IP Library › Granted Patent US 12697332

Granted Patent B2

US 12697332 · App. 18/287,158 · Granted Aug 4, 2026

Alpha protein kinase 1 inhibitors for use in treating Kawasaki disease

Inventors: Yuning Wei (Shanghai, CN); Danyang Liu (Shanghai, CN); Cong Xu (Shanghai, CN); Lawrence S. Melvin, Jr. (Shanghai, CN); Xiong Wei (Shanghai, CN); Tongruei Raymond Li (Shanghai, CN); Jieqing Fan (Shanghai, CN); Yanfang Pan (Shanghai, CN); Huaixin Dang (Shanghai, CN); Henri Lichenstein (Shanghai, CN); Tian Xu (Shanghai, CN)

Assignee: Shanghai Yao Yuan Biotechnology Co., Ltd.

A61K31/496 A61K31/426 A61K31/427 A61P9/00

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Quick Facts

Patent No.: US 12697332
App. No.: 18/287,158
Granted: Aug 4, 2026
Kind: B2

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Abstract

Provided herein are methods for inhibiting ALPK1 kinase activity using a compound of Formula I, and compositions and methods for therapy, for example in treating Kawasaki Disease.

Claims (76)

1 . A method for treating Kawasaki disease in a subject in need of such treatment, the method comprising administering to the subject a compound having a structure of:

or a pharmaceutically acceptable salt thereof, wherein

A is selected from a bond, azetidinyl, —O—, —N(R 6 )—, —CH 2 —N(R 6 )—, —CHR 9 —N(R 6 )—, wherein

R 6 is selected from H, —OH, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 aminoalkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted saturated or unsaturated C 3 -C 6 cycloalkyl, and optionally substituted saturated or unsaturated C 3 -C 6 cycloalkoxyl, wherein

the optionally substituted R 6 moieties comprise 0-3 substituents independently selected from halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, and C 1 -C 6 alkoxyl;

R 9 is selected from optionally substituted C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, optionally substituted saturated or unsaturated C 3 -C 6 cycloalkyl, optionally substituted saturated or unsaturated C 3 -C 6 cycloalkoxyl, wherein

optionally substituted R 9 moieties comprise 0-2 substituents independently selected from halo, —OH, —COOH, —NH 2 , —O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, —CHR 7f R 8f , —OR 7f , —OC(O)(R 7f ), —C(O)(R 7f ), —C(O)N(R 7f R 8f ), —C(O)O(R 7f ), —S(O) 2 (R 7f ), —S(O)ON(R 7f R 8f ) and —N(R 7f R 8f ) wherein

each R 7f and R 8f are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxy;

R 1 is selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 hydroxyalkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 haloalkoxyl, optionally substituted C 1 -C 6 aminoalkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted saturated or unsaturated C 3 -C 6 cycloalkyl, optionally substituted saturated or unsaturated C 3 -C 6 cycloalkoxyl, optionally substituted mono or bicyclic aryl, optionally substituted 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; optionally substituted saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; and optionally substituted saturated or unsaturated 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S;

wherein optionally substituted R 1 moieties comprise 0-4 substituents independently selected from halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, —R 7a , —X 1 —R 7a , CHR 7a R 8a , —OR 7a , —O—X 1 —R 7a , —X 1 —O—X 1 —R 7a , —OC(O)(R 7a ), —O—X 1 —C(O)(R 7a ), —C(O)(R 7a ), —C(O)N(R 7a R 8a ), —NR 7a (CO) R 8a , —C(O)O(R 7a ), S(O) 2 R 7a , —S(O) 2 N(R 7a R 8a ), —N(R 7a R 8a ), saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, mono or bicyclic aryl, 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, and 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; wherein

each X 1 is independently C 1 -6 alkylene;

each R 7a and R 8a are independently selected from H, C 1 -C 6 alkyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, aryl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein the aryl and 3-7 membered heterocyclyl groups are substituted with 0-3 substituents selected from halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl; and

the C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxyl, 3-7 membered heterocyclyl, the mono or bicyclic aryl, the 5-10 membered heteroaryl, the saturated or unsaturated 7-8 membered bridged heterocyclyl, the saturated or unsaturated 7-11 membered spiroheterocycly, and the 6-11 membered bicyclic heterocyclyl are each independently substituted with 0 to 3 moieties selected from halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, —CHR 70 R 8b , —OR 76 , —OC(O)(R 7b ), —C(O)(R 7b ), —C(O)N(R 7b R 8b ), —NR 7b (CO) R 8b , —C(O)O(R 7b ), —S(O) 2 N(R 7b R 8b ) and —N(R 7b R 8b ), wherein

each R 7b and R 8b are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl; or

R 1 and R 6 combine to form a 3-6 membered heterocycloalkyl substituted with 0-3 moieties independently selected from the group consisting of halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, and C 1 -C 6 alkoxyl;

R 5 is selected from H, deuterium, halo, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, and C 1 -C 6 haloalkyl;

R 2 and R 3 are each independently selected from H, OH, C 1 -C 6 alkyl and C 2 -C 6 alkynyl, wherein C 1 -C 6 alkyl and C 2 -C 6 alkynyl are each substituted with 0-3 moieties independently selected from halo, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, —OC(O)(R 7c ), —C(O)(R 7c ), C(O)O(R 7c ), S(O) 2 N(R 7c R 8c ), and N(R 7c R 8c ), wherein

each R 7c and R 8c are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxy, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl;

provided that R 2 and R 3 are not both H; or

R 2 and R 3 combine to form a C 3 -C 6 cycloalkyl ring or a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices independently selected from N, O, and S, wherein the ring formed can be optionally substituted with 1-2 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, halo, —OH, ═O, —CN, OC(O)(R 7d ), —C(O)(R 7d ), C(O)O(R 7d ), S(O) 2 N(R 7d R 8d ) and N(R 7d R 8d ), wherein

each R 7d and R 8d are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl;

each R 4 is independently selected from halo, —OH, —NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, CHR 7e R 8e , OR 7e , OC(O)(R 7e ), C(O)(R 7e ), C(O)N(R 7e R 8e ), C(O)O(R 7e ), S(O) 2 N(R 7e R 8e ) and N(R 7e R 8e ) wherein

each R 7e and R 8e are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, and

the subscript p is 0,1, 2 or 3.

2 . The method of claim 1 , wherein the compound of Formula I is also a compound of Formula IA:

or a pharmaceutically acceptable salt thereof.

3 . The method of claim 2 , wherein the subject in need of such therapy is a subject carrying one or more genetic mutations in ALPK1.

4 . The method of claim 1 , wherein the compound of Formula I is also a compound of Formula IA-I:

or a pharmaceutically acceptable salt thereof.

5 . The method of claim 1 , wherein R 1 is selected from H and optionally substituted C 1 -C 6 alkyl, wherein

optionally substituted C 1 -C 6 alkyl comprises 0-4 substituents independently selected from halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, —CHR 7a R 8a , —OR 7a , —OC(O)(R 7a ), —C(O)(R 7a ), —C(O)N(R 7a R 8a ), —C(O)O(R 7a ), —S(O) 2 R 7a , —S(O) 2 N(R 7a R 8a ) and —N(R 7a R 8a ),

wherein

each R 7a and R 8a are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl.

6 . The method of claim 1 , wherein R 1 is C 1 -C 6 alkyl substituted with 0-4 substituents independently selected from —OH, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyl, —OC(O)(R 7a ), —S(O) 2 N(R 7a R 8a ) and —N(R 7a R 8a ), wherein

each R 7a and R 8a are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl.

7 . The method of claim 1 , wherein R 1 is a 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S,

the 5-10 membered heteroaryl is substituted with 0 to 3 moieties selected from halo, —OH, —COOH, —NH 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, —CHR 7b R 8b , —OR 7b , —OC(O)(R 7b ), —C(O)(R 7b ), —C(O)N(R 7b R 8b ), —C(O)O(R 7b ), —S(O) 2 N(R 7b R 8b ) and —N(R 7b R 8b ), wherein

8 . The method of claim 1 , wherein R 1 is aryl substituted with 0-3 substituents selected from halo, a 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; a 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; and a saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein

the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl, and the 7-11 membered spiroheterocyclyl are substituted with from 0 to 3 moieties selected from halo, —OH, —COOH, —NH 2 , —O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, —CHR 7b R 8b , —OR 76 , —OC(O)(R 7b ), —C(O)(R 7b ), —C(O)N(R 76 R 8b ), —C(O)O(R 7b ), —S(O) 2 R 7b , —S(O) 2 N(R 7b R 8b ) and —N(R 7b R 8b ), wherein

9 . The method of claim 1 , wherein the compound of Formula I is also a compound of Formula IB:

or a pharmaceutically acceptable salt thereof, wherein

D is CR10 or N;

E is CR14 or N;

F is CR12 or N;

G is CR11 or N;

provided that no more than three of D, E, F, and G are N;

R 10 , R 11 , R 12 , R 13 and R 14 , when present, are each independently selected from H, halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, —R 7a , —X 1 —R 7a , X 1 —O—X 1 —R 7a , —CHR 7a R 8a , —OR 7a , —O—X 1 —R 7a , —OC(O)(R 7a ), —O—X 1 —C(O)(R 7a ), —C(O)(R 7a ), —C(O)N(R 7a R 8a ), —C(O)O(R 7a ), S(O) 2 R 7a , —S(O) 2 N(R 7a R 8a ), —N(R 7a R 8a ), saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, saturated or unsaturated 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; mono or bicyclic aryl, a 9-10 membered bicyclic heteroaryl containing 1-4 heteroatom ring vertices selected from N, O, and S; saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; and saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; 6-11 membered bicyclic heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S; wherein

each X 1 is independently C 1 -6 alkylene;

the 3-7 membered heterocyclyl, the mono or bicyclic aryl, the 9-10 membered bicyclic heteroaryl, the 7-8 membered bridged heterocyclyl, the 7-11 membered spiroheterocycly, and the 6-11 membered bicyclic heterocyclyl are each independently substituted with 0 to 2 moieties selected from halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, —CHR 7g R 8g , —OR 7g , —OC(O)(R 7g ), —C(O)(R 7g ), —C(O)N(R 7g R 8g ), —NR 7g (CO) R 8g , —C(O)O(R 7g ), —S(O) 2 N(R 7g R 8g ) and —N(R 7g R 8g ), wherein

each R 7g and R 8g are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl.

10 . The method of claim 9 , wherein D, E, F and G are CR 10 , CR 14 , CR 12 , and CR 11 , respectively.

11 . The method of claim 9 , wherein

R 12 and R 14 are H;

R 10 and R 11 are each independently selected from halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, —CHR 70 R 8b , —OR 7b , —OC(O)(R 7b ), —C(O)(R 7b ), —C(O)N(R 76 R 8b ), —C(O)O(R 7b ), —S(O) 2 N(R 7b R 8b ) and —N(R 7b R 8b ), wherein

R 7b and R 8b are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl; and

R 13 is selected from 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, and saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein

the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl, and the 7-11 membered spiroheterocyclyl are optionally substituted with 0-2 moieties independently selected from halo, —OH, —COOH, —NH 2 , ═O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl.

12 . The method of claim 9 , wherein

R 10 , R 11 , R 12 and R 14 , when present, are each H; and

R 13 is selected from saturated or unsaturated C 3 -C 6 cycloalkyl, 3-7 membered heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7-8 membered bridged heterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, saturated or unsaturated 7-11 membered spiroheterocyclyl containing 1-2 heteroatom ring vertices selected from N, O, and S, wherein

the 3-7 membered heterocyclyl, the 7-8 membered bridged heterocyclyl, and the 7-11 membered spiroheterocyclyl are optionally substituted with 0-2 moieties independently selected from halo, —OH, —COOH, —NH 2 , —O, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, and saturated or unsaturated C 3 -C 6 cycloalkoxyl.

13 . The method of claim 9 , wherein the subject in need of such therapy is a subject carrying one or more genetic mutations in ALPK1.

14 . The method of claim 9 , wherein the compound of Formula IB is also a compound of Formula IB-1 or Formula IB-2:

or a pharmaceutically acceptable salt thereof, wherein

R 15 is selected from —OH, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkoxyl, saturated or unsaturated C 3 -C 6 cycloalkyl, saturated or unsaturated C 3 -C 6 cycloalkoxyl, —CHR 70 R 8b , —C(O)(R 7b ), —C(O)N(R 70 R 8b ), —C(O)O(R 7b ), —S(O) 2 R 7b and —S(O) 2 N(R 7b R 8b ), wherein

15 . The method of claim 14 , wherein R 10 , R 11 , R 12 and R 14 are each independently selected from halo and C 1 -C 6 alkyl.

16 . The method of claim 14 , wherein the compound of Formula IB-1 is also a compound of Formula 1B-1-c, or the compound of Formula IB-2 is also a compound of Formula 1B-2-c:

or a pharmaceutically acceptable salt thereof.

17 . The method of claim 1 , wherein the carbon atom attached to R 2 and R 3 is the S isomer.

18 . The method of claim 1 , wherein the compound of Formula I is selected from

19 . The method of claim 1 , wherein the subject in need of such treatment is a subject carrying one or more genetic mutations in ALPK1.

20 . The method of claim 1 , wherein the subject in need of such treatment is a subject diagnosed with Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis” (“PFAPA”).