Tetrahydroisoquinolines as PRMT5 inhibitors

• US 10,421,743 B2
• Filed: 03/09/2017
• Issued: 09/24/2019
• Est. Priority Date: 03/09/2016
• Status: Active Grant

• Current Assignee: CTxT Pty., Ltd.
• Original Assignee: CTxT Pty., Ltd.
• Inventors: Bergman, Ylva Elisabet, Camerino, Michelle Ang, Walker, Scott Raymond, Stupple, Paul Anthony
• Primary Examiner(s): Aulakh, Charanjit
• Application Number:
  US16/081,696
• Publication Number:
  US 20190071425A1
• Time in Patent Office: 929 Days
• Field of Search: 546146, 514307
• 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 217/16 substituted by oxygen atoms
• CPC Class Codes: C07D 217/24 Oxygen atoms
• 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 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/08 Bridged systems
• 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 the group consisting of H, halo, C^1-4 alkoxy, C_1-4 alkyl, C_1-4 fluoroalkyl, C_3-4 cycloalkyl, NH—C_1-4 alkyl and cyano; 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; 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; wherein when R^2e is H, at least one of R^1a, R^1b, R^1c and R^1d is selected from C_1-4 alkoxy, C_2-4 alkyl, C_1-4 fluoroalkyl, C_3-4 cycloalkyl, NH—C_1-4 alkyl and cyano.

Claims

1. A compound of formula I:

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

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

4. A compound according to claim 1, wherein one of R^1a, R^1b, R^1c and R^1d is halo, C_1-4 alkoxy, C_1-4 alkyl, C_1-4 fluoroalkyl, C_3-4 cycloalkyl, NH—

C_1-4 alkyl or cyano.

5. A compound according to claim 1, wherein R^1c is methoxy.

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

7. A compound according to claim 1, wherein R⁴ is H.

8. A compound according to claim 1, wherein R⁵ is H.

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

10. A compound according to claim 1 which is of formula Ia:

11. A compound according to claim 1, which has the following stereochemistry:

12. A compound according to claim 1, wherein the optional substituents on A are independently selected from the group consisting of:

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, aminomethyl, sulfonamido, sulfonamino, sulfone, sulfoxide, nitrile and nitrilemethyl and when A is phenyl, the optional substituent may also be a fused C_5-6 N₁-containing heterocyclic ring.

13. A compound according to claim 12, wherein A is phenyl which has 1 or 2 substituents.

14. A compound according to claim 13, 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.

15. A compound according to claim 13, wherein in the ortho position of the phenyl group there is a halo, C_1-4 alkyl, methoxy or ethoxy substituent.

16. A compound according to claim 13, wherein in the para position of the phenyl group there is an amido or amidomethyl substituent.

17. A compound according to claim 1, wherein A is a C_5-12 heteroaryl group which is either pyridinyl or pyrimidinyl.

18. A compound according to claim 17, wherein the C_5-12 heteroaryl group is unsubstituted.

19. A compound according to claim 17, wherein the C_5-12 heteroaryl group has 1 substituent.

20. A compound according to claim 19, wherein in the ortho position of a C₆ heteroayl group, or α

-position of C₅ and C_7-12 heteroaryl group there is a halo or methoxy substituent.

21. A compound according to claim 19, wherein in the meta position of a C₆ heteroayl group, or in the β

-position of a C₅ or C_7-12 heteroaryl group, there is an amino substituent.

22. 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.

23. A compound according to claim 1, wherein the compound is selected from the group consisting of:

4-(3-Oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-ethoxy-N—

((R)-2-hydroxy-2-((S)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide (1);

4-(3-Oxa-8-azabicyclo[3.2.1] octane-8-carbonyl)-N—

((R)-2-hydroxy-2-((S)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide (2); and

4-(3-Oxa-8-azabicyclo[3.2.1] octane-8-carbonyl)-2-ethoxy-N—

((R)-2-hydroxy-2-((S)-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-yl)ethyl)benzamide (3).

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