# US 8,772,536 B2 · Proteasome inhibitors

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- Number: US 8,772,536 B2
- Document ID: US8772536B2
- Status: Granted
- Kind: B2
- Application number: 13/964,769
- Filed: 2013-08-12
- Published: 2013-12-12
- Granted: 2014-07-08
- Earliest claimed: 2007-08-06
- Assignees: Millennium Pharmaceuticals, Inc.
- Applicants: Millennium Pharmaceuticals, Inc.
- Inventors: Edward J. Olhava; Mihaela Diana Danca
- Web page: https://patentgrep.com/patent/US8772536B2

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/69: Boron compounds
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 35/00: Antineoplastic agents
- C07C 233/83: of an acyclic saturated carbon skeleton
- C07F 5/05: Cyclic compounds having at least one ring containing boron but no carbon in the ring
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention provides novel compounds useful as proteasome inhibitors. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

## Claims

### Claim 1

A process for generating a compound of Formula (v)
wherein Ring A is selected from the group consisting of
the process comprising:
(1) reacting a compound of Formula (i) with a compound of Formula (ii) to form a compound of Formula (iii)
wherein PG is a protecting group;
wherein Z1 and Z2, together with the Boron atom to which they are attached, form a boronic ester protecting group;
wherein X1− is a counter anion;
(2) deprotecting the compound of Formula (iii) to form a compound of Formula (iiia);
wherein X2 is a counter anion;
(3) reacting the compound of Formula (iiia) with a compound of Formula (viii) to form a compound of Formula (iv); and
(4) deprotecting the compound of Formula (iv) to form the compound of Formula (v).

### Claim 2 (depends on 1)

The process of claim 1, wherein the reaction of step (1) is conducted in the presence of a peptide coupling reagent.

### Claim 3 (depends on 2)

The process of claim 2, wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uranium reagent.

### Claim 4 (depends on 3)

The process of claim 3, wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (TBTU) and N-Hydroxybenzotriazole (HOBt).

### Claim 5 (depends on 1)

The process of claim 1, wherein the reaction of step (3) is conducted in the presence of a peptide coupling reagent.

### Claim 6 (depends on 5)

The process of claim 5, wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uranium reagent.

### Claim 7 (depends on 6)

The process of claim 6, wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (TBTU) and N-Hydroxybenzotriazole (HOBt).

### Claim 8 (depends on 1)

The process of claim 1, wherein the reaction of step (1) is conducted in the presence of a solvent comprising a polar aprotic solvent.

### Claim 9 (depends on 8)

The process of claim 8, wherein the polar aprotic solvent is selected from one or more of the group consisting of dichloromethane, tetrahydrofuran, and dimethylformamide.

### Claim 10 (depends on 1)

The process of claim 1, wherein the reaction of step (3) is conducted in the presence of a solvent comprising a polar aprotic solvent.

### Claim 11 (depends on 10)

The process of claim 10, wherein the polar aprotic solvent is selected from one or more of the group consisting of dichloromethane, tetrahydrofuran, and dimethylformamide.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

The process as in any one of claims 1-11, wherein PG is a protecting group selected from the group consisting of an acyl protecting group and a urethane protecting group.

### Claim 13 (depends on 12)

The process of claim 12, wherein PG is a protecting group selected from the group consisting of formyl, acetyl, succinyl, methoxysuccinyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc).

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

The process as in any one of claims 1-11, wherein X1− is CF3CO2−.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

The process as in any one of claims 1-11, wherein X2− is Cl−.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

The process as in any one of claims 1-11, wherein Z1 and Z2, together with the boron atom to which they are attached, form

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

The process as in any one of claims 1-11, wherein Ring A is

### Claim 18

A process for generating a compound of Formula (v)
wherein Ring A is selected from the group consisting of
the process comprising:
(1a) reacting a compound of Formula (viii) with a compound of Formula (vi) to form a compound of Formula (vii)
wherein PG is a protecting group;
wherein X2− is a counter anion;
(2a) deprotecting the compound of Formula (vii) to form a compound of Formula (viia);
(3a) reacting the compound of Formula (viia) with a compound of Formula (i) to form a compound of Formula (iv)
wherein Z1 and Z2, together with the Boron atom to which they are attached, form a boronic ester protecting group;
wherein X1− is a counter anion; and
(4) deprotecting the compound of Formula (iv) to form a compound of Formula (v).

### Claim 19 (depends on 18)

The process of claim 18, wherein the reaction of step (1a) is conducted in the presence of a peptide coupling reagent.

### Claim 20 (depends on 19)

The process of claim 19, wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uranium reagent.

### Claim 21 (depends on 20)

The process of claim 20, wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (TBTU) and N-Hydroxybenzotriazole (HOBt).

### Claim 22 (depends on 18)

The process of claim 18, wherein the reaction of step (3a) is conducted in the presence of a peptide coupling reagent.

### Claim 23 (depends on 22)

The process of claim 22, wherein the peptide coupling reagent is selected from the group consisting of a carbodiimide reagent, phosphonium reagent, and uranium reagent.

### Claim 24 (depends on 23)

The process of claim 23, wherein the peptide coupling reagent is selected from one or more of the group consisting of dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide (EDC), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), O-(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (TBTU) and N-Hydroxybenzotriazole (HOBt).

### Claim 25 (depends on 18)

The process of claim 18, wherein the reaction of step (1a) is conducted in the presence of a solvent comprising a polar aprotic solvent.

### Claim 26 (depends on 25)

The process of claim 25, wherein the polar aprotic solvent is selected from one or more of the group consisting of dichloromethane, tetrahydrofuran, and dimethylformamide.

### Claim 27 (depends on 18)

The process of claim 18, wherein the reaction of step (3a) is conducted in the presence of a solvent comprising a polar aprotic solvent.

### Claim 28 (depends on 27)

The process of claim 27, wherein the polar aprotic solvent is selected from one or more of the group consisting of dichloromethane, tetrahydrofuran, and dimethylformamide.

### Claim 29 (depends on 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The process as in one of claims 18-28, wherein PG is a protecting group selected from the group consisting of an acyl protecting group and a urethane protecting group.

### Claim 30 (depends on 29)

The process of claim 29, wherein PG is a protecting group selected from the group consisting of formyl, acetyl, succinyl, methoxysuccinyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc).

### Claim 31 (depends on 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The process as in any one of claims 18-28, wherein X1− is CF3CO2−.

### Claim 32 (depends on 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The process as in any one of claims 18-28, wherein X2− is Cl−.

### Claim 33 (depends on 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The process as in any one of claims 18-28, wherein Z1 and Z2, together with the boron atom to which they are attached, form

### Claim 34 (depends on 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The process as in any one of claims 18-28, wherein Ring A is

### Claim 35

A compound of Formula (iii)
wherein PG is a protecting group.

### Claim 36

A compound of Formula (iiia)

### Claim 37

A compound of Formula (iv)
wherein Ring A is selected from the group consisting of

### Claim 38 (depends on 37)

The compound of claim 37, wherein Ring A is

### Claim 39

A compound of Formula (vii)
wherein PG is a protecting group; and
Ring A is selected from the group consisting of

### Claim 40 (depends on 39)

The compound of claim 39, wherein Ring A is

### Claim 41

A compound of Formula (viia)
wherein Ring A is selected from the group consisting of

### Claim 42 (depends on 41)

The compound of claim 41, wherein Ring A is