US 2010/0136136 A1 · JAK-2 Modulators and Methods of Use

Abstract

This invention relates to the field of protein tyrosine kinases and inhibitors thereof. In particular, the invention relates to inhibitors of JAK-2, pharmaceutical compositions of the compounds for inhibiting JAK-2, methods of inhibiting JAK-2 in a cell, comprising contacting a cell in which inhibition of JAK-2 is desired with a compound or pharmaceutical composition comprising a compound according to the invention. The also comprises methods of treating a disease or condition that involves JAK-2 comprising administering to a patient a pharmaceutical composition comprising a compound according to the invention.

A compound according to Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein
R1 is selected from benzimidazole, indole, quinoline, dihydroquinoline, imidazole, piperazine, benzimidazole, pyridine, —CH2-pyridine, and —CH2-benzimidazole, wherein each benzimidazole, indole, quinoline, dihydroquinoline, imidazole, piperazine, benzothiazole, pyridine, —CH2-pyridine, and —CH2-benzimidazole is optionally substituted with 1 or 2 substituents selected from halo, —(C3-C10)cycloalkyl, —(C1-C6)alkyl, —(C1-C6)alkoxy, -(4-10 membered) heterocycloalkyl, —O-(4-10 membered)heterocycloalkyl, —C(O)O(C1-C6)alkyl, —O—(C1-C6)alkyl-C(O)NR8R9, —O—(C1-C6)alkyl-C(O)O(C1-C6)alkyl, —O—(C1-C6)alkyl(4-10 membered)heterocycloalkyl-C(O)O—(C1-C6)alkyl, -(4-10 membered)heterocycloalkyl(C1-C6)alkyl, -(4-10 membered)heterocycloalkyl(C1-C6)alkyl(C6-C10)aryl, -(4-10 membered)heterocycloalkyl(C1-C6)alkyl(4-10 membered)heterocycloalkyl, -(4-10 membered)heterocycloalkyl(C1-C6)alkyl(5-10 membered)heteroaryl, —O—(C1-C6)alkyl-(4-10 membered)heterocycloalkyl, —O(C1-C6)alkyl-C(O)NH(C5-C10)cycloalkyl, —O(C1-C6)alkyl-C(O)NH(C2-C6)alkyl(R6(R7), -(4-10 membered)heterocycloalkyl(C6-C10)aryl,
—[(C1-C6)alkyl-NH[(C1-C6)alkyl]2, —O—(C1-C6)alkyl]2, -(4-10 membered)heterocycloalkyl(C1-C6)alkoxy, -(4-10 membered)heterocycloalkyl-C(O)O—(C1-C6)alkyl, —(C1-C6)alkoxy(4-10 membered)heterocycloalkyl and —O—(C1-C6)alkyl-C(O)OH;
R2 is selected from —(C6-C10)aryl, —(C1-C6)alkyl(C6-C10)aryl, —NHC(O)(C4-C10)heterocycloalkyl(C1-C6)alkyl, -(5-10 membered)heteroaryl, -(5-10 membered)heteroaryl(C1-C6)alkyl, -(4-6 membered)heterocycloalkyl, —O—(C1-C6)alkyl(4-10 membered)heterocycloalkyl-C(O)O—(C1-C6)alkyl, —O—(C1-C6)alkyl-(4-10 membered)heterocycloalkyl, —(C1-C6)alkyl-(C3-C10)cycloalkyl, and —(C1-C6)alkyl-(5-10 membered)heteroaryl, wherein each —(C6-C10)aryl, —NHC(O)(C4-C10)heterocycloalkyl(C1-C6)alkyl, —(C1-C6)allyl(C6-C10)aryl, -(5-10 membered)heteroaryl, -(5-10 membered)heteroaryl(C1-C6)alkyl, -(4-10 membered)heterocycloalkyl, —O—(C1-C6)alkyl(4-10 membered)heterocycloalkyl-C(O)O—(C1-C6)alkyl, —O—(C1-C6)alkyl-(4-10 membered)heterocycloalkyl, —(C1-C6)alkyl-(C3-C10)cycloalkyl, and —(C1-C6)allyl-(5-10 membered)heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from —(C1-C6)alkyl, —(C1-C6)alkyl-R12, —(C1-C6)alkyl)NHC(O)O(C1-C6)alkyl, —(C1-C6)alkylhydroxy, —(C1-C6)alkoxy(C1-C6)alkoxy(C6-C10)aryl, —(C5-C10)heteroaryl, -(4-10 membered)heterocycloalkyl-S(O)2—(C6-C10)aryl, -(4-10 membered)heterocycloalkyl, -(4-10 membered)heterocycloalkyl(C6-C10)aryl, -(4-10 membered)heterocycloalkyl(C6-C10)aryl-R12, —NHC(O)(C4-C10)heterocycloalkyl(C1-C6)alkyl, -(4-10 membered heterocycloalkyl)C(O)NH(C6-C10)aryl, -(4-10 membered)heterocycloalkylC(O)NH(C1-C6)alkyl, —O—(C1-C6)alkyl(4-10 membered)heterocycloalkyl, —O—(C1-C6)alkyl(4-10 membered)heterocycloalkyl-S(O)2—(C6-C10)aryl, —S—(C1-C6)alkyl, halo, —(C1-C6)alkoxy, cyano, —O-(4-10 membered)heterocycloalkyl, —CF3, —NHC(O)O(C1-C6)alkyl, —C(O)CH3, —C(O)OR10, —O-(4-10 membered)heterocycloalkyl-C(O)O(C1-C6)alkyl, -(4-10 membered)hetero cycloalkyl-C(O)O(C1-C6)alkyl, —S(O)O(C1-C6)alkyl, —(C5-C6)cycloalkly(C1-C3)alkyl, -(C5-C10)cycloalkly(C1-C6)alkyl-amino(C1-C6)alkyl, —NHC(O)-(4-10 membered)heterocycloalkyl, —(C1-C6)alkyl-NR10(C1-C6)alkyl(C5-C6)cycloalkly, -(4-10 membered) heterocycloalkyl)C(O)NR7R8, —(C6-C10)aryl, —NH(C6-C10)aryl, —O-(4-10 membered)heterocycloalkyl(C1-C6)alkyl, —O-(4-10 membered)heterocycloalkyl(C6-C10)aryl, —O-(4-10 membered)heterocycloalkyl(C1-C6)alkyl-(C6-C10)aryl, —O-(4-10 membered)heterocycloalkyl-C(O)CN, —NH(C1-C6)alkyl, —OCF3, —NHC(O)(4-10 membered)heterocycloalkyl(C1-C6)alkyl, dimethylaminoalkyl,
—NH(C1-C6)alkyl), —(C1-C6)alkyl)N[(C1-C6)alkyl]2. —O-heterocycloalkyl, —O-(4-10 membered)heterocycloalkyl(C6-C10)aryl, and —(C1-C6)alkoxyhydroxy;
R4 and R5 are each independently H or (C1-C6)alkyl, or R1 and R5, together with the nitrogen atom to which they are attached, form a (5-10 membered)heteroaryl or (5-10 membered)heterocycloalkyl, wherein each of the -(5-10 membered)heteroaryl and -(5-10 membered)heterocycloalkyl groups is optionally substituted with one or more groups independently selected from —(C1-C6)alkyl, —(C1-C6)alkyl(C6-C10)aryl, and -(5-10 membered)heteroaryl;
or R2 and R4 together with the nitrogen atom to which they are attached form a
-(5-10 membered)heteroaryl or -(5-10 membered)heterocycloalkyl, wherein each of the
-(5-10 membered)heteroaryl or -(5-10 membered)heterocycloalkyl groups is optionally substituted with one or more groups independently selected from —(C1-C6)alkyl, —(C1-C6)alkyl(C6-C10)aryl, and -(5-10 membered)heteroaryl;
R6 and R7 are each independently selected from hydrogen, hydroxy, (5-10 membered)heteroaryl, (4-10 membered)heterocycloalkyl, and (C6-C10)aryl, and each R6 and R7 are independently selected when more than one R6 or R7 occurs;
R8, R9 and R10 are each independently selected from H and (C1-C6)alkyl, and R8, R9, R9 and R10 are each independently selected when more than one R8, R9 or R10 occurs;
R11 is selected from hydrogen, (C1-C6)alkyl, —(C1-C6)alkyl(R6)R7, and —(C1-C6)alkyl(R8)R9, (C5-C10)cycloalkyl;
and
R12 is halo, —OH or —NH2;
with the proviso that when R1 is
and R4 and R5 are each H, then R2 is not
and R1 and R2 cannot both be

14 more elements

JAK-2 Modulators and Methods of Use

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JAK-2 Modulators and Methods of Use

Life of this patent

Abstract

Claims27