# US 12,110,278 B2 · Selective JAK2 pseudokinase ligands and methods of use

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- Number: US 12,110,278 B2
- Document ID: US12110278B2
- Status: Granted
- Kind: B2
- Application number: 17/500,622
- Filed: 2021-10-13
- Published: 2022-04-14
- Granted: 2024-10-08
- Earliest claimed: 2020-10-13
- Assignees: Yale University
- Applicants: Yale University
- Inventors: William L. Jorgensen; Joseph Schlessinger
- Web page: https://patentgrep.com/patent/US12110278B2

## CPC

- C07D 249/14: Nitrogen atoms
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/4245: Oxadiazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The compounds of Formula I described herein regulate activity of JAK2 by specifically binding to the JAK2 pseudokinase domain, JH2, and are useful as therapeutic agents in the treatment or amelioration of myeloproliferative disorders. Also provided herein are methods of treating myeloproliferative disorders, and methods of making compounds of Formula I.

## Claims

### Claim 1

A compound of Formula Ia, or a pharmaceutically acceptable salt or tautomer thereof:
wherein:
X is N;
A′ 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 (C6-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)0-2 N(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 (C6-C6)hydrocarbyl; and
m is 1, 2, 3, 4, or 5.

### Claim 2 (depends on 1)

The compound of claim 1, wherein A1 is CN, OCF3, SO2NH2, or C(═O)NHCH3.

### Claim 3 (depends on 1)

The compound of claim 1, wherein m is 1.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound is of Formula Ib, Formula Ic, or Formula Id:

### Claim 5 (depends on 4)

The compound of claim 4, wherein A1 is CN, OCF3, SO2NH2, or C(═O)NHCH3.

### Claim 6 (depends on 1)

The compound of claim 1, wherein A2 is selected from the group consisting of:

### Claim 7 (depends on 6)

The compound of claim 6, wherein R5 is COOH or COOCH3.

### Claim 8 (depends on 6)

The compound of claim 6, wherein A2 is selected from the group consisting of:

### Claim 9

A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of:

### Claim 10

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.

### Claim 11 (depends on 10)

The method of claim 10, wherein the myeloproliferative neoplasm is selected from the group consisting of chronic myelogenous leukemia (CML), polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia.

### Claim 12 (depends on 10)

The method of claim 10, wherein the composition comprises at least one pharmaceutically acceptable excipient.

### Claim 13 (depends on 10)

The method of claim 10, wherein the patient is a mammal.

### Claim 14 (depends on 10)

The method of claim 10, wherein the patient is human.

### Claim 15 (depends on 10)

The method of claim 10, wherein the compound is administered by a route selected from the group consisting of oral, transdermal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.

### Claim 16 (depends on 10)

The method of claim 10, further comprising concurrently or sequentially administering at least one additional agent.

### Claim 17 (depends on 16)

The method of claim 16, wherein the at least one additional agent is selected from the group consisting of Adriamycin PFS (Doxorubicin Hydrochloride), Adriamycin RDF (Doxorubicin Hydrochloride), Arsenic Trioxide, Azacitidine Cerubidine (Daunorubicin Hydrochloride), Clafen (Cyclophosphamide), Cyclophosphamide, Cytarabine, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide), Dacogen (Decitabine), Dasatinib, Daunorubicin Hydrochloride, Decitabine Doxorubicin Hydrochloride, Etoposide Phosphate, Gleevec (Imatinib Mesylate), Imatinib Mesylate, Jakafi (Ruxolitinib Phosphate), Nilotinib, Rubidomycin (Daunorubicin Hydrochloride), Ruxolitinib Phosphate, Sprycel (Dasatinib), Tarabine PFS (Cytarabine), Tasigna (Nilotinib), Trisenox (Arsenic Trioxide), and Vidaza (Azacitidine).

### Claim 18

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.

### Claim 19 (depends on 18)

The method of claim 18, wherein the solvent comprises dioxane.

### Claim 20 (depends on 18)

The method of claim 18, wherein the reacting is at a temperature of about 95° C. to about 115° C.

### Claim 21 (depends on 18)

The method of claim 18, wherein the concentration of (A) in the solvent is about 0.35 M to about 0.7 M.