Substituted pyrimidine derivatives

A method of inhibiting the binding of CRF to the CRF1 receptor in vitro, the method comprising contacting, in the presence of CRF, a solution comprising a compound of Formula I,

• a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof form free hydroxyl, amino or sulfhydry groups are bonded to any group that cleave to form free hydroxyl, amino or sulfhydryl group respectively, or a pharmaceutically acceptable salt of a prodrug thereof, wherein:
• X is selected from —NR3R4, —OR3, —CR3R5R5, —C(O)R3, —S(O)mR3, —NR3C(O)R4, or —NR3S(O)mR4;
• m is 0, 1 or 2;
• G is selected from N or C(R2);
• R1 and R2 are independently selected from —H, —NH(alkyl), —N(alkyl)2—NH(substituted alkyl), —N(substituted alkyl)2, —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, —CR5R5Ar, —OAr, —S(O)mAr, —NR5Ar, —S(O)malkyl, —S(O)msubstituted alkyl, —CN, —NO2, —OH, —NH2, —SH, —C(O)NR4R5 and —C(S)NR4R5;
• R3 and R4 are independently selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R3 and R4 are present one of the R3 or R4 selected from a group provided herein above and the other R3 or R4 is selected from —H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl, heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;
• Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• and
• R5 each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl)2, —CO(O)NH(alkyl), —C(O)N(alkyl)2, —NHC(O)alkyl, —N(alkyl)C(O)alkyl, and —S(O)malkyl, heterocycloalkyl, substituted heterocycloalkyl and Ar,
• with cells expressing the CRF1 receptor, wherein the compound is present in the solution at a concentration sufficient to reduce levels of CRF binding to the cells in vitro.

A method of antagonizing a CRF1 receptor in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of Formula I,

• a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof wherein hydroxyl, amine or sulfhydry groups are bonded to any group that cleaves to form free hydroxyl, amino or sulfhydry groups respectively, or a pharmaceutically acceptable salt of a prodrug thereof, wherein:
• X is selected from —NR3R4, —OR3, —CR3R5R5, —C(O)R3, —S(O)mR3, —NR3C(O)R4, or —NR3S(O)mR4;
• m is 0, 1 or 2;
• G is selected from N or C(R2);
• R1 and R2 are independently selected from —H, —NH(alkyl), —N(alkyl)2, —NH(substituted alkyl), —N(substituted alkyl)2, —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, —CR5R5Ar, —OAr, —S(O)mAr, —NR5Ar, —S(O)malkyl, —S(O)msubstituted alkyl, —CN, —NO2, —OH, —NH2, —SH, —C(O)mAr, —NR5 and —C(S)NR4R5;
• R3 and R4 are independently selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl, heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R3 and R4 are present one of the R3 or R4 is selected from a group provided herein above and the other R3 or R4 is selected from —H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;
• Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• and
• R5 each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl)2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —NHC(O)alkyl, —N(alkyl) C(O)alkyl, and —S(O)malkyl, heterocycloalkyl, substituted heterocycloalkyl and Ar.

A method for screening for ligands for CRF1 receptors, which method comprises:

• a) carrying out a competitive binding assay with a CRF1 receptor, a compound of Formula I,
• a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof wherein hydroxyl, amine or sulfhydry groups are bonded to any group that cleaves to form free hydroxyl, amino or sulfhydryl group respectively, or a pharmaceutically acceptable salt of prodrug thereof, wherein:
• X is selected from —NR3R4, —OR3, —CR3R5R5, —C(O)R3, —S(O)mR3, —NR3C(O)R4, or —NR3S(O)mR4;
• m is 0, 1 or 2;
• G is selected from N or C(R2);
• R1 and R2 are independently selected from —H, —NH(alkyl), —N(alkyl)2, —NH(substituted alkyl), —N(substituted alkyl)2, —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroalkyl, —CR5R5Ar, —OAr, —S(O)mAr, —NR5Ar, —S(O)malkyl, —S(O)msubstituted alkyl, —CN, —NO2, —OH, —NH2, —SH, —C(O)NR4R5 and —C(S)NR4R5;
• R3 and R4 are independently selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R3 and R4 are present one of the R3 or R4 is selected from a group provided herein above and the other R3 or R4 is selected from —H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, aryl cycloalkyl, substituted aryl, cycloalkyl, heteroaryl, cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;
• Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• and
• R5 each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl)2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —NHC(O)alkyl, —N(alkyl)C(O)alkyl, and —S(O)malkyl, heterocycloalkyl, substituted heterocycloalkyl and Ar, which is labeled with a detectable label, and a candidate ligand;
• and b) determining the ability of said candidate ligand to displace said labeled compound.

A method of promoting hair growth in a human, comprising administering to the human in need thereof an effective amount of a compound of Formula I,

• a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof wherein hydroxyl, amine or sulfylhydry groups are bonded to any group that cleaves to form free hydroxyl, amino or sulfhydryl group respectively, or a pharmaceutically acceptable salt of a prodrug thereof, wherein;
• X is selected from —NR3R4, —OR3, —CR3R5R5, —C(O)R3, —S(O)mR3, —NR3C(O)R4, or —NR3S(O)mR4;
• m is 0, 1 or 2;
• G is selected from N or C(R2);
• R1 and R2 are independently selected from —H, —NH(alkyl), —N(alkyl)2, —NH(substituted alkyl), —N(substituted alkyl)2, —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, —CR5R5Ar, —OAr, —S(O)mAr, —NR5Ar, —S(O)malkyl, —S(O)msubstituted alkyl, —CN, —NO2, —OH, —NH2, —SH, —C(O)NR4R5 and —C(S)NR4R5;
• R3 and R4 are independently selected from heteroaryl substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R3 and R4 are present one of the R3 or R4 is elected from a group provided herein above and the other R3 or R4 is selected from —H, alkyl, substituted, alkyl, haloalkyl, cycloalkyl, substituted, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;
• Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• and
• R5 each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl)2, —CO(O)NH(alkyl), —C(O)N(alkyl)2, —NHC(O)alkyl, —N(alkyl)C(O)alkyl, and —S(O)malkyl, heterocycloalkyl, substituted heterocycloalkyl Ar.

A method of promoting smoking cessation in a human, comprising administering to the human in need thereof an effective amount of a compound of Formula I,

• a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof wherein hydroxyl, amine or sulfylhydry groups are bonded to any group that cleaves to form free hydroxyl, amino or sulfhydryl group respectively, or a pharmaceutically acceptable salt of a prodrug thereof, wherein:
• X is selected from —NR3R4, —OR3, —CR3R5R5, —C(O)R4, —S(O)mR3, —NR3C(O)R4, or —NR3S(O)mR4;
• m is 0, 1 or 2;
• G is elected from N or C(R2);
• R1 and R2 are independently selected from —H, —NH(alkyl), —N(alkyl)2, —NH(substituted alkyl), —N(substituted alkyl)2, —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, —CR5R5Ar, —OAr, —S(O)mAr, —NR5Ar, —S(O)malkyl, —S(O)msubstituted alkyl, —CN, —NO2, —NH2, —SH, —C(O)NR4R5 and —C(S)NR4R5;
• R3 and R4 are independently selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R3 and R4 are present one of the R3 or R4 is selected from a group provided herein above and the other R3 or R4 is selected from —H, alkyl, substituted alkyl, haloalkyl, cycloakyl, substituted cycloalkyl, aryl, heteroaryl heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;
• Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
• and
• R5 each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl)2, —C(O)NH(alkyl), —C(O)N(alkyl)2, —NHC(O)alkyl, —N(alkyl)C(O)alkyl, and —S(O)malkyl, heterocycloalkyl, substituted heterocycloalkyl and Ar.