# US 2014/0194387 A1 · Derivatives of 1-amino-2-cyclobutylethylboronic acid

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- Number: US 2014/0194387 A1
- Document ID: US20140194387A1
- Status: Published application
- Kind: A1
- Application number: 14/153,752
- Filed: 2014-01-13
- Published: 2014-07-10
- Earliest claimed: 2008-09-29
- Assignees: Millennium Pharmaceuticals, Inc.
- Applicants: Millennium Pharmaceuticals, Inc.
- Inventors: Paul E. Fleming; Jing Li
- Web page: https://patentgrep.com/patent/US20140194387A1

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 5/04: Esters of boric acids
- C07K 5/06: Dipeptides
- C07K 5/06078: {and aromatic or cycloaliphatic}
- C07K 5/08: Tripeptides
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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 compound of formula (I):
or a pharmaceutically acceptable salt or boronic acid anhydride thereof, wherein:
A is 0, 1, or 2;
P is hydrogen or an amino-group-blocking moiety;
Ra1 is C1-6 aliphatic, C1-6 fluoroaliphatic, —(CH2)m—CH2—RB, —(CH2)m—CH2—NHC(═NR4)NH—Y, —(CH2)m—CH2—CON(R4)2, —(CH2)m—CH2—N(R4)CON(R4)2, —(CH2)m, —CH(R6)N(R4)2, —(CH2)m—CH(R)—OR5, or —(CH2)m—CH(R5)—SR5;
each Ra2 independently is hydrogen, C1-6 aliphatic, C1-6 fluoroaliphatic, —(CH2)m—CH2—RB, —(CH2)m—CH2—NHC(═NR4)NH—Y, —(CH2)m—CH2—CON(R4)2, —(CH2)m—CH2—N(R4)CON(R4)2, —(CH2)m—CH(R6)N(R4)2, —(CH2)m—CH(R5)—OR5, or —(CH2)m—CH(R5)—SR5;
each Y independently is hydrogen, —CN, —NO2, or —S(O)2—R10;
each RB independently is a substituted or unsubstituted mono- or bicyclic ring system;
each R4 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form a substituted or unsubstituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
each R5 independently is hydrogen or a substituted or unsubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R6 independently is a substituted or unsubstituted aliphatic, aryl, or heteroaryl group;
each R10 independently is C1-6 aliphatic, C6-10 aryl, or —N(R4)2;
m is 0, 1, or 2;
Z1 and Z2 are each independently hydroxy, alkoxy, aryloxy, or aralkoxy; or Z1 and Z2 together form a moiety derived from a boronic acid complexing agent.

### Claim 2 (depends on 1)

The compound of claim 1, wherein P is Rc—C(O)—, RcC—O—C(O)—, Rc—N(R4c)—C(O)—, Rc—S(O)2—, or RcC—N(R4c)—S(O)2—;
Rc is selected from the group consisting of C1-6 aliphatic, C1-6 fluoroaliphatic, —RD, -T1-RD, and -T1-R2c;
T1 is a C1-6 alkylene chain substituted with 0-2 independently selected R3a or R3b, wherein the alkylene chain optionally is interrupted by —C(R5)═C(R5)—, —C≡C—, or —O—;
RD is a substituted or unsubstituted mono- or bicyclic ring system;
R2c is halo, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)—N(R4)2, —NR4CO2R6, —N(R4)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OC(O)N(R4)2, —C(O)R5, —CO2R5, or —C(O)N(R4)2;
each R3a independently is selected from the group consisting of —F, —OH, —O(C1-4 alkyl), —CN, —N(R4)2, —C(O)(C1-4 alkyl), —CO2H, —CO2(C1-4 alkyl), —C(O)NH2, and —C(O)—NH(C1-4 alkyl);
each R3b independently is a C1-3 aliphatic substituted or unsubstituted with R3a or R7;
each R7 is a substituted or unsubstituted aromatic group; and
R4c is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C6-10 ar(C1-4)alkyl, the aryl portion of which is substituted or unsubstituted.

### Claim 3 (depends on 2)

The compound of claim 2, characterized by formula (I-B):
or a pharmaceutically acceptable salt or boronic acid anhydride thereof.

### Claim 4 (depends on 3)

The compound of claim 3, wherein A is 0.

### Claim 5 (depends on 3)

The compound of claim 3, wherein Ra1 and Ra2 are each independently C1-6 aliphatic, C1-6 fluoroaliphatic, or —(CH2)m—CH2—RB, and m is 0 or 1.

### Claim 6 (depends on 5)

The compound of claim 5, wherein RB is a substituted or unsubstituted phenyl.

### Claim 7 (depends on 6)

The compound of claim 6, wherein Ra1 is —CH2—RB, and RB is phenyl.

### Claim 8 (depends on 3)

The compound of claim 3, wherein Ra1 is —(CH2)m—CH(C1-4 alkyl)-OH.

### Claim 9 (depends on 3)

The compound of claim 3, wherein RD is substituted on substitutable ring carbon atoms with 0-2 Rd and 0-2 R8d;
each Rd independently is selected from the group consisting of C1-6 aliphatic,
C1-6 fluoroaliphatic, halo, —R1d, —R2d, T2-R1d, -T2-R2d,
T2 is a C1-6 alkylene chain substituted with 0-2 independently selected R3a or R3b, wherein the alkylene chain optionally is interrupted by —C(R5)═C(R5)—, —C≡C—, or —O—;
each R1d independently is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;
each R2d independently is —NO2, —CN, —C(R5)═C(R5)2, —C≡C—R5, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—R6, —NR4CO2R6, —N(R4)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OC(O)N(R4)2, —C(O)R5, —CO2R5, —C(O)N(R4)2, —C(O)N(R4)—OR5, —C(O)N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—N(R4)—C(O)R5, or —C(═NR4)—N(R4)2;
each R3a independently is selected from the group consisting of —F, —OH, —O(C1-4 alkyl), —CN, —N(R4)2, —C(O)(C1-4 alkyl), —CO2H, —CO2(C1-4 alkyl), —C(O)NH2, and —C(O)NH(C1-4 alkyl);
each R3b independently is a C1-3 aliphatic substituted or unsubstituted with R3a or R7, or two substituents R3b on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring;
each R7 independently is a substituted or unsubstituted aryl or heteroaryl ring;
each R8d independently is selected from the group consisting of C1-4 aliphatic, C1-4 fluoroaliphatic, halo, —OH, —O(C1-4 aliphatic), —NH2, —NH(C1-4 aliphatic), and —N(C1-4 aliphatic)2; and
each substitutable ring nitrogen atom in RD is unsubstituted or is substituted with —C(O)R5, —C(O)N(R4)2, —CO2R6, —SO2R6, —SO2N(R4)2, C1-4 aliphatic, a substituted or unsubstituted C6-10 aryl, or a C6-10 ar(C1-4)alkyl, the aryl portion of which is substituted or unsubstituted.

### Claim 10 (depends on 3)

The compound of claim 3, wherein:
each saturated ring carbon atom in RD is unsubstituted or is substituted with ═O, Rd or R8d;
each unsaturated ring carbon atom in RD is unsubstituted or is substituted with Rd or R8d;
each Rd independently is selected from the group consisting of C1-6 aliphatic, C1-6 fluoroaliphatic, halo, —R1d, —R2d, -T2-R1d, -T-R2d,
T2 is a C1-6 alkylene chain substituted with 0-2 independently selected R3a or R3b, wherein the alkylene chain optionally is interrupted by —C(R5)═C(R5)—, —C≡C—, or —O—;
each R1d independently is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;
each R2d independently is —NO2, —CN, —C(R5)═C(R5)2, —C≡C—R5, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—R6, —NR4CO2R6, —N(R4)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OC(O)N(R4)2, —C(O)R5, —CO2R5, —C(O)N(R4)2, —C(O)N(R4)—OR5, —C(O)N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—N(R4)—C(O)R5, or —C(═NR4)—N(R4)2;
each R3a independently is selected from the group consisting of —F, —OH, —O(C1-4 alkyl), —CN, —N(R4)2, —C(O)(C1-4 alkyl), —CO2H, —CO2(C1-4 alkyl), —C(O)NH2, and —C(O)NH(C1-4 alkyl);
each R3b independently is a C1-3 aliphatic substituted or unsubstituted with R3a or R7, or two substituents R3b on the same carbon atom, taken together with the carbon atom to which they are attached, form a 3- to 6-membered cycloaliphatic ring;
each R7 independently is a substituted or unsubstituted aryl or heteroaryl ring;
each R8d independently is selected from the group consisting of C1-4 aliphatic, C1-4 fluoroaliphatic, halo, —OH, —O(C1-4 aliphatic), —NH2, —NH(C1-4 aliphatic), and —N(C1-4 aliphatic)2; and
each substitutable ring nitrogen atom in RD is unsubstituted or is substituted with —C(O)R5, —C(O)N(R4)2, —CO2R6, —SO2R6, —SO2N(R4)2, C1-4 aliphatic, a substituted or unsubstituted C6-10 aryl, or a C6-10 ar(C1-4)alkyl, the aryl portion of which is substituted or unsubstituted.

### Claim 11 (depends on 7)

The compound of claim 7, wherein RD is a substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl.

### Claim 12 (depends on 7)

The compound d of claim 7, characterized by formula (II):
or a pharmaceutically acceptable salt or boronic acid anhydride thereof, wherein:
P has the formula RD—SO2— or RD—C(O)—;
RD is a substituted or unsubstituted mono- or bicyclic ring system selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, naphthyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and dihydrobenzoxazinyl;
each saturated ring carbon atom in RD is unsubstituted or is substituted with ═O, Rd, or R8d;
each unsaturated ring carbon atom in RD is unsubstituted or is substituted with Rd or R8d;
each Rd independently is selected from the group consisting of —R1d, —R2d, -T2-R1d, and -T2-R2d;
T2 is a C1-3 alkylene chain that is unsubstituted or is substituted with R3a or R3b;
each R1d independently is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;
each R2d independently is —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —O—C(O)R5, —OC(O)N(R4)2, —C(O)R5, —CO2R5, or —C(O)N(R4)2; and
each R8d independently is selected from the group consisting of C1-4 aliphatic,
C1-4 fluoroaliphatic, halo, —OH, —O(C1-4 aliphatic), —NH2, —NH(C1-4 aliphatic), and
—N(C1-4 aliphatic)2.

### Claim 13 (depends on 12)

The compound of claim 12, wherein Rd has the formula -Q-RE;
Q is —O—, —NH—, or —CH2—; and
RE is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl or cycloaliphatic ring.

### Claim 14 (depends on 12)

The compound of claim 12, wherein where RD is a phenyl, pyridinyl, pyrazinyl, or pyrimidinyl, which is substituted with a substituent of formula —O—RE, and RE is a substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, or pyrimidinyl.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 15)

A method for treating cancer, comprising administering to a patient in need of such treatment a pharmaceutical composition according to claim 15.