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 structure (I):

• or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:
• W is
• P is C1-C4 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more Rp;
• Q is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more Rq;
• T1 is —C(O)NH—, —N(H)C(O)—, —S(O)2CH2C(O)N(H)—, —C(O)N(H)S(O)2—, —S(O)2N(H)—, or —SCH2C(O)—;
• T2 is —(C(Rt)(Rt′))—;
• E is —(C(H)Re)n— or —(C(H)Re)n—X2—(C(Rt)(Rt′)p—;
• Z is C or N;
• X is —X1—(C(Rt)(Rt′)p;
• X1 is —O—, —NH—, —N(H)C(O)—, —C(O)NH— or —S(═O)2—;
• X2 is —O—, —C(═O)—, —N(H)C(O)— or —C(O)NH—;
• Rp and Rq are at each occurrence, independently H, —OH, —NH2, —N(Me)2, —NHC(═NH)NH2, —S(═O)2Me, —NHS(═O)2Me, halo, oxo, —CO2H, —C(O)Me, —C(O)NHMe, alkoxy, haloalkoxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• Re is at each occurrence independently H, OH, or C1-C4 alkyl;
• Rt is at each occurrence independently H, C1-C4 alkyl, or cycloalkyl;
• Rt′ is at each occurrence independently H, OH, C1-C4 alkyl, cycloalkyl or R and Rt′ together with the atom to which they are bonded form a ring;
• R1, R2, R3, and R4 are at each occurrence, independently H, —OH, —NH2, halo, —CO2H, —C(O)Me, alkoxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• m is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• and
• p is 0 or 1.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having structure (I):

• or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:
• W is
• P is C1-C4 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more Rp;
• Q is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more Rq;
• T1 is —C(O)NH—, —N(H)C(O)—, —S(O)2CH2C(O)N(H)—, —C(O)N(H)S(O)2—, —S(O)2N(H)—, or —SCH2C(O)—;
• T2 is —(C(Rt)(Rt′))—;
• E is —(C(H)Re)n— or —(C(H)Re)n—X2—(C(Rt)(Rt′)p;
• Z is C or N;
• X is —X1—(C(Rt)(Rt′)p;
• X1 is —O—, —NH—, —N(H)C(O)—, —C(O)NH— or —S(═O)2—;
• X2 is —O—, —C(═O)—, —N(H)C(O)—, —C(O)NH—;
• Rp and Rq are at each occurrence, independently H, —OH, —NH2, N(Me)2, —NHC(═NH)NH2, —S(═O)2Me, —NHS(═O)2Me, halo, oxo, —CO2H, —C(O)Me, —C(O)NHMe, alkoxy, haloalkoxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• Re is at each occurrence independently H, OH or C1-C4 alkyl;
• Rt is at each occurrence independently H, C1-C4 alkyl or cycloalkyl;
• Rt′ is at each occurrence independently H, OH, C1-C4 alkyl, cycloalkyl or R and R together with the atom to which they are bonded form a ring;
• R1, R2, R3, and R4 are at each occurrence, independently H, —OH, —NH2, halo, —CO2H, —C(O)Me, alkoxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• m is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• and
• p is 0 or 1.

A compound having structure (I):

• or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:
• W is
• P is C1-C4 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more Rp;
• Q is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more Rq;
• T1 is —C(O)NH—, —N(H)C(O)—, —S(O)2CH2C(O)N(H)—, —C(O)N(H)S(O)2—, —S(O)2N(H)—, or —SCH2C(O)—;
• T2 is —(C(Rt)(Rt′))—;
• E is —(C(H)Re)n— or —(C(H)Re)n—X2—(C(Rt)(Rt′)p—;
• Z is C or N;
• X is —X1—(C(Rt)(Rt′)p;
• X1 is —O—, —NH—, —N(H)C(O)—, —C(O)NH— or —S(═O)2—;
• X2 is —O—, —C(═O)—, —N(H)C(O)— or —C(O)NH—;
• Rp and Rq are at each occurrence, independently H, —OH, —NH2, —N(Me)2, —NHC(═NH)NH2, —S(═O)2Me, —NHS(═O)2Me, halo, oxo, —CO2H, —C(O)Me, —C(O)NHMe, alkoxy, haloalkoxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• Re is at each occurrence independently H, OH, or C1-C4 alkyl;
• Rt is at each occurrence independently H, C1-C4 alkyl, or cycloalkyl;
• Rt′ is at each occurrence independently H, OH, C1-C4 alkyl, cycloalkyl or R and R together with the atom to which they are bonded form a ring;
• R1, R2, R3, and R4 are at each occurrence independently H, —OH, —NH2, halo, —C(O)Me, —CO2H, alkoxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• m is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• and
• p is 0 or 1.