# US 9,040,549 B2 · Thiopyrimidine-based compounds and uses thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,040,549 B2
- Document ID: US9040549B2
- Status: Granted
- Kind: B2
- Application number: 13/861,344
- Filed: 2013-04-11
- Published: 2014-02-20
- Granted: 2015-05-26
- Earliest claimed: 2007-01-31
- Assignees: YM Biosciences Australia Pty Ltd
- Applicants: Cytopia Research Pty Ltd.
- Inventors: David Gerard Bourke; Xianyong Bu; Christopher John Burns; Anthony Nicholas Cuzzupe; John Thomas Feutrill; Tracy Leah Nero; Beata Maria Blannin; Jun Zeng; Shaun Patrick Gaynor
- Web page: https://patentgrep.com/patent/US9040549B2

## CPC

- C07D 413/12: linked by a chain containing hetero atoms as chain links
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/38: One sulfur atom
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 487/00: Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D 487/02: in which the condensed system contains two hetero rings
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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 present invention relates to thiopyrimidine-based compounds that are inhibitors of protein kinases including JAK kinases. In particular, the compounds are selective for JAK1, JAK2 or JAK3 kinases and combinations thereof such as JAK1 and JAK2. The kinase inhibitors can be used in the treatment of kinase associated diseases such as immunological and inflammatory diseases including organ transplants; hyperproliferative diseases including cancer and myeloproliferative diseases; viral diseases; metabolic diseases and vascular diseases.

## Claims

### Claim 1

A method for the treatment of a kinase associated disease, wherein said method comprises administering to a subject in need of such treatment a therapeutically effective amount of:
(a) a compound of formula I:
wherein:
X is N and Y is CR3;
wherein each R3 is independently hydrogen, C1-6alkyl, C2-6alkenyl, hydroxyl, halogen, nitro, substituted or unsubstituted amino, cyano, trifluoromethyl, methoxy, trifluoromethoxy, aryl, or substituted or unsubstituted 5 or 6 membered heterocyclyl containing 1 to 2 N atoms;
R1 is aryl; heterocyclyl; C1-6alkyl; or aryl substituted with one or more substituents R9 or R;
wherein each R9 is independently substituted or unsubstituted C1-6alkyl, OH, OC1-6alkyl, CN, SR7, CHO, CO2R7, COR7, CONR5R6, CONR5R7, NR5COR7, NR5R6, or NR5COOR7, or a heterocyclyl optionally substituted with 1 to 4 substituents selected from the group consisting of NH2, CN, OH, CO2R7, CH2CN, and 5 membered N-containing heterocyclyl; and
wherein R5 and R6 are each independently H, C1-6alkyl, C1-6alkylCN, C3-8cycloalkyl, aryl, heterocyclyl, C1-6alkylene, cycloalkyl, substituted or unsubstituted C1-6alkylene, SO2C1-6alkyl, or C1-6alkylene heterocyclyl; or
R5 and R6 together with the nitrogen to which they are attached form a 4 to 8 membered ring having 1 to 3 heteroatoms independently selected from the group consisting of NR8, O, and S(O)m, wherein m is 0, 1, or 2, and wherein the ring may be optionally substituted with C1-6alkyl or NR5R6;
wherein R8 is H, C1-6alkyl, C2-6alkyleneOH, C2-6alkyleneNR5R6, C3-8cycloalkyl, aryl, heterocyclyl, C1-6alkylenecycloalkyl, C1-6alkylenearyl, C1-6alkyleneheterocyclyl, or C1-6alkyleneCN,
R7 is H, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted OC1-6alkyl, substituted or unsubstituted SC1-6alkyl, CNOH, C1-6alkyleneCN, substituted or unsubstituted C3-8cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl,C1-6alkylenecycloalkyl,C1-6alkylenearyl, C1-6alkyleneheterocyclyl, C2-6alkenyl, C2-6alkynyl, NR5R6, C1 6alkyleneNR5R6, or C1-6alkyleneOR5;
each R is C1-6alkyleneR9 or OC1-6alkyleneR9 (except when R9 is NR5R6 or OC1-6alkyl, then R is OC2-6alkyleneR9); or
R9 and R together with the groups to which they are attached form a substituted or unsubstituted 5 or 6 membered N-containing heterocyclyl;
W is absent, CO, SO2 or C1-6alkylene;
R2 is aryl; imidazolyl; (methylenedioxy)phenyl; or aryl substituted with one or more substituents selected from the group consisting of an N-containing 5 or 6 membered heterocyclyl; substituted or unsubstituted OC1-6alkyl; NR5COR7 wherein in this instance only, R5 is H and R7 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, CH2CN, or CN; NH2; halo; CO2R7; SO2NR5R6; NO2; NHSO2Me; CHOHCF3CH3; CH2NHSO2Me; OH; and SH;
wherein each alkenyl or alkynyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6alkyl, CO2R7, CONR5R6, aryl, heterocyclyl, C1-6alkylene OH, and C1-6alkyleneNH2; and
each heterocyclyl is independently a 5 to 7 membered saturated or unsaturated heterocyclyl having 1 to 4 heteroatoms independently selected from the group consisting of N, O, S, and SO2;
provided that at least one of R1 and R2 is substituted with a substituent selected from the group consisting of:
wherein
D is O or N;
R10 is H or substituted or unsubstituted C1-4alkyl;
R11 and R12 are each independently H, substituted or unsubstituted C1-4alkylNR14R15, C1-4alkylOR8, or substituted or unsubstituted aryl, or R11 and R12 are joined to form a substituted or unsubstituted 5 to 8 membered ring optionally containing one or more heteroatoms selected from the group consisting of O, S, SO2, and NR10;
R13 is OH, OC1-4alkyl, or NR14R15;
p is 0, 1, 2, 3, or 4; and
R14 and R15 are each independently H, or substituted or unsubstituted C1-4alkyl, or R14 and R15 are joined to form a substituted 3-8 membered ring optionally containing one or more heteroatoms selected from the group consisting of O, S, SO2 and NR10;
or a salt and/or isomer thereof; or
(b) a pharmaceutical composition comprising a compound of formula I or a salt and/or isomer thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound of formula I has the formula Ia
wherein W, R1, R2 and R3 are as defined in claim 1.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound of formula I has the formula lb
wherein W, R1 and R3 are as defined in claim 1, and R′ is H, R, or R9, wherein R and R9 are as defined in claim 1.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound of formula I has the formula Ic
wherein W and R3 are as defined in claim 1;
R′ is H, R or R9, wherein R and R9 are as defined in claim 1, and
R1 is phenyl substituted as defined in claim 1.

### Claim 5 (depends on 1)

The method of claim 1, wherein W is absent, CO or C1-6alkylene.

### Claim 6 (depends on 1)

The method of claim 1, wherein R3 is H; C1-6alkyl; halo; C2-6alkenyl; amino which may be substituted with C2-6alkenyl; cyano; nitro; methoxy; aryl; or 5 or 6 membered heterocyclyl containing 1 or 2 N atoms which may be substituted with trimethylcarboxy.

### Claim 7 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of said compound is administered using an implant, wherein said implant comprises a compound of claim 1 or a pharmaceutical composition comprising a compound of claim 1.

### Claim 8 (depends on 1)

A method of claim 1, wherein the kinase associated disease is an immunological disease, an inflammatory disease, a hyperproliferative disease, a viral disease, a metabolic disease or a vascular disease.

### Claim 9 (depends on 1)

A method for suppressing the immune system of a subject, wherein said method comprises administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition comprising a compound of claim 1.

### Claim 10 (depends on 1)

A method of inhibiting a kinase in a cell, wherein said method comprises contacting the cell with a compound of claim 1.