Tetrahydroisoquinoline derived PRMT5-inhibitors

• US 10,494,376 B2
• Filed: 09/03/2015
• Issued: 12/03/2019
• Est. Priority Date: 09/03/2014
• Status: Active Grant

• Current Assignee: CTxT Pty., Ltd.
• Original Assignee: CTxT Pty., Ltd.
• Inventors: Bergman, Ylva Elisabet, Foitzik, Richard Charles, Morrow, Benjamin Joseph, Camerino, Michelle Ang, Walker, Scott Raymond, Lagiakos, H. Rachel, Feutrill, John, Stevenson, Graeme Irvine, Stupple, Paul Anthony
• Primary Examiner(s): Morris, Patricia L
• Application Number:
  US15/508,053
• Publication Number:
  US 20170298075A1
• Time in Patent Office: 1,552 Days
• Field of Search: 546146, 514307, 517307
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 217/00 Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
• CPC Class Codes: C07D 217/16 substituted by oxygen atoms
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 271/10 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 295/18 by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07D 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/08 : Bridged systems

Abstract

A compound of formula I wherein: n is 1 or 2: p is 0 or 1; R¹ is optionally one or more halo or methyl groups; 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^3a and R^3b are independently selected from H and Me; R⁴ is either H or Me; R⁵ is either H or Me; R^6a and R^6b are independently selected from H and Me; A is either (i) optionally substituted phenyl; (ii) optionally substituted naphthyl; or (iii) optionally substituted C_5-12 heteroaryl.

Claims

1. A compound of formula I:

2. A compound according to claim 1, wherein R¹ represents one to four Me or halo groups.

3. A compound according to claim 1, wherein:

(a) R^2a, R^2b, R^2c and R^2d are all H;

or

(b) R^2a, R^2b, R^2c and R^2d consists of three H and one Me or CH₂OH group;

or

(c) R^2a, R^2b, R^2c and R^2d consists of two H and two Me groups.

4. A compound according to claim 1, wherein:

(a) R^3a is H and R^3b is Me;

or

(b) R^3a and R^3b are both H;

or

(c) R^3a and R^3b are both Me.

5. A compound according to claim 1, wherein:

(a) R^6a is H and R^6b is Me;

or

(b) R^6a and R^6b are both H;

or

(c) R^6a and R^6b are both Me.

6. A compound according to claim 1 which is of:

7. A compound according to claim 1, which is a racemate at the carbon atom to which OH is attached.

8. A compound according to claim 1, which is a single enantiomer at the carbon atom to which OH is attached.

9. A compound according to claim 1, wherein A is optionally substituted phenyl, wherein the substituents are 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)NⁱPrH, —

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.

10. A compound according to claim 9, wherein:

(a) in the ortho position of the phenyl group there is a halo, C_1-4 alkyl, methoxy or ethoxy substituent;

or

(b) in the meta position of the phenyl group there is a C_1-4 alkyl or C_5-6 heteroaryl substituent;

or

(c) in the para position of the phenyl group there is an amido or amidomethyl substituent;

or

(d) the phenyl group bears a halo or methoxy substituent in the ortho position, and an amido or amidomethyl substituent in the para position of the phenyl group;

or

(e) the phenyl group bears a halo or methoxy substituent in the ortho position, and an amido or amidomethyl substituent in the para position of the phenyl group;

or

(f) in the meta position of the phenyl group there is an amino substituent.

11. A compound according to claim 1, wherein A is:

(a) optionally substituted naphthyl;

or

(b) optionally substituted C_5-12 heteroaryl selected from the group consisting of;

pyridinyl, pyrimidinyl, pyrazinyl, isoxazolyl, oxazolyl, thiophenyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridonyl, imidazolyl, benzimidazolyl, imidazopyridinyl and quinolinyl.

12. A compound according to claim 1, wherein A is selected from one of the following groups:

13. A compound according to claim 1, wherein A is selected from one of the following groups:

14. A compound according to claim 13, wherein A is selected from one of the following groups:

15. A compound according to claim 1, wherein A is selected from one of the following groups:

16. A compound according to claim 1, wherein A is selected from one of the following groups:

17. A compound according to claim 1, wherein A is selected from

phenyl with a para-amido substituent;

phenyl with a para-amido substituent, and an ortho-ethoxy group;

pyridyl with para ether or amino group, where the ether or amino substituent is a C_5-6 heterocyclic group, with an optional ortho-ethoxy group; and

pyridyl with a meta ether group, where the pyridyl N is in the para position.

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

19. A method of inhibiting PRMT5 in a patient in need thereof, comprising administering to the patient a PRMT5 inhibiting effective amount of a composition according to claim 18.

20. A method of inhibiting PRMT5 in a patient in need thereof comprising administering to the patient a PRMT5 inhibiting effective amount of a pharmaceutical composition according to claim 18, wherein said inhibition of PRMT5 inhibits γ

-globin gene expression during the treatment of hemoglobinopathies.

21. The method of claim 19, wherein said inhibition of PRMT5 treats a cancer that overexpresses PRMT5.

22. The method of claim 21, wherein said cancer is chosen from prostate cancer, lung cancer, melanoma cancer, breast cancer, colorectal cancer, gastric cancer, esophagus carcinoma, lung carcinoma, B-cell lymphoma and B-cell leukemia.