Sarm1 modulators, preparations, and uses thereof

A compound of the following structural Formula 1:

• a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein:
• X1 is C, N, or O;
• X2 is C or N;
• X3 is C or N;
• R1 and R2:
• are independently selected from H, optionally substituted C1-C4 alkyl, and optionally substituted C3-C6 cycloalkyl, or
• join to form a 5- to 7-membered ring such that the 5- to 7-membered ring and Ring A together form Fused Ring A selected from Fused Ring A-1, Fused Ring A-2, Fused Ring A-3, and Fused Ring A-4 shown below:
• wherein:
• Y1, Y2, Y3, and Y4 are each independently selected from C and N;
• p is an integer selected from 0, 1, and 2;
• R7 is selected from halogen, —CN, —CONH2, —SO2Me, optionally substituted 3-6 membered cycloalkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, optionally substituted C1-C4 alkyl, ═O (provided that Fused Ring A is not Fused Ring A-1), and —ORs, wherein Rs is optionally substituted C1-C4 alkyl, and m is an integer selected from 0, 1, 2, and 3;
• Rx is selected from H, optionally substituted 3- to 5-membered cycloalkyl, optionally substituted C1-C4 alkyl, and —C(═O)Ry, wherein Ry is optionally substituted 3-5 membered cycloalkyl or optionally substituted C1-C4 alkyl;
• R3:
• is selected from absent, H, —CN, —C(═O)NH2, and optionally substituted C1-C4 alkyl;
• R4:
• is selected from H, optionally substituted C1-C6 alkyl, optionally substituted 3- to 5-membered cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 6-membered heteroaryl,
• —RaC(═O)Rb, —RaNHC(═O)Rb, —RaNRcRd, —RaS(═O)Rb, —RaS(═O)2Rb,
• —RaNHS(═O)2Rb, and —RaC(═O)NRcRd, wherein:
• Ra, for each occurrence, is independently selected from C1-C8 alkyl optionally substituted by 1-3 groups selected from —OH and halogen;
• Rb, for each occurrence, is independently selected from H, —OH, —O(C1-C3 alkyl), 4- to 6-membered heterocyclyl, and C1-C6 alkyl optionally substituted by 1-3 groups selected from —OH and halogen;
• Rc and Rd, for each occurrence, are independently selected from H and C1-C6 alkyl, or
• Rc and Rd join to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl wherein the 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl of Rc and Rd is optionally substituted by 1-3 groups selected from —OH and halogen;
• R5:
• is selected from optionally substituted C1-C7 alkyl, optionally substituted phenyl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered cycloalkyl, and optionally substituted 5- to 6-membered heterocyclyl;
• and
• R6 is H, optionally substituted C1-C4 alkyl, or CH2CONH2, provided that R6 is absent when X1 is O.