Modulators of mas-related g-protein receptor x4 and related products and methods

A method for treating an MRGPR X4 dependent condition by administering to a subject in need thereof an effective amount of a compound having the structure of Formula (I):

• or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
• n is 0 or 1;
• x is 0, 1 or 2;
• A is aryl or heteroaryl;
• Q1 and Q2 are both CR10, or one of Q1 or Q2 is CR10 and the other is N;
• Z is —O—, —S—, —N(R11)—, —CH2— or —C≡C—;
• each R10 is H or alkyl;
• R is —(CH2)mC(═O)OR12, —(CH2)mNHR13, —(C═O)NR14R15, —CH2OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic acid isostere;
• m is 0 or 1;
• R11, R12 and R13 are the same or different and individually H or alkyl;
• R14 is H and R15 is H, —SO2CH3, carbocycle, heterocyle, or alkyl substituted with 0, 1, 2 or 3 substituents selected from —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO2OH, alkoxy, carbocycle, or heterocycyle, wherein R′ and R″ are individually H or alkyl, or
• R14 and R15 are taken together with the nitrogen atom to which they are attached to form heterocycle;
• R1 is H or alkyl;
• R2 is halo, cyano, amino, alkyl, alkoxy, carbocycle or heterocycle;
• R3, R4 and R5 are the same or different and either absent or, when present, cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, —(C═O)alkyl, —(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or —O-heterocycle, or
• any two R and R2 taken together with the atoms to which they are attached form heterocycle;
• any two R3, R4, R5 and R10, taken together with the atoms to which they are attached form carbocycle or heterocycle;
• and wherein each occurrence of carbocycle or heterocycle is substituted with 0, 1, 2 or 3 substituents individually selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle.

A pharmaceutical composition comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable excipient:

• or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
• n is 0 or 1;
• x is 0, 1 or 2;
• A is aryl or heteroaryl;
• Q1 and Q2 are both CR10, or one of Q1 or Q2 is CR10 and the other is N;
• Z is —O—, —S—, —N(R11)—, —CH2— or —C≡C—;
• each R10 is H or alkyl;
• R is —(CH2)mC(═O)OR12, —(CH2)mNHR13, —(C═O)NR14R15, —CH2OH, —CN, haloalkyl, carbocycle, heterocycle, or a carboxylic acid isostere;
• m is 0 or 1;
• R11, R12 and R13 are the same or different and individually H or alkyl;
• R14 is H and R15 is H, —SO2CH3, carbocycle, heterocyle, or alkyl substituted with 0, 1, 2 or 3 substituents selected from —OH, —CN, —NR′R″, C(═O)OH, C(═O)NR′R″, —SO2OH, alkoxy, carbocycle, or heterocycyle, wherein R′ and R″ are individually H or alkyl, or
• R14 and R15 are taken together with the nitrogen atom to which they are attached to form heterocycle;
• R1 is H or alkyl;
• R2 is halo, cyano, amino, alkyl, alkoxy, carbocycle or heterocycle;
• R3, R4 and R5 are the same or different and either absent or, when present, cyano, nitro, halogen, alkyl, haloalkyl, cyanoalkyl, alkoxy, haloalkoxy, —(C═O)alkyl, —(C═O)NHalkyl, carbocycle, heterocycle, —O-carbocycle or —O-heterocycle, or
• any two R and R2 taken together with the atoms to which they are attached form heterocycle;
• any two R3, R4, R5 and R10, taken together with the atoms to which they are attached form carbocycle or heterocycle;
• and wherein each occurrence of carbocycle or heterocycle is substituted with 0, 1, 2 or 3 substituents individually selected from halogen, hydroxyl, oxo, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, carbocycle, or heterocycle.