# US 10,479,785 B2 · N-(pyridin-2-yl)-4-(thiazol-5-yl)pyrimidin-2-amine derivatives as therapeutic compounds

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- Number: US 10,479,785 B2
- Document ID: US10479785B2
- Status: Granted
- Kind: B2
- Application number: 15/749,652
- Filed: 2016-08-04
- Published: 2018-08-09
- Granted: 2019-11-19
- Earliest claimed: 2015-08-04
- Assignees: Aucentra Therapeutics Pty Ltd
- Applicants: University of South Australia
- Inventors: Shudong Wang; Solomon Tadesse Zeleke; Mingfeng Yu
- Web page: https://patentgrep.com/patent/US10479785B2

## CPC

- C07D 417/14: containing three or more hetero rings
- A61P 35/02: specific for leukemia
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A novel class of inhibitors of protein kinases that are useful in the treatment of cell proliferative diseases and conditions, and especially those characterised by over-expression of CDK4, CDK6 and/or cyclin D, including certain cancers of lung, breast, brain, central nervous system, colorectal cancer and leukaemias. The inhibitors have the general structure I:

## Claims

### Claim 1

A compound of formula I shown below:
wherein:
z represents an optional bond such that the bond between N and the adjacent carbon atom can be a single or double bond;
R1, R4, R6 and R7 are each independently selected from the group consisting of H, alkyl, alkyl- R10, aryl, aryl-R10, aralkyl, aralkyl-R11, halogen, NO2, CN, CF3, OH, O-alkyl, COR10, COOR10, O-aryl, O—R10, NH2, NH-alkyl, NH-aryl, N-(alkyl)2, N-(aryl)2, N-(alkyl)(aryl), NH—R10, N—(R10)(R11), N-(alkyl)(R10), N-(aryl)(R10), SH-alkyl, SH-aryl, S-(alkyl)2, S-(aryl)2, S-(alkyl)(aryl), SH—R10,S—(R10)(R11), S-(alkyl)(R10), S-(aryl)(R10), COOH, CONH2, CONH-alkyl, CONH-aryl, CON-(alkyl)(R10), CON(aryl)(R10), CONH—R10, CON—(R10)(R11), SO3H, SO2-alkyl, SO2-alkyl-R10, SO2-aryl, SO2-aryl-R10, SO2NH2, SO2NH—R10, SO2N—(R10)(R11), CF3, CO-alkyl, CO-alkyl-R10, CO-aryl, CO-aryl-R10 and R12,
wherein said alkyl, aryl and aralkyl groups may be optionally substituted with one or more groups selected from halogen, CN, OH, O-methyl, NH2, COOH, CONH2 and CF3, and wherein when bond z is absent, R1 is taken together with R8 and is ═O or ═S;
R2 is alkyl;
R3 is H, C1-6 alkyl, CN or halogen;
R5 is selected from alkyl, alkyl-R10, aryl, aryl-R10, aralkyl, aralkyl-R11, halogen, NO2, CN, CF3, OH, O-alkyl, COR10, COOR10, O-aryl, O—R10, NH2, NH-alkyl, NH-aryl, N-(alkyl)2, N-(aryl)2, N-(alkyl)(aryl), NH—R10, N—(R10)(R11), N-(alkyl)(R10), N-(aryl)(R10), SH-alkyl, SH-aryl, S-(alkyl)2, S-(aryl)2, S-(alkyl)(aryl), SH—R10, S—(R10)(R11), S-(alkyl)(R10), S-(aryl)(R10), COOH, CONH2, CONH-alkyl, CONH-aryl, CON-(alkyl)(R10), CON(aryl)(R10), CONH—R10, CON—(R10)(R11), SO3H, SO2-alkyl, SO2-alkyl-R10, SO2-aryl, SO2-aryl-R10, SO2NH2, SO2NH—R10, SO2N—(R10)(R11), CF3, CO-alkyl, CO-alkyl-R10, CO-aryl, CO-aryl-R10 and R12, wherein said alkyl, aryl and aralkyl groups may be optionally substituted with one or more groups selected from halogen, CN, OH, O-methyl, NH2, COOH, CONH2 and CF3;
R8 is together with R1═O or ═S when bond z is absent, or is not present when bond z is present; R9 is H, alkyl, aryl or heterocyclic group when bond z is absent, or is not present when bond z is present; and
R10, R11 and R12 are independently selected from water solubilising groups;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein the compound is of formula II:
wherein
R1, R4, R6 and R7 are each independently selected from the group consisting of H, alkyl, aryl, aralkyl, halogen, NO2, CN, CF3, OH, O-alkyl, O-aryl, NH2, NH-alkyl, NH-aryl, N-(alkyl)2, N-(aryl), N-(alkyl)(aryl), SH-alkyl, SH-aryl, S-(alkyl)2, S-(aryl)2, S-(alkyl)(aryl), COOH, CONH2, CONH-alkyl, CONH-aryl, SO3H, SO2-alkyl, SO2-aryl, SO2NH2, CF3, CO-alkyl, and CO-aryl, wherein said alkyl, aryl and aralkyl groups may be optionally substituted with one or more groups selected from halogen, CN, OH, O-methyl, NH2, COOH, CONH2 and CF3;
R2 is alkyl;
R3 is H, C1-6 alkyl, CN or halogen; and
R5 is R12,
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R1 is H, C1-6 alkyl, aryl, NH—C1-6alkyl, N(C1-6 alkyl)2, NH-aryl, N—(C1-6 alkyl)(aryl) or SH—C1-6 alkyl.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein the compound is of formula III:
wherein R2, R3, R4, R5, R6 and R7 are as defined in claim 1, R8 is together with R1 is ═O or ═S, and R9 is H, alkyl, aryl or heterocyclic group.

### Claim 5 (depends on 2)

A compound according to claim 2, wherein R2 is C1-6 alkyl.

### Claim 6 (depends on 2)

A compound according to claim 2, wherein R3 is C1-3 alkyl, CN or halogen.

### Claim 7 (depends on 2)

A compound according to claim 2, wherein R4 is H, O—C1-6 alkyl or halogen.

### Claim 8 (depends on 2)

A compound according to claim 2, wherein R12 is N—, O— and/or S-containing heterocyclic groups substituted with one or more hydroxyl or amino groups, aliphatic and aryl groups comprising one or more carboxamide, sulfoxide, sulfone or sulfonamide groups, and halogenated alkylcarbonyl groups.

### Claim 9 (depends on 8)

A compound according to claim 8, wherein R12 is selected from the following:

### Claim 10 (depends on 8)

A compound according to claim 8, wherein R6 is H.

### Claim 11 (depends on 8)

A compound according to claim 8, wherein R6 is R12 and R5 is H.

### Claim 12 (depends on 8)

A compound according to claim 8, wherein R12 is an N—, O— and/or S-containing heterocyclic group substituted with one or more hydroxyl, amino or alkoxy group.

### Claim 13 (depends on 8)

A compound according to claim 8, wherein R12 is selected from the following:

### Claim 14 (depends on 8)

A compound according to claim 8, wherein R12 is selected from the following:

### Claim 15 (depends on 1)

A compound according claim 1, wherein R7 is H.

### Claim 16 (depends on 1)

A method of treating cancer in a subject, the method comprising administering to said subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, optionally in combination with a pharmaceutically acceptable carrier, diluent and/or excipient.

### Claim 17 (depends on 16)

The method of claim 16, wherein the cancer is selected from those characterized by over-expression of CDK4 and/or CDK6.

### Claim 18 (depends on 17)

The method of claim 17, wherein the cancer is selected from the group consisting of cancers of lung, breast, brain, central nervous system and colorectal cancer.

### Claim 19 (depends on 17)

The method of claim 17, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL).

### Claim 20 (depends on 2)

A pharmaceutical composition or medicament comprising the compound of claim 2 and at least one pharmaceutically acceptable carrier, diluent or excipient.

### Claim 21 (depends on 2)

A method for modulating protein kinase activity in a cell, comprising introducing to or contacting said cell with an effective amount of the compound of claim 2 or a pharmaceutically acceptable salt or solvate thereof.

### Claim 22 (depends on 2)

A compound according to claim 2, wherein R2 is C1-3 alkyl.

### Claim 23 (depends on 2)

A compound according to claim 2, wherein R2 is methyl.

### Claim 24 (depends on 2)

A compound according to claim 2, wherein R3 is halogen.

### Claim 25 (depends on 24)

A compound according to claim 24, wherein R3 is F.

### Claim 26 (depends on 2)

A compound according to claim 2, wherein R1 is NH—C1-6 alkyl or N(C1-6 alkyl)2.

### Claim 27 (depends on 26)

A compound according to claim 26, wherein R1 is NH-methyl, NH-cyclopentyl or N(methyl)2.

### Claim 28 (depends on 2)

A compound according to claim 2, wherein the compound is:
5-(5-fluoro-2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,N,4-trimethylthiazol-2-amine,
5-(2-((5 -(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine,
N-cyclopentyl-5-(2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine, or
N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)mcthyppyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine.

### Claim 29

A pharmaceutical composition or medicament comprising a compound selected from
5-(5-fluoro-2-((5-(4-methylpiperazin-1 -yl)pyridin-2-yl)amino)pyrimidin-4-yl)-N,N,4-trimethylthiazol-2-amine, 5-(2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-N,4-dimethylthiazol-2-amine, N-cyclopentyl-5-(2-((5-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine, and N-cyclopentyl-5-(2-((5-((4-ethylpiperazin-1-yl)mcthyppyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-amine; and
at least one pharmaceutically acceptable carrier, diluent or excipient.