# US 11,111,245 B2 · Derivatives of N-cycloalkyl/heterocycloalkyl-4-(imidazo[1,2-a]pyridine)pyrimidin-2-amine as therapeutic agents

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- Number: US 11,111,245 B2
- Document ID: US11111245B2
- Status: Granted
- Kind: B2
- Application number: 16/482,867
- Filed: 2018-02-01
- Published: 2020-07-23
- Granted: 2021-09-07
- Earliest claimed: 2017-02-01
- Assignees: Aucentra Therapeutics Pty Ltd
- Applicants: Aucentra Therapeutics Pty Ltd
- Inventors: Shudong Wang; Sarah Al Haj Diab; Yi Long
- Web page: https://patentgrep.com/patent/US11111245B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- 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 one or more CDK enzyme and/or by one or more aberrant CDK activity, including certain cancers of lung, breast, brain, ovary, prostate, colorectal cancer and leukaemias. The inhibitors have the general structure (I).

## Claims

### Claim 1

A compound of Formula I:
or a pharmaceutically acceptable salt, wherein:
A is a cycloalkyl or heterocycloalkyl, optionally substituted by one or more R6 groups such that m is an integer from 0 to 5 inclusive, and wherein said heterocycloalkyl has 1-2 heteroatoms selected from N, O and S; and
wherein R and R6 are each independently selected from the group consisting of H, alkyl, alkyl-R7, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, CH2-heteroaryl, aralkyl, halogen, NO2, CN, CF3, OH, O-alkyl, O-alkyl-R7, O-cycloalkyl, O-heterocycloalkyl, O-aryl, O-heteroaryl, NH2, NH-alkyl, NH-alkyl-R7, NH-cycloalkyl, NH-heterocycloalkyl, NH-aryl, NH-heteroaryl, NH—R7, NHO-aryl, NHCH2-aryl, N-(alkyl)2, N-(cycloalkyl)2, N-(heterocycloalkyl)2, N-(aryl)2, N-(heteroaryl)2, N-(alkyl)(R7), N-(cycloalkyl)(R7), N-(heterocycloalkyl)(R7), N-(aryl)(R7), N-(heteroaryl)(R7), COOH, CONH2, CONH-alkyl, CONH-aryl, CON-(alkyl)(R7), CON(aryl)(R7), CON(heteroaryl)(R7), CONH—R7, SO3H, SO2-alkyl, SO2-alkyl-R7, SO2-aryl, SO2-aryl-R7, SO2NH2, SO2NH-R7, CO-alkyl, CO-alkyl-R7, CO-aryl, CO-aryl-R7, CO—R7, and COOR7;
R1, R2, R3, and R4 are each independently selected from the group consisting of H, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, CH2-heteroaryl, aralkyl, O-cycloalkyl, O-heterocycloalkyl, O-aryl, O-heteroaryl, NH-cycloalkyl, NH-heterocycloalkyl, NH-aryl, NH-heteroaryl, NHO-aryl, NHCH2-aryl, N-(cycloalkyl)2, N-(heterocycloalkyl)2, N-(aryl)2, N-(heteroaryl)2, N-(cycloalkyl)(R7), N-(heterocycloalkyl)(R7), N-(aryl)(R7), N-(heteroaryl)(R7), S-(heteroaryl)(R7), CONH-aryl, CON(aryl)(R7), CON(heteroaryl)(R7), SO2-aryl, SO2-aryl-R7, CO-aryl, and CO-aryl-R7, with the proviso that at least one of R1, R2, R3 and R4 is not H; and
wherein R7 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, halogen, NO2, CN, CF3, OH, O-alkyl, O-cycloalkyl, O-heterocycloalkyl, O-aryl, O-heteroaryl, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocycloalkyl, NH-aryl, NH-heteroaryl, NH—R10, N-(alkyl)2, N-(cycloalkyl)2, N-(heterocycloalkyl)2, N-(aryl)2, N-(heteroaryl)2, COOH, COO-alkyl, CONH2, CONH-alkyl, CONH-aryl, SO3H, SO2-alkyl, SO2-aryl, SO2NH2, CO-alkyl, CO-aryl;
R5 is selected from alkyl, O-alkyl, CN, and halogen; and
wherein said heterocycloalkyl and heteroaryl groups comprise 1-2 heteroatoms selected from N, S and O, and wherein said alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl and heteroaryl groups may be optionally substituted with one or more groups selected from halogen, alkyl, CN, OH, O-methyl, O-ethyl, O-CF3, NH2, COOH, CONH2, heterocycloalkyl, CO-heterocycloalkyl, CF3, and SO2N(CH3)2.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein A is a 5- to 7-membered cycloalkyl or heterocycloalkyl group optionally substituted with one or more R6 groups.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R is H.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, CH2-heteroaryl, halogen, NO2, CF3, OH, O-alkyl, O—C3-8 cycloalkyl, O-aryl, O-heteroaryl, NH2, NH-alkyl, NH-cycloalkyl, NH-heterocycloalkyl, NH-aryl, NH-heteroaryl, NH—C1-3O-aryl, NHO-aryl, NHO-heteroaryl, NHCH2-aryl, N(alkyl)2, N(cycloalkyl)2, N(heterocycloalkyl)2, and N-(alkyl)(aryl); wherein said heterocycloalkyl and heteroaryl groups have 1-2 heteroatoms selected from N, S and O, and wherein said alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, and heteroaryl groups may be optionally substituted with one or more groups selected from halogen, alkyl, CN, OH, O-methyl, O-ethyl, O—HCF2, NH2, COOH, CONH2, heterocycloalkyl, CO-heterocycloalkyl, CF3, and SO2N(CH3)2.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein either or both of R1 and R4 is H.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R1, R2, R3 and R4 are independently selected from the group consisting of H, aryl, heteroaryl, CH2-heteroaryl, NH-aryl, NH-heteroaryl, O-aryl, O-heteroaryl, NH—C1-3O-aryl, NHO-aryl, NHO-heteroaryl, NHCH2-aryl, and N-(alkyl)(aryl)(arylaryl); wherein said heteroaryl groups have 1-2 heteroatoms selected from N, S and O, and wherein said aryl and heteroaryl groups may be optionally substituted with one or more groups selected from halogen, alkyl, CN, OH, O-methyl, O-ethyl, O—HCF2, NH2, COOH, CONH2, heterocycloalkyl, CO-heterocycloalkyl, CF3, and SO2N(CH3)2; but with the proviso that at least one of R1, R2, R3 and R4 is not H.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R2 or R3 is phenyl.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R5 is methyl or halogen.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R6 is independently selected from the group consisting of H, alkyl, OH, halogen, O-alkyl, CO2-alkyl, COOH, C1-3-heterocycloalkyl, NH2, NH-alkyl, NH-cycloalkyl, NH—R7 where R7 is CO(NH-alkyl), SO2-alkyl, NH-alkyl-R7 where R7 is CF3, O-alkyl, CO(NH2), CO2-alkyl, N-(alkyl)2, N-(alkyl)(R7) where R7 is SO2-alkyl, SO2NH2, alkyl-R7 where R7 is CO2-alkyl, and COOR7 where R7 is a C1-3 alkyl or C1-6 alkyl; wherein said heterocycloalkyl and heteroaryl groups have 1-2 two heteroatoms selected from N, S and O, and wherein said alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, and heteroaryl groups may be optionally substituted with one or more groups selected from halogen, alkyl, CN, OH, O-methyl, O-ethyl, O—HCF2, NH2, COOH, CONH2, heterocycloalkyl, CO-heterocycloalkyl, CF3, and SO2N(CH3)2.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R6 is independently selected from the group consisting of heterocycloalkyl, NH2, NH—C1-3 alkyl, NH—R7 where R7 is CO(NH-alkyl), SO2-C1-3 alkyl, or SO2NH2; wherein said heterocycloalkyl has 1-2 N heteroatoms, and wherein said alkyl and heterocycloalkyl groups may be optionally substituted with one or more groups selected from halogen, alkyl, CN, OH, O-methyl, O-ethyl, O—HCF2, NH2, COOH, CONH2, CF3, and SO2N(CH3)2.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R6 is independently selected from the group consisting of azetidine, NH2, NH—C1-3 alkyl substituted with O-methyl or O-ethyl, SO2-C1-3 alkyl, and SO2NH2.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein m is selected from 1, 2 and 3.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein m is 1.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein A is cyclohexane, adamantane, tetrahydro-2H-pyran or piperidine optionally substituted with at least one of R6.

### Claim 15 (depends on 1)

A pharmaceutical composition or medicament comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent and/or excipient.

### Claim 16 (depends on 1)

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

### Claim 17

A compound selected from the group consisting of:
(1r,4r)-N1-(5-Fluoro-4-(6-((4-fluorobenzyl)amino)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1r,4r)-N1-(5-Methyl-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1r,4r)-N1-(5-Fluoro-4-(6-((3-fluorophenyl)amino)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1r,4r)-N1-(5-Fluoro-4-(6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1r,4r)-N1-(5-Fluoro-4-(6-(3-fluoropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1r,4r)-N1-(5-Methyl-4-(6-(phenylamino)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1r,4r)-N1-(5-Methyl-4-(6-(pyridin-3-ylamino)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
N1,N1-Dimethyl-N4-(5-Methyl-4-(6-(pyridin-3-ylamino)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
N1,N1-dimethyl-N4-(5-Methyl-4-(6-(pyrimidin-5-ylamino)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1r,4r)-N1-(5-Chloro-4-(7-(pyrimidin-5-ylamino)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
3-(2-(((1r,4r)-4-(Aziridin-1-yl)cyclohexyl)amino)-5-methylpyrimidin-4-yl)-N-(pyrimidin-5-yl)imidazo[1,2-a]pyridin-7-amine,
(1r,4r)-N1-(2-Methoxyethyl)-N4-(5-methyl-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1s,4s)-N1-(2-Methoxyethyl)-N4-(5-methyl-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1r,4r)-N1-Ethyl-N4-(5-methyl-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
(1s,4s)-N1-ethyl-N4-(5-Methyl-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine,
N-((1r,4r)-4-(Azetidin-1-yl)cyclohexyl)-5-methyl-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine,
N-((1s,4s)-4-(Azetidin-1-yl)cyclohexyl)-5-methyl-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine,
5-Fluoro-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)-N-((1r,4r)-4-(pyrrolidin-1-yl)cyclohexyl)pyrimidin-2-amine,
N-((1r,4r)-4-(Azetidin-1-yl)cyclohexyl)-5-fluoro-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine,
5-Fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine,
N-(1-(Ethylsulfonyl)piperidin-4-yl)-5-fluoro-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine,
(1r,4r)-N-Cyclopropyl-4-((5-methyl-4-(6-(pyrimidin-5-ylamino)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexane-1-carboxamide, and
4-((5-fluoro-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)amino)cyclohexane-1-sulfonamide.

### Claim 18 (depends on 17)

A method of treating a cancer selected from breast cancer, ovarian cancer, prostate cancer and leukaemia, the method comprising administering to said subject a therapeutically effective amount of a compound according to claim 17 or a pharmaceutically acceptable salt or thereof, optionally in combination with a pharmaceutically acceptable carrier, diluent and/or excipient.