkyl.

31 . The process of claim 30 , wherein the reducing agent is a borohydride.

32 . The process of claim 30, or 31 , wherein the process further comprises contacting the compound of formula (III-3) with a deprotecting agent to provide a compound of formula (I).

33 . The process of any one of claims 24-32 , wherein the protecting group is a Boc, or THP group.

34 . The process of any one of claims 26, 29, or 31 , wherein the deprotecting agent comprises an acid.

35 . A pharmaceutical composition comprising (i) a compound of any one of claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii) one or more pharmaceutically acceptable excipients.

36 . A method of modulating SLC6A19 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 35 .

37 . A method of inhibiting SLC6A19 in a cell, comprising exposing the cell to a composition comprising an effective amount of a compound of any one or claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 35 .

38 . 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 compound of any one of claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 35 .

39 . A method of treating a SLC6A19-mediated disease, disorder, or condition in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 35 .

40 . The method of claim 37 , wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, metabolic diseases, hyperphenylalaninemia, tyrosinemia (Type I, II, or III), nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, hyperammonemia, diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity related disorders, and neurodevelopmental and autism-spectrum disorders.

41 . The method of claim 39 or claim 40 , wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), methabolic syndrome, and metabolic diseases.

42 . The method of claim 39 , wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

43 . The method of claim 39, or claim 42 , wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

44 . A kit, comprising (i) a compound of any one of claims 1-23 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 35 , and (ii) instructions for use in treating an SLC6A19-mediated disease, disorder, or condition in an individual in need thereof.

45 . The kit of claim 44 , wherein the disease, disorder, or condition is associated with abnormal levels of amino acids.

46 . The kit of claim 44, or 45 , wherein the disease, disorder, or condition is associated with a genetic defect in phenylalanine hydroxylase.

47 . The kit of claim 44 , wherein the disease, disorder, or condition is selected from the group consisting of phenylketonuria (PKU), chronic kidney disease (CKD), metabolic syndrome, metabolic diseases, hyperphenylalaninemia, tyrosinemia (Type I, II, or III), nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders, hyperammonemia, diabetes, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity related disorders, and neurodevelopmental and autism-spectrum disorders.

48 . The kit of claim 44 , wherein the individual has a genetic defect in phenylalanine hydroxylase.