GLUCOSYLCERAMIDE SYNTHASE INHIBITORS FOR THE TREATMENT OF DISEASES

• US 20160229830A1
• Filed: 09/19/2014
• Published: 08/11/2016
• Est. Priority Date: 09/20/2013
• Status: Active Grant

• Current Assignee: Biomarin Pharmaceutical Incorporated (Amgen Inc.)
• Original Assignee: Biomarin Pharmaceutical Incorporated (Amgen Inc.)
• Inventors: Wang, Bing, Chu, Daniel, Bridges, Alexander James
• Granted Patent: US 10,227,323 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07B 59/002 Heterocyclic compounds
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 209/04 Indoles; Hydrogenated indoles
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 213/46 Oxygen atoms
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 215/06 : having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 235/06 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 235/08 : Radicals containing only hydrogen and carbon atoms
• CPC Class Codes: C07D 265/30 : not condensed with other rings
• CPC Class Codes: C07D 277/22 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/30 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 277/62 : Benzothiazoles
• CPC Class Codes: C07D 295/12 : substituted by singly or doubly bound nitrogen atoms nitro radicals C07D295/06
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 305/08 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
• CPC Class Codes: C07D 307/79 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 307/81 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 309/10 : Oxygen atoms
• CPC Class Codes: C07D 309/12 : only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• CPC Class Codes: C07D 311/12 : substituted in position 3 and unsubstituted in position 7
• CPC Class Codes: C07D 311/58 : other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 333/16 : by oxygen atoms
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/60 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/62 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• 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 407/12 : linked by a chain containing hetero atoms as chain links
• 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 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 471/08 : Bridged systems
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07D 491/056 : with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein the compound of Formula I is according to Formula I(b):

3. The compound of claim 1, wherein the compound of Formula I is according to Formula I(c):

4. The compound of claim 1, wherein R² and R³ together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl;

each of which is optionally substituted with 1 or 2 R⁸;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

5. The compound of claim 4, wherein R² and R³ together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring, optionally substituted with 1 or 2 R⁸;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein R⁴ is aryl which is optionally substituted with 1, 2, or 3 R⁹ groups;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein each R⁹, when present, is independently halo, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

8. The compound of claim 6, wherein R⁴ is phenyl substituted with a halo and a cycloalkyloxy group;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein R⁴ is heteroaryl which is optionally substituted with 1, 2, or 3 R⁹ groups;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, wherein R⁴ is 2,3-dihydrobenzo[b][1,4]dioxin-6-yl optionally substituted with a halo;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein R¹ is —

C(O)C(R⁶)(R^6a)R^1a;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein R¹ is —

C(O)C(R⁶)(R^6a)—

X¹—

R^1a;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

13. The compound of claim 12, wherein X¹ is C_1-3 alkylene;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein R^1a is aryl optionally substituted with 1, 2, or 3 R⁷ groups;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

15. The compound of claim 14, wherein R^1a is phenyl optionally substituted with 1 R⁷ group, wherein each R⁷, when present, is independently phenyl, heterocycloalkyl, or heteroaryl;

where the phenyl and the heteroaryl are independently optionally substituted with 1 or 2 R^7a;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein R^1a is heteroaryl optionally substituted with 1, 2, or 3 R⁷ groups;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

17. The compound of claim 16, wherein R^1a is heteroaryl optionally substituted with 1 or 2 R⁷ groups, wherein each R⁷, when present, is independently halo, alkyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, or heteroaryl;

where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with 1 R^7a;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein R⁶ and R^6a together with the carbon to which they are attached form C(O) or C(═

NOH);

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

19. The compound of claim 18, wherein R⁶ and R^6a together with the carbon to which they are attached form C(O);

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein R⁶ and R^6a are halo;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

21. The compound of claim 20, wherein R⁶ and R^6a are fluoro;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 wherein:

R¹ is —

C(O)C(R⁶)(R^6a)R^1a or —

C(O)C(R⁶)(R^6a)—

X¹—

R^1a;

X¹ is alkylene, alkenylene, or cycloalkylene;

R^1a is alkyl, heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R⁷ groups;

R² and R³ together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl;

each of which is optionally substituted with 1 or 2 R⁸;

R⁴ is aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R⁹ groups;

R⁵ is —

OH, and R^5a is hydrogen;

R⁶ and R^6a are halo;

or R⁶ and R^6a together with the carbon to which they are attached form C(═

NOH) or C(O);

each R⁷, when present, is independently nitro, cyano, halo, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or heteroaryloxy;

where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with 1, 2 or 3 R^7a;

each R^7a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;

each R⁸, when present, is independently amino, alkylamino, dialkylamino, alkyl, halo, or cycloalkyl;

or two R⁸ together with the carbon to which they are attached form C(O);

each R⁹, when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl;

where the heterocycloalkyl and the phenyl, either alone or as part of another group, are independently optionally substituted with 1 or 2 R^9a;

each R^9a, when present, is independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino; and

R¹² is hydrogen or CH₃;

optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 wherein:

R¹ is —

C(O)C(R⁶)(R^6a)R^1a or —

C(O)C(R⁶)(R^6a)—

X¹—

R^1a;

X¹ is alkylene;

R^1a is heterocycloalkyl, aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R⁷ groups;

R² and R³ together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl;

each of which is optionally substituted with 1 or 2 R⁸;

R⁴ is aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R⁹ groups;

R⁵ is —

OH, and R^5a is hydrogen;

R⁶ and R^6a are halo;

or R⁶ and R^6a together with the carbon to which they are attached form or C(O);

each R⁷, when present, is independently nitro, cyano, halo, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or heteroaryloxy;

where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with 1, 2 or 3 R^7a;

each R^7a, when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;

each R⁸, when present, is independently amino, alkylamino, dialkylamino, alkyl, or halo;

each R⁹, when present, is independently amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl;

where the heterocycloalkyl and the phenyl, either alone or as part of another group, are independently optionally substituted with 1 or 2 R^9a;

each R^9a, when present, is independently selected from alkyl and halo; and

R¹² is hydrogen or CH₃;

optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising i) a compound of claim 1 optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof, and ii) a pharmaceutically acceptable excipient or pharmaceutically acceptable carrier.

27. A method of treating a disease or disorder comprising administering a compound according to claim 1 or the pharmaceutical composition of claim 26.

28. The method of claim 27, wherein the disease or disorder is a glycolipid storage disease;

a disease associated with glycolipid accumulation;

a disease that causes renal hypertrophy or hyperplasia;

a disease that causes hyperglycemia or hyperinsulemia;

a cancer in which glycolipid synthesis is abnormal;

an infectious disease caused by organisms which use cell surface glycolipids as receptors or in which synthesis of glucosylceramide is essential or important;

atherosclerosis;

polycystic kidney disease;

renal hypertrophy;

diabetes mellitus;

breast cancer;

renal adenocarcinoma;

brain cancer;

neuroblastoma;

lung cancer;

intestinal cancer;

pancreatic cancer;

prostate cancer;

a neuronal disorder;

a neuronal injury;

an inflammatory disease or disorder;

or obesity.

24. A compound selected from Tables 1, 2 or 3;

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

25. A compound selected from the group consisting of:

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(6-chloronaphthalen-2-yl)-2-oxoacetamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxo-2-(4-(pyridin-2-yl)phenyl)acetamide;

N-((1R,2R)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-(2-(4-fluorophenyl)thiazol-5-yl)-2-oxoacetamide;

N-((1R,2R)-3-(azetidin-1-yl)-1-(3-chloro-4-cyclopropoxyphenyl)-1-hydroxypropan-2-yl)-2-(4′

-fluoro-[1,1′

-biphenyl]-4-yl)-2-oxoacetamide; and

2-(4′

-chloro-[1,1′

-biphenyl]-4-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)-2-oxoacetamide.