Selective JAK2 pseudokinase ligands and methods of use

A method of treating or ameliorating a myeloproliferative neoplasm in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt or tautomer thereof.

• wherein:
• X is N;
• A1 is independently selected from the group consisting of F, Cl, Br, I, OC (═O) N(R)2, CN, NO2, CF3, OCF3, (C1-C6) hydrocarbyl, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(═O)R, C(═O)OR, OC(═O)R, O(CH2)0-2C(═O)OR, C(═O)N(R)2, OC(═O)N(R)2, (CH2)0-2N(R)C(═O)R, N(R)SO2R, N(R)C(═O)OR, N(R)C(═O)R, N(R)C ═O)N(R)2, and C(═NH)N(R)2,
• wherein each occurrence of R is independently selected from the group consisting of hydrogen and (C1-C6) hydrocarbyl;
• or
• wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can combine with the nitrogen atom or atoms to form a heterocyclyl;
• R2 is:
• wherein:
• each of Z1, Z2, Z3, Z4, and Z5 is C-A2, provided at least one of Z1 and Z5 is CH;
• each occurrence of A2 is independently selected from the group consisting of
• F, Cl, Br, I, OR, OC(═O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(═O)R, C(═O)OR, OC(═O)R, C2-6 alkenyl-COOR, C2-6 alkenyl-CONR2, O(CH2)0-2C(═O)OR, C(═O)N(R)2, OC(═O)N(R)2, (CH2)0-2N(R)C(═O)R, N(R)SO2R, N(R)C(═O)OR, N(R)C(═O) R. N (R) C (=O) N (R) 2, and C (=NH) N (R) 2,
• provided at least one occurrence of A2 is not hydrogen;
• wherein zero, one, or two A2 can be independently
• wherein Y, Z, and Q are each independently C-R5 or N, wherein each R5 is independently selected from the group consisting of H, F, Cl, Br, I, OR, OC(═O) N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(═O)R, C(═O)OR, OC(═O)R, O(CH2)0-2C(═O)OR, C(═O)N(R)2, OC(═O)N(R)2, (CH2)0-2N (R)C(═O)R, N(R)SO2R, N(R)C(═O)OR, N(R)C(═O)R. N(R)C(═O)N(R)2, and C(═NH) N(R)2;
• wherein each occurrence of R is independently selected from the group consisting of hydrogen and (C1-C6) hydrocarbyl;
• and
• m is 1, 2, 3, 4, or 5.

A method of making a compound of Formula Ia, or a pharmaceutically acceptable salt or tautomer thereof,

• wherein:
• X is N;
• A1 is independently selected from the group consisting of F, Cl, Br, I, OC (═O) N(R)2, CN, NO2, CF3, OCF3, (C1-C6) hydrocarbyl, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(═O)R, C(═O)OR, OC(═O)R, O(CH2)0-2C(═O)OR, C(═O)N(R)2, OC(═O)N(R)2, (CH2)0-2N(R)C(═O)R, N(R)SO2R, N(R)C(═O)OR, N(R)C(═O)R, N(R)C ═O)N(R)2, and C(═NH)N(R)2,
• wherein each occurrence of R is independently selected from the group consisting of hydrogen and (C1-C6) hydrocarbyl;
• or
• wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can combine with the nitrogen atom or atoms to form a heterocyclyl;
• R2 is:
• wherein:
• each of Z1, Z2, Z3, Z4, and Z5 is C-A2, provided at least one of Z1 and Z5 is CH;
• each occurrence of A2 is independently selected from the group consisting of
• F, Cl, Br, I, OR, OC(═O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(═O)R, C(═O)OR, OC(═O)R, C2-6 alkenyl-COOR, C2-6 alkenyl-CONR2, O(CH2)0-2C(═O)OR, C(═O)N(R)2, OC(═O)N(R)2, (CH2)0-2N(R)C(═O)R, N(R)SO2R, N(R)C(═O)OR, N(R)C(═O) R. N (R) C (=O) N (R) 2, and C (=NH) N (R) 2,
• provided at least one occurrence of A2 is not hydrogen;
• wherein zero, one, or two A2 can be independently
• wherein Y, Z, and Q are each independently C-R5 or N, wherein each R5 is independently selected from the group consisting of H, F, Cl, Br, I, OR, OC(═O) N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(═O)R, C(═O)OR, OC(═O)R, O(CH2)0-2C(═O)OR, C(═O)N(R)2, OC(═O)N(R)2, (CH2)0-2N (R)C(═O)R, N(R)SO2R, N(R)C(═O)OR, N(R)C(═O)R. N(R)C(═O)N(R)2, and C(═NH) N(R)2;
• wherein each occurrence of R is independently selected from the group consisting of hydrogen and (C1-C6) hydrocarbyl;
• and
• m is 1, 2, 3, 4, or 5;
• the method comprising reacting a compound having the structure:
• with a compound having the structure:
• wherein o is 1, 2, 3, 4, or 5,
• in a solvent to yield a compound of Formula Ia.