Tetrahydroisoquinolines as PRMT5 inhibitors

• US 10,550,096 B2
• Filed: 03/09/2017
• Issued: 02/04/2020
• Est. Priority Date: 03/09/2016
• Status: Active Grant

• Current Assignee: CTxT Pty., Ltd.
• Original Assignee: CTxT Pty., Ltd.
• Inventors: Stupple, Alexandra Elizabeth, Walker, Scott Raymond, Stupple, Paul Anthony
• Primary Examiner(s): Shiao, Rei Tsang
• Application Number:
  US16/081,745
• Publication Number:
  US 20190062304A1
• Time in Patent Office: 1,062 Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 498/08 Bridged systems

Abstract

A compound of formula (I) wherein: n is 1 or 2; p is 0 or 1; R^1a, R^1b, R^1c and R^1d are independently selected from H, halo, methyl and methoxy; R^2a and R^2b are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH₂OH; R^2c and R^2d are independently selected from the group consisting of: (i) F; (ii) H; (iii) Me; and (iv) CH₂OH; R^2e is H or Me; R^3a and R^3b are independently selected from H and Me; R⁴ is either H or Me; R^6a and R^6b are independently selected from H and Me; X is either N or CH; R⁷ is selected from H and C_1-4 alkyl; (a) one of R^8a, R^8b, R^8c, and R^8d is selected from H, halo, C_1-4 alkyl, C_1-4 alkoxy, NHC_1-4 alkyl; (b) another of R^8a, R^8b, R^8c and R^8d is selected from H, C_1-4 alkyl, C_1-4 fluoroalkyl, C_3-6 cycloalkyl, C_5-6 heteroaryl, C_5-6 heteroaryl methyl, C_4-6 heterocyclyl, C_4-6 heterocyclyl methyl, phenyl, benzyl, halo, amido, amidomethyl, acylamido, acylamidomethyl, C_1-4 alkyl ester, C_1-4 alkyl ester methyl, C_1-4 alkyl carbamoyl, C_1-4 alkyl carbamoyl methyl, C_1-4 alkylacyl, C_1-4 alkylacyl methyl, phenylcarbonyl, carboxy, carboxymethyl, ether, amino, amino methyl, sulfonamido, sulfonamino, sulfone, sulfoxide, nitrile and nitrilemethyl; (c) the others of R^8a, R^8b, R^8c and R^8d are H.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein n is 1.

3. The compound according to claim 1, wherein p is 0.

4. The compound according to claim 1, wherein R^1a, R^1b, R^1c and R^1d are all H.

5. The compound according to claim 1, wherein R^2a, R^2b, R^2c and R^2d are all H.

6. The compound according to claim 1, wherein R⁴ is H.

7. The compound according to claim 1, wherein R^6a and R^6b are both H.

8. The compound according to claim 1 which is of formula Ia:

9. The compound according to claim 1, which has the following stereochemistry:

10. The compound according to claim 1, wherein X is N.

11. The compound according to claim 1, wherein X is CH.

12. The compound according to claim 1, wherein R⁷ is H.

13. The compound according to claim 1, wherein R⁷ is methyl or ethyl.

14. The compound according to claim 13, wherein R⁷ is ethyl.

15. The compound according to claim 1, wherein R^8a is selected from H, halo, C_1-4 alkyl, C_1-4 alkoxy and NHC_1-4 alkyl.

16. The compound according to claim 1, wherein the one of R^8a, R^8b, R^8c and R^8d that is selected from H, C_1-4 alkyl, C_1-4 fluoroalkyl, C_3-6 cycloalkyl, C_5-6 heteroaryl, C_5-6 heteroaryl methyl, C_4-6 heterocyclyl, C_4-6 heterocyclyl methyl, phenyl, benzyl, halo, amido, amidomethyl, acylamido, C_1-4 alkyl ester, C_1-4 alkyl ester methyl, C_1-4 alkyl carbamoyl, C_1-4 alkyl carbamoyl methyl, C_1-4 alkylacyl, C_1-4 alkylacyl methyl, phenylcarbonyl, carboxy, carboxymethyl, ether, amino, amino methyl, sulfonamido, sulfonamino, sulfone, sulfoxide, nitrile and nitrilemethyl is selected from C_1-4 alkyl, fluoro, chloro, bromo, acetyl, methoxy, ethoxy, —

C(═

O)Me, —

C(═

O)Et, —

CH₂C(═

O)Me, phenyl, —

CF₃, —

CF₂H, —

CN, —

CH₂CN, —

OBn, —

OPh, —

OCF₃, —

OCF₂H, —

O—

(C₆H₄)—

CN, —

COOH, —

CH₂COOH, —

C(═

O)OMe, —

C(═

O)NH₂, —

C(═

O)NMeH, —

C(═

O)NMe₂, —

C(═

O)N′

PrH, —

C(═

O)-piperidinyl, —

C(═

O)-pyrrolidinyl, —

C(═

O)-morpholino (which may be bridged or substituted with one or two methyl groups), —

C(═

O)-azetidinyl, —

CH₂C(═

O)NH₂, —

CH₂C(═

O)-azetidinyl, —

CH₂C(═

O)NMeH, —

CH₂C(═

O)NⁱPrH, —

CH₂C(═

O)-pyrrolidinyl, —

CH₂C(═

O)-morpholino, —

CH₂-morpholino, —

CH₂-methylpiperazinyl, —

OCH₂pyridinyl, —

OCH₂-methyloxadiazolyl, —

CH₂-imidazolyl, —

O-tetrahydropyranyl, —

CH₂—

tetraydropyanyl, —

NH-methylpyrazinyl, —

CH₂-triazolyl, —

NHSO₂Ph, —

NHSO₂Me, —

SO₂NMePh, —

SO₂NMe₂, —

SO₂NHEt, —

SO₂CF₃, —

γ

-lactam, —

CH₂NHC(═

O)Me, —

CH₂NHC(═

O)OMe, —

CH₂NHC(═

O)CF₃, morpholino, —

CH₂NH₂, —

C(═

O)Ph, —

OCH₂-isoxazolyl, —

NH-pyrimidinyl, pyridizinyl, pyrimidinyl, pyridinyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl, pyrazinyl, pyridazinyl, methyloxadiazolyl, oxadiazolyl, dimethyloxadiazolyl, isoxazolyl, dimethyltriazolyl, imidazolyl, benzimidazolyl and thiadiazolyl.

17. The compound according to claim 1, wherein one of R^8b, R^8c and R^8d is selected from H, C_1-4 alkyl, C_1-4 fluoroalkyl, C_3-6 cycloalkyl, C_5-6 heteroaryl, C_5-6 heteroaryl methyl, C_4-6 heterocyclyl, C_4-6 heterocyclyl methyl, phenyl, benzyl, halo, amido, amidomethyl, acylamido, C_1-4 alkyl ester, C_1-4 alkyl ester methyl, C_1-4 alkyl carbamoyl, C_1-4 alkyl carbamoyl methyl, C_1-4 alkylacyl, C_1-4 alkylacyl methyl, phenylcarbonyl, carboxy, carboxymethyl, ether, amino, amino methyl, sulfonamido, sulfonamino, sulfone, sulfoxide, nitrile and nitrilemethyl.

18. The compound according to claim 17, wherein one of R^8b, R^8c and R^8d is selected from C_1-4 alkyl, fluoro, chloro, bromo, acetyl, methoxy, ethoxy, —

C(═

O)Me, —

C(═

O)Et, —

CH₂C(═

O)Me, phenyl, —

CF₃, —

CF₂H, —

CN, —

CH₂CN, —

OBn, —

OPh, —

OCF₃, —

OCF₂H, —

O—

(C₆H₄)—

CN, —

COOH, —

CH₂COOH, —

C(═

O)OMe, —

C(═

O)NH₂, —

C(═

O)NMeH, —

C(═

O)NMe₂, —

C(═

O)N′

PrH, —

C(═

O)-piperidinyl, —

C(═

O)-pyrrolidinyl, —

C(═

O)-morpholino (which may be bridged or substituted with one or two methyl groups), —

C(═

O)-azetidinyl, —

CH₂C(═

O)NH₂, —

CH₂C(═

O)-azetidinyl, —

CH₂C(═

O)NMeH, —

CH₂C(═

O)NⁱPrH, —

CH₂C(═

O)—

pyrrolidinyl, —

CH₂C(═

O)-morpholino, —

CH₂-morpholino, —

CH₂-methylpiperazinyl, —

OCH₂pyridinyl, —

OCH₂-methyloxadiazolyl, —

CH₂-imidazolyl, —

O-tetrahydropyranyl, —

CH₂—

tetraydropyanyl, —

NH-methylpyrazinyl, —

CH₂-triazolyl, —

NHSO₂Ph, —

NHSO₂Me, —

SO₂NMePh, —

SO₂NMe₂, —

SO₂NHEt, —

SO₂CF₃, —

γ

-lactam, —

CH₂NHC(═

O)Me, —

CH₂NHC(═

O)OMe, —

CH₂NHC(═

O)CF₃, morpholino, —

CH₂NH₂, —

C(═

O)Ph, —

OCH₂-isoxazolyl, —

NH-pyrimidinyl, pyridizinyl, pyrimidinyl, pyridinyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl, pyrazinyl, pyridazinyl, methyloxadiazolyl, oxadiazolyl, dimethyloxadiazolyl, isoxazolyl, dimethyltriazolyl, imidazolyl, benzimidazolyl and thiadiazolyl.

19. The compound according to claim 18, wherein R^8c is selected from amido or amidomethyl.

20. The compound according to claim 19, wherein R^8c is selected from:

21. The compound according to claim 1, which is selected from:

6-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)isoquinolin-1(2H)-one hydrochloride (1);

2-((R)-2-Hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)-4-methylphthalazin-1(2H)-one hydrochloride (2); and

6-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-4-ethyl-2-((R)-2-hydroxy-2-((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)phthalazin-1(2H)-one hydrochloride (3).

22. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable excipient.

23. A method of treatment of cancer, comprising administering to a patient in need of treatment, a compound according to claim 1.

24. A method of treatment of hemoglobinopathies, comprising administering to a patient in need of treatment, a compound according to claim 1.